Reading rejuvenation research

September 2003 issue

2012-01-28T02:55:00.000+11:00

Another one mostly by the abstracts. A couple of interesting things in this one.

"An Ethical Assessment of Anti-Aging Medicine". Ethics.

"A Telomere-Binding Protein (TRF2/MTBP) from Mouse Nuclear Matrix with Motives of an Intermediate Filament-Type Rod Domain". telomere membrane binding protein = telomere repeat factor 2 = (?) protein that binds telomere to nuclear membrane.

"Apparent Induction of Partial Thymic Regeneration in a Normal Human Subject: A Case Report". Growth hormone plus DHEA maybe made the thymus in one person larger and with a larger active region. Rare growth hormone article that I'd be interested in reading.

Report on a meeting for the association and politics for life science. Sounds like mainly ethics.

Report on the 10th congress of the International Association of Biomedical Gerontology, which also seemed to function as a SENS meeting. Found the summary of highlights on the net. Impossible to summarise, but LOTS of interesting papers presented.

Review of the books "The iron factor of aging: why do americans age faster?" which seems to suggest that iron supplementation helps (!?) and one on ethics.

A review of a paper that looks at the link between telomere length and telomerase activity in glioblastomas.

The dissertations section, or at least the first page which I can see, looks at a thesis that compares the hydrogen peroxide production in a bat, a shrew and a mouse, and comes up with them all having similar lifetime free radical production per mitochondrial protein. It also says free radical production in the bat is higher in youth than in old age, which the author says contradicts the free radical theory of aging. She suggests this is due to selection of efficient mitochondria during the lifetime. As far as I understand it, this contradicts de Grey's version of the FRTA too. The thesis was easy to find online from the university's site but I haven't read it properly yet. Interesting nevertheless. The thesis is titled "Aging and mitochondrial efficiency in the little brown bat, Myotis Lucifugus".

The second dissertation mentioned was about the effects of HIV on CD8+ T cell senescence.

June 2003

2012-01-26T19:30:00.000+11:00

Only reading abstracts.

"Telomere-Binding TRF2/MTBP Localization during Mouse Spermatogenesis and Cell Cycle of the Mouse Cells L929". Spot the telomere and the telomere membrane binding protein. Maybe I should be interested in this one, but don't seem to be.

A review of Werner's and Hutchinson-Gilford progerias.

A review of "Geriatric Medicine: an evidence based approach". Supposedly good.

An interesting new section called Dissertations, where they publish abstracts of thesis that are relevant. Very cool idea. I can only see the first one and a half. One about the roles of telomere-binding proteins have in telomere function in yeast, another one about targeting telomere and telomerase for cancer treatment, maybe mainly with a combination of paclitaxel, which damages telomeres, and AZT, which inhibits telomerase.

The review of the literature looks at a paper about the relationship between telomere length and Alzheimer's, stroke, and vascular dementia patients. I can't tell what happened since the results are on the second page, but going by the title of the paper, vascular dementia patients probably have shorter telomeres. (PS: actually, the paper is available in full, and yes, people with vascular dementia seem to have shorter telomeres on their peripheral blood mononuclear cells)

March 2003, sadly without access

2012-01-24T02:28:00.000+11:00

I'm still only reading the abstracts, but in this one there were two that sounded interesting, but I couldn't find them around.

"Early Programming of Adult Longevity: Demographic and Experimental Studies". They look at 100,000 people that died in the 1990s in Kiev and see a "strong association" between the month of the year they were born in and longevity, with the lowest longevity for people born April to July, and highest around December. The July and December low/high agree with what the Gavrilovs found in their studies of aristocratic families (see http://readingrejuvenationresearch.blogspot.com/2011/02/season-of-birth-and-human-longevity.html ) . On a seemingly completely unrelated study, they look at the lifespan of fruit flies and see them living longer when they are irradiated with low doses of radiation. Their hypothesis is that both effects, and many other anti-aging treatments, are due to the hormetic effect (ie response to low level stressor). Would like to read this one.

"Neuroprotective, Anti-Apoptotic Effects of Apomorphine". Looks at apomorphine's effects on the brain, with the possible focus on Parkinson's.

"The Role of Somatic and Germline Mutations in Aging and a Mutation Interaction Model of Aging". Another interesting one. Seems like a theoretical paper on the effect of accumulated mutations that don't affect us negatively until past reproductive age. Hypothesises that some of this could increase mutations in non-reproductive cells, leaving different random mutations around the body as we age.

The literature review section looks at a paper which lengthens telomeres in vitro by inserting a short circular bit of DNA matching the telomere repetition sequence's complement. The review has some concerns about validity and missing information to show that this did actually happen.

December 2002, briefly

2012-01-20T19:16:00.002+11:00

No content still. Almost nothing interesting either.

"Effect of DL-α-Lipoic Acid on the Status of Lipids and Membrane-Bound ATPases in Various Brain Regions of Aged Rats". Shoved lipoic acids into rats, levels of lipids in the brain went down. Had to double-check to make sure it wasn't the same paper as in the previous issue

"Comparison of a Broad Spectrum Anti-Aging Nutritional Supplement with and without the Addition of a DNA Repair Enhancing Cat's Claw Extract". They gave what sounds like a multi-vitamin with or without added cat claw extract to humans (?).

"A Comparison of Growth Hormone Administration and Exercise in the Elderly". Probably what it says. I could only read the introduction.

"The Third Annual Monte Carlo Anti-Aging Conference". This I wouldn't have minded reading.

A review of the book "Oxidative stress biomarkers and antioxidant protocols". Lab methods.

The literature review looking at a paper that gave amyloid beta peptides to embryonic mouse neurons and to some tumour line, and watched for effects on telomeres and telomerase.

September 2002 issue

2012-01-19T22:53:00.000+11:00

Only abstracts. Another relatively thin issue, with only three papers, none of them very interesting.

"α-Lipoic Acid Enhances Reduced Glutathione, Ascorbic Acid, and α-Tocopherol in Aged Rats". Shoved lipoic acid into rats, levels of lipid peroxidation went down, and levels of vitamins C and E, and of reduced glutathione went up.

"Telomere Dynamics, Aging, and Cancer: Study of Human Syndromes Characteristic of Premature Aging". Looks at telomere length and endoreduplication (DNA replication outside cell replication) in Fanconi's anaemia, ataxia-telangiectasia, Bloom syndrome and xeroderma pigmentosum syndrome, all predisposing for cancer. Telomeres mostly shorter (not in xeroderma pigmentosum).

"Age-Related Susceptibility of Chemical Carcinogenesis in BALB/c Mice". They inject carcinogens into young, middle and old aged mice, count the number that get cancer (4/10, 10/10, and 1/10 respectively).

Literature review section again looks at an old paper, but one I hadn't heard of before, that analyses how much telomerase is active in young, middle and old aged rainbow trouts. Lots of telomerase activity everywhere at all ages, even compared to human tumour cells. Levels in muscle and brain cells down to human tumour cell levels. The title of the paper is 'Telomerase activity in "immortal" fish'. Do rainbow trouts not age? Couldn't find anything on a brief search.

June 2002 by the very few abstracts

2012-01-18T21:20:00.003+11:00

Still without access and nothing here that would make them look hard for them elsewhere. Quite a light issue overall.

"Vitamin E and Age Alter Liver Mitochondrial Morphometry". Mice liver's mitochondria measured across different ages and vitamin E supplementation. Mitochondria smaller in vitamin E'd mice compared to controls in old mice. Also, as mice get older, their mitochondria elongate, also in vitamin E'd mice. I had no idea that mitochondria elongated with age.

"In Search of a Model Species for Aging Research: A Study of the Life Span of Tree Shrews". Using shrews for animal aging as a shortish-life (10-14 years) but evolutionary close animals (close compared to mice).

A review of de Grey's book "The mitochondrial free radical theory of aging".

The regular literature review column reviewing the original telomerase-gets-fibroblasts-to-replicate-and-not-look-senescent paper.

There was also a letter to the editor that I should read if I ever read Arking's paper on mortality plateau from last issue that looked interesting.

March 2002, by the abstracts

2012-01-17T17:07:00.002+11:00

Still only reading the abstracts due to lack of access.

This issue is a continuation on the growth hormone papers from last issue. There is a lot more mentions of ghrelin in these papers than in the ones I read from 1999. It's one of the secretagogues.

"Relationship Between Exercise and Growth Hormone Neuroendocrine Function". A review of the effects of exercise on growth hormone. This one could be interesting.

"Cellular and Molecular Mechanisms of Growth Hormone Action on Skeletal Muscle: Implications for Treatment of Age-Associated Sarcopenia". How growth hormone/IGF-1 make muscles grow.

"Assessing Safety and Efficacy of Growth Hormone Replacement in Aging by Community Physicians". Review on safety profile I think.

"Growth Hormone: Challenges and Opportunities for the Biotechnology Sector". Some kind of review. Dunno.

"Localization and the Role of Growth Hormone Secretagogues in the Central Nervous System". Which bits of the brain the secretagogues touch.

"Growing Pains: Bioethical Perspectives on Growth Hormone Replacement Research". Ethics.

"Sex-Steroid Hormone Modulation of the Tripeptidyl Control of the Human Somatotropic Axis". I think it's on estrogen modulation of GH. Maybe testosterone too.

"N⁶-Furfuryladenine (Kinetin) as a Potential Anti-Aging Molecule". Something completely different. A cell-division inducer being touted as an anti-oxidant. Not growth hormone related, but doesn't sound like much fun either.

Book review of the 5th edition of the Handbook of the Biology of Aging. Supposedly good.

The usual literature review section reviewing a paper about alternative splicings of human telomerase reverse transcriptase, and possible control mechanisms of telomerase through control of splicing enzymes.

December 2001, sourceless.

2012-01-16T17:37:00.000+11:00

Continuing the cheating. Only have abstracts available and I'm mostly happy about that, since it's an issue on growth hormone and I've had enough of that particular topic.

"Issues Regarding the Routine and Long-Term Use of Growth Hormone in Anti-Aging Medicine". Probably what it says in the title.

"A Word of Caution: Can Growth Hormone Accelerate Aging?". Creator of the GH receptor knock-out mice warning that growth hormone is maybe not great.

"Age-Related Decreases in Growth Hormone and Insulin-Like Growth Factor (IGF)–1: Implications for Brain Aging". Growth hormone and the brain, and why the knock-out mice are not relevant maybe.

"Growth Hormone Releasing Hormone Treatment in Normal Aging". 6 month study injecting growth hormone releasing hormone into old people. Lean body mass increase, abdominal fat decrease (5-8%), maybe improved cognition, no better sleep. Didn't work for women under estrogen supplementation.

"Natural and Synthetic Growth Hormone Secretagogues: Endocrine and Nonendocrine Activities Suggesting Their Potential Usefulness as Anti-Aging Drug Interventions". On the non-growth-hormonal effects of growth hormone secretagogues.

"Hormone Modulation, Low Glycemic Nutrition, and Exercise Instruction: Effects on Disease Risk and Quality of Life". Results of looking at 100 people on growth hormone, DHEA, testosterone, estrogen and progesterone supplementation.

"Growth Hormone Excess and Cancer". Does it make it more likely.

After that barrage, there is a short report on the second SENS roundtable, too short to have any details.

Finally, the usual literature review, looking at telomerase ectopically expressed in heart cells of mice. It inhibited apoptosis after heart attacks, and decreased affected area by 23%. Made the hearts bigger too.

September 2001 issue, by the abstracts

2012-01-15T18:02:00.001+11:00

This issue seemed to be about calorie restriction. They all sound quite interesting. Only abstracts available.

"Mechanisms of Prolonged Longevity: Mutants, Knock-Outs, and Caloric Restriction". Compares growth hormone receptor knock-out mice with calorie-restricted mice.

"Caloric Restriction in Nonmammalian Models". A review of what is known about calorie restriction in non-mammals, and molecular commonalities among them.

"Endocrine Effects of Dietary Restriction and Aging: The National Institute on Aging Study". More data from the long-term rhesus study. This is a summary of hormonal changes, maybe focusing on melatonin and DHEA.

"Progress in the Development of Caloric Restriction Mimetic Dietary Supplements". Review of initial studies on caloric restriction mimetics. They mention 2-deoxy-D-glucose, phenformin and iodoacetate as examples.

A review of a book on telomeres and telomerase from a symposium in 1997.

The literature review section looked at a paper that inserted mutant versions of the RNA template component of telomerase into immortal lines, and watched them slow down growth.

Rest of June, 2001 issue by abstracts

2012-01-15T16:38:00.001+11:00

Again, going just by abstracts:

"Antioxidant Genes, Hormesis, and Demographic Longevity" pushes a theoretical explanation for the mortality plateau at old age. Something to do with the Antioxidant Defense System ramping up. I always thought the effect was over-hyped and that it is not very important in humans. I wouldn't have minded reading it.

"The Impact of Glutathione on Health and Longevity". Lots about glutathione.

"The Role of L-Carnitine in the Activities of Membrane-Bound Enzymes in the Brains of Aged Rats". Lipid peroxidation leading to less activity for membrane enzymes in rats. L-carnitine lowering lipid peroxidation and raising membrane enzymes.

The regular literature review. They look at a paper on telomere length on cow clones. Telomere lengths look normal. Telomerase induced by the nuclear transfer process somehow.

When Does Human Longevity Start?: Demarcation of the Boundaries for Human Longevity

2012-01-15T00:45:00.001+11:00

Interestingness:5

By Natalia S. Gavrilova and Leonid A. Gavrilov. Journal of Anti-Aging Medicine. June 2001, 4(2): 115-124. doi:10.1089/10945450152466161.

More Gavrilovs. This one is another paper where they continue to extract results from the historical records of the european aristocracy from the 1600s onwards. In this one, they focus on the period 1800-1880s so as to have complete data for women (recent records are more complete) but also to make sure everyone in it is dead.

They analyse longevity of 5800 daughters that made it to adulthood (30 years) compared to longevity of their mothers and fathers (separately). They avoid sons due to frequent military deaths. They find almost no correlation if the mother died before 85 years of age, but strong correlation otherwise, with a line of best fit with a slope of 0.412±0.204. Similarly for the father, with no correlation if he died before 75 years of age, but a strong correlation with a slope of 0.236±0.078 otherwise. They don't show results with a combined mother plus father variable. The graphs are quite nice.

There's something somewhat dodgy about the method since they were looking for a piecewise linear regression, and they determined where to start the significant line by inspecting the graph visually. I don't know how much that detracts from the result.

Like they mention, this does "resolve" the contradictions found where some research says that the genetic component of longevity is small, while others show that people with very old age are bunched in families.

Extension of Life-Span with Superoxide Dismutase/Catalase Mimetics

2012-01-14T02:43:00.000+11:00

Interestingness: 4

By Simon Melov, Joanne Ravenscroft, Sarwatt Malik, Matt S Gill, David W Walker, Peter E Clayton, Douglas C Wallace, Bernard Malfroy, Susan R Doctrow and Gordon J Lithgow, in Science 1 September 2000, Volume 289, Issue 5484 (pp 1567-1569 DOI: 10.1126/science.289.5484.1567 )

This is one of the papers that was being reviewed in the gerontology review of the Journal of Anti-Aging Medicine. This supposed superoxide dismutase and catalase mimetics (EUK-8 and EUK-134), extend the average lifespan of C Elegans by 44%. Maximum lifespan also seems to go up by about that much. Strangely to me, the effect is not dose dependent, which they explain it to be due it most likely being ingested, and because they stop eating when they are old, the effect is self-limitting or something like that, but I don't see how that explanation explains much. Nice strong effect anyway.

Epidemiology of Human Longevity: The Search for Appropriate Methodology

2012-01-14T02:03:00.001+11:00

Interestingness: 1

By Leonid A Gavrilov and Natalia S Gavrilova, in the Journal of Anti-Aging Medicine, March 2001 (pp 13-30, doi:10.1089/109454501750225659.)

So I found the paper anyway, on the Gavrilovs site, and I always read the Gavrilovs. This one wasn't interesting though. It's a longish paper suggesting a study to pick up genes that are associated with longevity, by looking at past records and looking at consanguinity and the age of the father at conception. They go through basis for the study, lost of things to look for and account for.

Out of material

2012-01-13T02:37:00.003+11:00

My access to the journal has been cut, so I won't be able to keep doing this.

For now, I'll summarise what I am able to see in the abstracts, for future reference so that I can go back and see which ones sounded interesting.

Finishing issue 4 of 2000, there was the regular review of the gerontological literature column, but I'm only able to tell that one of the reviews was about AIDS shortening telomeres of CD4+ lymphocytes by inducing continuous replenishment.

On the first issue of 2001, there was:

Some meta-methodological paper by the Gavrilovs which I didn't grok from the abstract.

The Pierpaoli dude with his "crazy" experiments, implanting pineal glands from old and young rats into other young rats, and observing that those implanted old pineal glands aged and died younger but those with young pineal glands were not affected.

Another article characterising senescence-accelerated mice.

One of those very specific papers looking at effects of a variety of antioxidants on the oxidation of a variety of neurotransmitters.

Some experiments oxidising red blood cells with and without membranes, and something about the membranes making it worse due to lipid peroxidation, and quercetin (some flavonoid wikipedia tells me) helping somehow.

None of the papers sound very interesting, but I would read the pineal gland transplants one for fun.

Then there was a review of a book "Endocrinology of Aging", and the literature review which reviews at least one paper saying that inserting telomerase on CD8+ T cells doesn't immortalise them, and an extension of lifespan by superoxide dismutase/catalase mimetics, which I would be interested to read.

Age-Associated Plasma Lipids, Lipid Peroxidation, and Antioxidant Systems in Relation to Vitamin C Supplementation in Humans

2012-01-11T20:58:00.002+11:00

Interestingness: 2

By Muthuvel Jayachandran, Palaniyappan Arivazhagan and Chinnakkannu Panneerselvam, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 437-445, doi:10.1089/rej.1.2000.3.437.)

They looked at vitamin C, cholesterol, lipid peroxides, and a whole bunch of antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione S-transferase) in young (20-30 year olds) and old (> 60 year olds) and see that antioxidants in old are lower, cholesterol and lipids are higher in old people. They give both groups 200 mg/day of vitamin C for 90 days. All numbers in old people get a lot better.

I'd have been more interested if I didn't already "know" that vitamin C does nothing good for mortality.

Adrenocortical Cells Immortalized by Telomerase: Potential Use for Ex Vivo Gene Therapy

2012-01-09T00:52:00.001+11:00

Interestingness:2

By Peter J Hornsby, Khan Ozol, and Keyi Yang, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4 2000 (pp 411-417, doi:10.1089/rej.1.2000.3.411.)

Report on injecting bovine adrenocortical cells into rat brains, after immortalisation via telomerisation and addition of SV40 T antigen, which suppresses p53 and retinoblastoma activation. In one experiment, they also added nerve growth factor (NGF) gene to see if it'd produce it.

Results: lots of immune reaction to the foreign tissue, even when using cyclosporin A, an immunosuppressant, so most cells killed quite quickly.

Also, brief review stating that telomerised cells don't induce tumours in nude mice, and look as if they maintain their cell type.

Telomere Length Dynamics in Normal and Malignant Hematopoiesis

2012-01-05T03:58:00.001+11:00

Interestingness: 2

By Tim H Brümmendorf, Peter M Lansdorp and Nathalie Rufer, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 397-409, doi:10.1089/rej.1.2000.3.397.)

This seems to be a double-length episode of the previous paper, relating how telomere lengths change in blood cells across time and diseases. One thing it clarified was that they thought the shortening of telomeres in bone marrow donor recipients was due to the repopulation of the bone marrow stem cells from the few donor cells. Also, they kept on a theme that the telomere lengths of most blood cells are merely reflecting the lengths in the haematopoietic stem cells (HSC aka bone marrow stem cells) which produced them.

Telomerase Activity and Telomere Length in the Haemopoietic System: Changes with Aging, Disease, and Therapy

2012-01-03T19:10:00.001+11:00

Interestingness: 3

By JD Robertson and RF Wynn, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 389-395, doi:10.1089/rej.1.2000.3.389)

Review of what was known about telomere length and telomerase in blood cells. Haemopoietic stem cells (HSC) have active telomerase but their telomeres shorten gradually. Same for T-cells. Telomeres in neutrophils also shorten at about the same rate as in T-cells (20-50 base pairs per year), but from what I understood, they don't have active telomerase, so the telomerase is acting as a compensation method for the occasional clonal expansion of T-cells.

Checking for which X chromosome is inactivated, in old women most blood cells have the same one, as if they come from fewer and fewer stem cells.

In people with acute leukemia, telomeres are short and telomerase long, and they suggest this suggests that telomerase activates late in the process of disease. Also short telomeres on aplastic anemia and Fanconi's anemia. Also shorter telomeres in bone marrow transplant recipients than in donors (about 15 years worth), but I'm not clear if they are saying this is because the transplanted tissue has had to undergo quick replication to refill the recipient's system, or that this was there before.

DNA Damage and Telomere Length in Human T Cells

2012-01-02T01:25:00.001+11:00

Interestingness: 3

By Yvonne A Barnett, Christopher R Barnett, and Thomas Von Zglinicki, in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 383-388, doi:10.1089/rej.1.2000.3.383. )

Seemed speculative on the link between T-cell, telomere length and oxidation damage in vivo, but presented a series of facts to suggest a link: increasing mutations in one particular gene in lymphocytes with age, senescent-looking T-cells in vivo in centenarians and people with Down's syndrome, and fibroblast with higher anti-oxidant capacity having a slower telomere shortening rate in vitro.

(Interesting: link between shorter telomeres and vascular dementia, but not with Alzheimer's, stroke or heart attack)

Cellular Senescence Mechanisms Independent of Telomere Shortening and Telomerase: Other Barriers to Cell Immortalization and Carcinogenesis

2011-12-29T19:30:00.000+11:00

Interestingness: 4

By Izumi Horikawa, Toshio Yawata, and J Carl Barrett in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000 (pp 373-382, doi:10.1089/rej.1.2000.3.373.)

Not all cells given telomerase escape senescence and cells with active telomerase can be made to senesce in lots of ways. The p16^INK4A/RB pathway can trigger senescence as well as the p14^ARF/MDM2/p53 pathway. p53 is probably related to telomeres but other parts probably aren't. By introducing single chromosomes into immortal cancer cell-lines and making them senesce, they infer the existence of other independent pathways of senescence. The mechanisms that trigger senescence are cell-type dependent.

Interesting factoid: mouse cells senesce after much fewer replications (10-20 vs 50-80) even though much longer telomeres.

Telomeres, Telomerase, and Premature Aging

2011-12-28T23:52:00.000+11:00

Interestingness: 4

By Corrin V Wallis and Richard GA Faragher in the Journal of Anti-Aging Medicine, Volume 3, Issue 4, 2000.

Nice summary of telomeres, telomerase and also about the relations of telomeres, Werner's syndrome, Hutchinson-Gilford progeria syndrome and aging. Quite a few details of the proteins involved that I wasn't aware of and that I'll forget about in the next hour.

Review of the Gerontology Literature in Volume 3, Issue 3

2011-12-26T19:41:00.000+11:00

To be clear, this is the summary of the reviews, not the reviews themselves. Reviews by Barry Flanary

Subsenescent telomere lengths in fibroblasts immortalized by limiting amounts of telomerase, by Ouellette MM, Liao M, Herbert BS, Johnson M, Holt SE, Liss HS, Shay JW, Wright WE, in Biol Chem 2000;275:10072-10076

I don't think I understand this result. They transfected cells in-vitro with telomerase reverse transcriptase. Those cells had decreasing telomerase activity as they got older, and then lived longer (their number of doublings went from 60-70 to 250-400). Their telomeres shortened from the 1.5kb-10kb range to the 1.5kb-6kb range. Some theorising that the telomerase was preferentially taken up by the shorter telomeres, thus keeping it from hitting the criticial length at which the cells would go senescent.

Cytotoxic T cell immunity against telomerase reverse transcriptase in humans, by Minev B, Hipp J, Firat H, Schmidt JD, Langlade-Demoyen P, Zanetti M, in Proc Nati Acad Sci USA 2000;97:4796-4801.

Experimenting with using the immune system that naturally attacks hTERT to hammer tumor cells, since they produce hTERT. T cells from prostate cancer patient hammered some tumour lines.

Extension of cell life-span and telomere length in animals cloned from senescent somatic cells, by Lanza RP, Cibelli JB, Blackwell C, Cristofalo VJ, Francis MK, Baerlocher GM, Mak J, Schertzer M, Chavez EA, Sawyer N, Lansdorp PM, West MD, in Science 2000;288:665-669.

Cloning of cows from a 45 day old fetus. Resulting cells extracted from fibroblasts had higher replicative capacity and telomere lengths than controls. I'm sure we know much more about cloning now, so this has probably been overturned and back a hundred times.

Glucagon-Like Peptide 1 (GLP-1) in Diabetes and Aging

2011-12-26T02:15:00.001+11:00

By David D'Alessio in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, 2000.

Interestingness: 2

I'd never heard of GLP-1, but it seems to accentuate the glucose-lowering effect of insulin, by including but maybe not limiting to, increasing insulin secretion. Maybe also acts as a satiety marker. GLP-1 is synthesised in the intestines. Glucose eaten has much higher effect on increasing insulin than glucose injected. Lots of problems in studies caused by mixing detection of active and inactive form of the peptide.

Giving up and Adrenal Andropause and Aging

2011-12-24T18:30:00.000+11:00

Writing even the half-arsed summaries takes too long, so I'm giving up on those. From now on, it will be most likely down to an interestingness score, tags and a one line summary, mainly for me to keep track of them. Also, no more abstract cut-n-pasting, since it probably is not as legit as I thought it was before.

So, Adrenal Andropause and Aging, by Samuel SC Yen, in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, 2000.

Interestingness: 2

Nice review on cortisol changes with aging and DHEA/DHEA-S changes with aging, and how they diverge, cortisol going up and DHEA-S going down, post adrenopause (30s), even though they are both produced by the adrenal glands. Mentions possible link to immune system (DHEA-S inversely correlated to IL-6)

Predictors of Growth Hormone Secretion in Aging

2011-07-17T21:21:00.002+10:00

Summary: Growth hormone again

Interestingness: 2

Paper by Mark L Hartman, Jody L Clasey, Arthur Weltman and Michael O Thorner in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, Spring 2000.

(((
Growth hormone (GH) secretion goes down with age at an inversely logarithmic rate. It is almost down all the way by time we are in our 30s. This may not be due to age alone though, since there are high correlations between integrated GH concentration and each of BMI, percentage body fat and fitness, as measured by oxygen consumption, especially in men (in women the effect does not reach the magic 0.05).

Most of the reasons listed for the decrease we've seen before already (growth hormone papers). Some that I haven't:

GH secretions four times higher during stage 3 and 4 sleep. Deep sleep goes to the shit with age.
Possible path by which high fat reduces GH: high free insulin-like growth factor 1 (IGF-1). But then they quote study showing inverse correlation between free IGF-1 and visceral fat.

In their own studies, they find correlations between integrated GH concentration and each of abdominal visceral fat, fasting insulin and IGF-1, independent of age, sex, total body fat mass, percentage fat, 24 hour mean estradiol and testosterone, and peak oxygen uptake, in a group of 40 people in their 20s and 62 in the 57-80 year old range. Also, a high correlation between the combination of age and sex with IGF-1.

)))

Abstract follows:

Growth hormone (GH) secretion decreases progressively after mid-puberty in both men and women. This decrease occurs predominantly before age 40-50 and affects both daytime and nocturnal GH secretion. A reduction in the amplitude of GH secretory pulses accounts for the majority of the reduction in GH secretion. With aging, changes in hypothalamic function may occur that result in decreased GH secretion. These changes may include decreased secretion of GH-releasing hormone and/or the putative natural ligand for the GH secretagogue receptor or an increase in somatostatin release. Multiple physiological factors have been reported to regulate GH secretion including sleep, body composition (% body fat and amount of abdominal visceral fat), aerobic physical fitness and serum concentrations of insulin-like growth factor-I (IGF-I), gonadal steroids and insulin. Changes in these factors with aging may contribute to the reduction in GH secretion observed in older adults. However, these physiological predictors of GH secretion are not independent of one another and the relative importance of these factors in the regulation of GH secretion is not known. Preliminary evidence suggests that the amount of abdominal visceral fat and fasting serum concentrations of insulin and IGF-I are the most important predictors of 24-hour GH release in healthy adults, independent of age and gender. Bi-directional feedback between these three factors and GH secretion may account for the strong relationships observed.

Network-Like Facets of Neuroendocrine Aging in the Human: Specific Disruption of Feedback and Feedforward Linkages Within the Aging Somatotropic ...

2011-07-03T17:57:00.001+10:00

Full title, since it didn't fit: Network-Like Facets of Neuroendocrine Aging in the Human: Specific Disruption of Feedback and Feedforward Linkages Within the Aging Somatotropic, Gonadotropic, and Corticotropic Axes in Men and Women

Summary: Lots of facts about growth hormone, leutinising hormone, follicle-stimulating hormone and gonadotropin-releasing hormone, with very little cohesion.

Interestingness: 3

Paper by Johannes D Veldhuis in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, Spring 2000.

(((
This is another long review paper by Veldhuis mainly about growth hormone (GH) and its friends, even though its supposedly about the interaction between different hormonal axes. It has 266 references. It's too much information to summarise. I'll jot some notes. A lot of the same information as in Veldhuis's previous paper is covered as well as in all the other GH papers. I'll skip bits that I think are repeated. A lot of the graphs presented don't look very convincing. They tend to have around 10 people per group, so the curves look like they could change easily.

Newer data says more GH secreted by women than men, and decline with aging is half as slow.
Secretion pulses more irregular and lower in older people for GH, leutinising hormone (LH), insulin and prolactin. Follicle-stimulating hormone (FSH) secretion pulse and base go up.
Intra-venous gonadotropin releasing hormone (GnRH) pulses normalised LH secretion in older men.

Inferenced mechanisms mentioned:

Lower endogenous growth hormone-releasing hormone (GHRH) secretion and/or lower growth hormone releasing peptide (GHRP) effect could explain loss of GH secretory pulse.
Evidence for too much somatostatin and GHRH deficiency. Neither alone enough.
Partial GnRH deficiency and Leydig-cell steroidogenic defect both exist, and the latter is not fixed by external GnRH.

They do some computer models of the GnRH-LH-T axis and from those they like the following hypotheses for the loss of synchrony between LH and T release in older men:

Lower feed-forward drive of T synthesis by Leydig cells.
Same, plus lowered negative-feedback by T of GnRH and LH release.

)))

Abstract follows:

The present update highlights the impact of age on dynamic regulatory changes arising singly and multiply within several prototypical neuroendocrine axes in the human. A neuroendocrine axis is viewed here as a homeostatic unit maintained by multivalent interactions or network-like integration among CNS-hypothalamic, pituitary, and target-tissue sites; for example, the GHRH/somatostatin-GH-IGF-I, GnRH-LH-sex-steroid and CRH/AVP-ACTH-cortisol feedback-controlled axes. Homeostatic control is driven by (time-lagged) interglandular signaling and dose-sensitive interfaces. According to this broader perspective, a neuroendocrine system operates as an interdependent ensemble of reciprocally communicating control nodes. This dynamic precept provides a foundation for identifying among the earliest vivid features of signaling disruption within the somatotropic, gonadotropic, and corticotropic (as well as insulinotropic) axes in healthy aging men and women. Internodal linkages likely deteriorate further in the face of acute or chronic illness, medication use, systemic stress and/or hospitalization, resulting at times in overt failure of neuroglandular output. This extended concept offers a notion of neuroendocrine axis frailty as a precursor to frank endocrinesystem disability in aging. Such a framework also confers the expectation that pluri- or multiaxis disruption (e.g., combined somatotropic and gonadal) would further adversely impact homeostatic vigor in aging individuals.

About-Daily (Circadian) and About-Weekly (Circaseptan) Patterns of Human Salivary Melatonin

2011-06-09T23:28:00.000+10:00

Summary: Chronobiology weekly.

Interestingness: 1

Paper by Manfred Herold, Germaine Cornélissen, Mary Jo Rawson, George S. Katinas, Cheryl Alinder, Chris Bratteli, Denis Gubin, Franz Halberg in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, Spring 2000.

(((
They analysed the melatonin and cortisol content of the saliva of five people 29-73 years of age for a week. They think there's a weekly cycle in melatonin, peaking on Tuesday. I'm close-minded.
)))

Abstract follows:

Circadian rhythms in circulating, urinary, salivary, pineal, pituitary and hypothalamic melatonin have been mapped. About weekly (circaseptan) rhythms, mapped previously in several other species, are demonstrated herein for human saliva, in individuals of widely differing ages. Whether or not the now demonstrated decrease with age in the circadian amplitude of human adults is accompanied by an increase in the circaseptan amplitude, as it is the case for blood pressure, remains to be determined.

Serum Schiff Bases Are Elevated in Patients with Dementia

2011-06-09T01:05:00.000+10:00

Summary: Schiff bases are more prevalent in demented people's blood, whatever that means. Lipid peroxide levels are lower, whatever that means as well.

Interestingness: 2

Paper by Aleksandra Musial, Tadeusz Pietras And Dariusz Nowak in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, Spring 2000.

(((
Straight forwards report of testing of four oxidation markers in the blood of 30 old people with clear dementia compared against 18 old people without clear dementia. Conjugated dienes (CnH(2n-2) for values of n, wikipedia tells me) were at about the same concentration in both groups; TBARS (ThioBarbituric Acid Reactive Substances, formed by lipid peroxidation, again, thanks wikipedia) were about 20% higher in demented, but not significant to the 0.05 standard; lipid peroxides were three and a half times higher in the non-demented, and Schiff bases were about 80% higher in the demented.

They are obviously trying to claim higher oxidation levels in the demented. Schiff bases fits their model (I didn't look into how they form). The lower lipid peroxides doesn't, so they come up with reasons. They also find lower lipid peroxides with age in the non-demented group. One possible excuse: lower amounts of poly-unsaturated fatty acids in the brains of older people, supposedly found by someone else.

Anyway, not very interesting, but bonus points for the cool abstract.
)))

Abstract follows:

Hypothesis

Increased oxidative stress may accompany diseases of the central nervous system either as a perpetrator or merely as the result of tissue damage in the course of neurodegeneration. The brain is especially susceptible to damage mediated by reactive oxygen species because it has a high rate of oxygen consumption and contains large amounts of readily oxidizable substrates, such as polyunsaturated fatty acids. Indices of systemic oxidative stress, including serum lipid-peroxidation products, may be greater in dementia than in normal aging.

Methods

Study groups consisted of 30 patients with dementia and 18 healthy age-matched controls. All patients underwent neuropsychological testing and qualified for the study on the basis of history, physical examination, complementary laboratory tests, and brain computed tomography scan. Serum levels were assessed for the following lipid-peroxidation products: conjugated dienes, lipid peroxides, thiobarbituric acid reactive substances, and Schiff bases.

Results

There were two statistically significant differences in serum levels of lipid-peroxidation products between the study groups. Lipid peroxides were significantly lower (0.34 Å 0.09 U532/mL versus 1.12 Å 0.96 U532/mL, p = 0.000055), while Schiff bases were statistically higher (589.4 Å 267.3 AU/mL versus 329.0 Å 107.5 AU/mL, p = 0.000282) in the subjects with dementia. There were statistically significant correlations between all measured products of lipid peroxidation in the controls and between all products of lipid peroxidation except for Schiff bases in the subjects with dementia. Cognitive impairment did not correlate with levels of lipid-peroxidation products. Age correlated negatively with Mini-Mental State Examination score and lipid peroxides in healthy controls.

Conclusion

More final fluorescent products of lipid peroxidation (Schiff bases) were found in subjects with dementia than in healthy controls, implying that oxidative stress is increased in dementia. Our data suggests a decrease in lipid peroxides during normal aging.

Serum Thiols as a Surrogate Estimate of DNA Repair Correlates to Mammalian Life Span

2011-06-05T01:40:00.002+10:00

Summary: Mammalian species with higher thiol fractions in their protein live longer

Interestingness: 2

Paper by Ronald W Pero, Catharina Hoppe and Yezhou Sheng in the Journal of Anti-Aging Medicine, Volume 3, Issue 3, Spring 2000.

(((
These people grabbed blood samples from mostly one or two specimens of 17 different mammalian species (mouse, rat, wolf, dog, goat, sheep, rabbit, bear, cat, lynx, musk ox, fallow deer, cow, gorilla, chimpanzee, horse and human) and precipitated the proteins in those samples. They found a correlation (r=0.819) between the proportion of thiol in the precipitate and the lifespan of the species (not the specimen, they didn't measure how long the actual specimen they took blood from lived), and a stronger correlation (r=0.841) between the proportion of thiols in the thiol-rich fraction of the proteins and the lifespan of the species.

The plots don't look as good as the r-numbers would indicate because they are heavily influenced by the human specimens since they were many more of them (25 vs 1 or 2 of each of the others), and they are out there way on the right in the lifespan axis (they were assigned a lifespan of 95 years). The graphs don't look horrible either.

Their theoretical explanation confuses me. They are saying that this shows that creatures with higher lifespan have lower oxidation levels. I don't know if they are saying that this is being shown directly, that is oxidation would get rid of the thiol (this assumes that their measuring of the thiols wouldn't count oxidised thiols in them), or that this is being shown indirectly, that is if high lifespan animals didn't have lower oxidisation levels their higher thiol-fractioned proteins would be more affected by oxidation, their enzymes would not work, and so these animals wouldn't have high lifespans. I think they mean the second explanation, but I'm not sure. Backing this second interpretation, is them pointing at the unoxidised thiol-dependence of poly adenosine diphosphate-ribose polymerase (PARP), a DNA-repair enzyme, and from there making other claims about the link between mutation, DNA repair and oxidative stress.
)))

Abstract follows:

Biologically occurring thiols are a sensitive estimate of the reduction/oxidation balance of cells, being easily and reversibly converted from sulfhydryl to disulfide structures in proteins and amino acids. Thiols are also known to regulate DNA repair, especially via the influence on poly (adenosine diphosphate-ribose) polymerase activity. Here the thiol content of saturated ammonium sulphate-precipitated proteins from sera was correlated to a mammalian life span of 17 species. A close correlation was established between the thiol-rich proteins and the life span of the mammals (r = 0.841, p < 0.001). These data provide a strong scientific connection between mechanisms of DNA repair and oxidative stress leading to DNA damage accumulation and mutation, which may be important to the aging process.

Rest of volume 3, Issue 2

2011-05-28T16:37:00.002+10:00

The rest of issue 2 of 2000 consists of:

A summary of the Templeton conference "Extended Life - Eternal Life" by Michael Fossel. About ethics.

A review of the book "Time of Our Lives: The Science of Human Aging". Book by Tom Kirkwood, review by Robert Arking. Positive review, popular access book.

A review of a paper by Junji Yodoi and Lester Packer, "Redox Regulation in Eukaryotic Cells Based on Thio-Redoxin Enzymes". Interesting bit about mice with upregulated thioredoxyn ("against UV in the bone marrow" it says, no idea what that means in this context) gene having an increased lifespan.

Endocrinology of Benign and Malignant Prostate Disease in Aging

2011-05-25T00:13:00.002+10:00

Summary: Prostate cancers are out to get us, and too many hypothesis on why they grow.

Interestingness: 3

Paper by Marco Marcelli, TC Shao and Glenn R Cunningham in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

(((
This paper is about the relationship between androgens, testosterone (T) and dihydrotestosterone(DHT), and estrogens, and prostate cancer (CaP in the text for some reason, but I'll go with the more obvious PC) and benign prostate hyperplasia (BPH), but the bits that interested me were the general stats and information about PC and BPH. It is also one of those that is a summary itself so there's too much information and I end up paying attention to none of it.

Check these numbers out, mostly related to USA population, male only:

28.7% of new, nonskin cancers
12.7% of cancer-related deaths
BPH in 10% of 35 year olds, >80% of 80 year olds.

Latent PCs found in

15-20% of 40-50 year olds (found in autopsies, deaths from other reasons)
>50% of 60-70 year olds.

The latent PC numbers seem especially scary for me. They seem to indicate that if we do extend lifespan, these will become active problems, not just latent.

The study focuses quite a bit on cross-ethnic variation of PC and BPH rates, and correlations or lack thereof with androgen levels. It then runs through the non-exclusive hypothesis for the cause/s of BPH and PC. For BPH: increased androgen concentration, something about estrogen, dysregulation of growth factors, and an increased in the number of stem cells. For PC: mutation in SRD4A2, androgen receptor (AR) gene codon repeats, and insulin-like growth factor 1 (IGF-1). I didn't pay much attention to the details of the hyopthesis.

Treatment/preventions: 5alpha-reductase inhibitors (5alpha-reductase converts T to DHT), like finasteride, which supposedly work well in the prevention of BPH, but don't do much once BPH is severe (well, 20-30% reduction in volume). For PC, castration, I assume chemical, induces remission on 80% of PC patients, but it mostly lasts 12-18 months, after which the PC recovers and 70% of the patients die.

)))

Leptin Resistance with Age-Related Obesity

2011-05-07T22:11:00.002+10:00

Summary: Explains the link between leptin, neuropeptide Y (NPY) and obesity in a rat model of age-related obesity they like

Interestingness: 1

Paper by Philip J Scarpace and Nihal Tümer in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

(((
They found a type of rat, F-344xBn, that gains weight in a similar manner to humans, slowly building up until 60 years of age/24 months for human/rat, and then slowly going down.

In young rats, higher leptin led to lower NPY. "NPY stimulates feeding and decreases energy expenditure". Fasting lowers leptin levels. Leptin is produced by white adipose tissue (not sure if only there). In young rats, there's a nice inverse relation between NPY and leptin. The relation isn't clear in old rats, and the inhibition of NPY by leptin also becomes clear. They track the relation to some other proteins and brown adipose tissue, but I don't care enough so I'd probably misrepresent the content.

They think the same thing could be true in humans. I remember something about leptin acting differently in rats (or was it mice) and humans. Maybe not in these rats.
)))

Abstract follows:

Leptin, synthesized by white adipose tissue, interacts with the appetite and satiety centers to regulate body weight, and this hormone contributes to the regulation of both food intake and energy expenditure. Serum leptin is elevated in most obese humans, and that obesity persists in spite of the elevated leptin, suggesting leptin resistance. The F-344xBn rat strain, similar to humans, demonstrates a steady increase in body fat and serum leptin into early senescence. Thus, these aged rats become obese in spite of the elevated leptin, suggesting the relationship between leptin, adiposity, and food intake is altered with age. Leptin modulates a number of neuropeptides in the hypothalamus, including neuropeptide Y (NPY). NPY both stimulates feeding and suppresses thermogenesis in brown adipose tissue. Following leptin infusion, the decrease in food intake and the increase in energy expenditure were blunted in the aged rats. Moreover, leptin decreased NPY mRNA in young but not senescent rats, suggesting that leptin signal transduction may be impaired. Leptin receptor signal transduction involves phosphorylation of cytosolic signal transducer and activator of transcription (STAT) proteins, specifically phosphorylation of STAT3 (P-STAT3). Leptin-induced P-STAT3 levels were unchanged with age, but the dose of leptin required for half maximal stimulation was 5-fold greater in the older rats, suggesting that sensitivity for leptin signal transduction is diminished with age. In summary, aged rats demonstrate a reduced responsiveness to leptin, and the mechanism may involve impaired suppression of hypothalamic NPY mRNA that may be a consequence of impaired leptin signal transduction. This leptin resistance may be due to either the elevated obesity and serum leptin with age or due to age itself or both.

Contemporary Clinical Research on Menopause

2011-05-03T20:06:00.000+10:00

Summary: More studies needed on menopause

Interestingness: 1

Paper by Robert W Rebar in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

(((
I think this is meant to be a review paper but it doesn't have much content. The author wants some interventional studies done. There doesn't seem to be any reliable predictive markers of when menopause will happen. Hot flashes happen to 85% of women during the perimenopausal and early menopausal periods. Estrogen sometimes cures hot flashes. Author doesn't like studies that combine women without ovaries with ones that do, and the same about women with premature ovarian failure. That's it.
)))

Abstract follows:

To the present time, knowledge about menopause has accumulated largely because of observational and epidemiological studies in postmenopausal women. The challenge for the years ahead is to utilize the information learned from several large epidemiological studies, including the Postmenopausal Estrogen-Progestin Intervention (PEPI) trial, the Women's Health Initiative (WHI), and the Study of Women's Health across the Nation (SWAN), to develop testable hypotheses. Studies of pharmacological agents have also provided information that may be of use in this regard. Some women with so-called premature ovarian failure may form another appropriate experimental group. Appropriate questions for future study are abundant. Why do some women develop vasomotor instability, whereas others never complain of any associated symptoms? Can we predict which women will develop osteoporosis and which will not? Which changes occurring after menopause are related to the cessation of ovarian function and which changes are related to aging? Investigation of these and other such questions will require a return to clinical research that is not population based. This presentation will review some of the advances that have been made by clinical investigation and suggest approaches and questions for the years ahead.

Progress in Erectile Dysfunction and Hormone Function

2011-05-02T22:24:00.002+10:00

Summary: If your dick don't work try Viagra

Interestingness: 1

Paper by Pejman Cohan and Stanley G Korenman in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

(((
Lots of overlap between this paper and the previous two. It describes the mechanism of how an erection comes to be and all the stages at which it can stop working, the non-effectiveness of testosterone in solving the issue, even though it helps with libido (something that the previous paper had some doubts over), and then lists possible solutions with Viagra at the top of the list, supposedly working 50-70% of the time.

Some interesting random numbers from the rest:

Testosterone drops 110 ng/dL every decade.
15% of people over 80 had normal levels of testosterone in a study of 300.
In the Massachusetts Male Aging Study, which google tells me was on 1290 men, a quarter of the 40-70 year olds had a moderate degree of erectile dysfunction (ED). Not sure what a moderate amount is though

)))

Abstract follows:

The concept of "andropause" has recently gained popularity as increasing evidence suggests that aging in men is accompanied by a progressive decline in serum testosterone levels. The pathophysiologic mechanism responsible for this decline is not fully understood. However, perturbations at every level of the hypothalamic-pituitary-gonadal system have been demonstrated. Age is also a strong risk factor for erectile dysfunction (ED). Although it is tempting to conclude that a causal relationship exists between declining androgen levels and ED, our current understanding of the erectile process and the failure of testosterone supplementation to restore erectile function in older men suggest that these processes are independent. Furthermore, the recent availability of effective oral therapies for ED argues against the indiscriminate administration of androgens to elderly men with ED. However, the beneficial effects of testosterone on libido, mood, bone density, and body fat composition may justify its use on an individual patient basis.

Endocrine Determinants of Successful Aging in the Male

2011-05-01T17:03:00.002+10:00

Summary: A whole bunch of hormone levels go down when men get old

Interestingness: 3

Paper by Annewieke W van den Beld and Steven WJ Lamberts in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

(((
This is another paper that reads like a review paper, even though they keep referring to their study of 400 73-94 year old men in the Netherlands. Most of what's quoted is about other studies. When they talk about their own study, I'll note it, and I'll mainly focus on their results, not the survey. Their study mostly lacks graphs and numbers, so I'll stick to what they describe it as (increase, decrease, etc).

They "confirm" other studies that say that muscle strength is the major feature that determines whether an old man remains functionally independent.

Mean serum total testosterone (T) in males goes down by about 30% between being 25 and 75. Mean serum free T goes down by 50%. The difference is explained by an increase in sex-hormone-binding globulin (SHBG). In their study they found a correlation between free T and muscle strength, but none between T and life satisfaction.

In their study they see luteinising hormone (LH), which triggers release of T by the testicles, going up with age, and it being inversely correlated with T concentrations. Other studies show mixed results for this relation.

Drop in estradiol (E2) and estrone (E1) with age. In their study, strong correlation between E2 and bone density, and E2 and life satisfaction.

Drop in dehydroepiandrosterone (DHEA) and DHEA sulphate (DHEAS) with age. DHEAS level at 85 is one fifth of level at 30. DHEAS levels in adults > 10 times higher than cortisol (!). In their study, no relation between DHEAS and muscle strength, and relation between DHEAS and bone density disappears when adjusting for T and E1,E2 levels.

And again growth hormone (GH) secretion drops with age, insulin-like growth factor 1 (IGF-1) drops with age, IGF-binding protein 3 (IGFBP-3) drops with age, but IGFBP-2 and IGFBP-1 increase with age. Their study concurs. Also in their study, they didn't see relation between IGF-1 and physical functional status, but did see a strong inverse relation between IGFBP-2 and muscle strength, and they like IGFBP-2 as an indicator of overall level of physical functional status.
)))

Abstract follows:

Frailty is characterized by generalized weakness, impaired mobility and balance, and poor endurance. Loss of muscle strength is an important factor in the process of frailty, and is the limiting factor for an individual's chances of living an independent life until death. In men, several hormonal systems show a decline in activity during aging. Serum bioavailable testosterone (T) and estradiol (E2), dehydroepiandrosterone (DHEA) and its sulphate (DHEAS), and growth hormone (GH) and insulin-like growth factor (IGF)-I concentrations all decrease during aging in men. Physical changes during aging have been considered physiological, but there is evidence that some of these changes are related to this decline in hormonal activity. Studies on hormone administration in the elderly appear to be promising. However, until now, hormone replacement is not yet proven to beneficial and safe.

GH Secretagogues in Aging

2011-04-27T01:29:00.003+10:00

Summary: Growth hormone secretagogues bind all over the place. Not much to recommend them.

Interestingness: 2

Paper by Emanuela Arvat, Roberta Giordano, Fabio Broglio, Laura Gianotti, Lidia Di Vito, Gianni Bisi, Andrea Graziani, Mauro Papotti, Giampiero Muccioli, Romano Deghenghi and Ezio Ghigo in the Journal of Anti-Aging Medicine, Volume 3, Issue 2, June 2000.

(((
This covers similar ground to the other papers on growth hormone that I've summarised before (http://readingrejuvenationresearch.blogspot.com/search/label/growth hormone) but talks only about the synthetic compounds. I think all the studies it mentions are very small (around 20-30 people). This is an eighth-assed attempt at a summary.

The GHS are treated as a group but it seems like there's a lot of differences between them which I won't summarise. The method of inducing growth hormone (GH) release seems to be as a somatostatin (SS) antagonist. The GH stimulation effect is high in puberty and adults, but not on old people. Hypothalamic receptors were lower in middle aged and old people, than in young adults.

Some studies show increase in GH, insulin-like growth factors (IGF) I and II, and IGF binding protein 3 (IGFBP3) in old people when given specific GHSes, others increase in fat-free mass and energy expenditure in obese people, others no change in fat or lean mass in elderly. All of these are shortish (2-month), small studies.

Also reported on non-GH effects of GHS, like release of prolactin (PRL) and adrenocorticotropic hormone (ACTH), and bindings all over the cardiovascular system, with maybe some anti-apoptotic effect.

)))

Abstract follows:

Growth hormone (GH) secretagogues (GHS) are synthetic peptidyl and nonpeptidyl molecules which possess strong, dose-dependent and reproducible GH-releasing activity, even after oral administration. GHS release GH via actions on specific receptors at the pituitary and, mainly, at the hypothalamic level. GHS likely act as functional SS antagonists and meantime enhance the activity of growth hormone-releasing hormone (GHRH)-secreting neurons. In fact, GHS need the integrity of hypothalamus-pituitary unit to fully show their GH-releasing effect. The GH-releasing effect of GHS is reduced in aging likely reflecting concomitant GHRH hypoactivity and somatostatinergic hyperactivity, though impaired activity of the putative GHS-like ligand and/or receptors has also to be taken into account. Orally active GHS have been proposed as rejuvenating anabolic treatment of somatopause (age-related changes in metabolism, structure functions, and body composition partially reflecting the aging of GH/IGF-I axis). No definitive evidence of their clinical usefulness as anabolic agents has been provided yet. On the other hand, GHS have specific receptors in other central and peripheral endocrine and nonendocrine tissues. These receptor subtypes mediate GH-independent biological activities linked to the neuro-endocrinology of aging. For instance, GHS: (a) possess adrenocorticotropic hormone (ACTH)-releasing activity, which is increased in elderly subjects; (b) influence sleep pattern rejuvenating it in elderly subjects; (c) stimulate food intake; (d) have cardiovascular activities including protection against cardiac ischemia and cardiomyocyte apoptosis as well as increase in cardiac contractility. These "other than GH" central and peripheral activities are now carefully under evaluation.

Rest of volume 3, Issue 1

2011-04-19T01:01:00.002+10:00

The rest of issue 1 of 2000 consists of:

A summary of the 52nd Annual Meeting of the Gerontological Society of America, by ADNJ de Grey. Highlighted results: Extension of fruit fly maximum lifespan by overexpression of mitochondrial superoxide dismutase. Extension of maximum lifespan in nematode by supplementation of something that has superoxide dismutase and catalase activity.
A summary of the Oxygen Society/Free Radical Research Society Annual Meeting, by GR Buettner and FQ Schafer, which seemed to be a mixture of lectures and conference. Talks about the importance of nitric oxide in mitochondrial respiration, protein carbonyls as aging markers, various supplements, and iron(II)-dioxygen as main oxidisers.
A four-part discussion about the paper by Kowald and Kirkwood (http://readingrejuvenationresearch.blogspot.com/2011/01/modeling-role-of-mitochondrial.html) from volume 2, issue 3, that extends de Grey's model on mutant mitochondrial amplification.
- A letter by SR Primmer adding a selection effect to the demise of mutant mitochondria in replicating cells, by mutant mitochondria-containing cells committing apoptosis. On the other hand, it points out that aged rats have higher percentage of mitochondria with lower membrane potential. It mainly presents an alternative hypothesis to the survival of mutant mitochondria by suggesting that the mitochondrion takes an active role in destroying itself and that the mutant version probably survives by failing to perform the self-destruction. It also claims that telomere shortening will be important in-vivo quoting examples similar to the ones in the article in this issue (http://readingrejuvenationresearch.blogspot.com/2011/04/role-of-cell-senescence-in-human-aging.html)
- A Kowald gives a short reply saying he can't see how mitochondria can be part of their own destruction given the genes they have, and that various different mutations are amplified (if most genes are needed for self-destruction, then most mutations would stop it from performing that action though)
- de Grey gives a longer reply pointing out a difference in methodology of the study showing lower membrane potential in older cells making it irrelevant. He also tries to split the theorising of the mechanism of mitochondria destruction from the trigger/selection of which mitochondrion to destruct, (wouldn't keeping them joined lead to simpler theories?) and assigns Primmer's mitochondrial involvement in the self-destruction as part of the mechanism, not the trigger, thus being compatible with the other theory.
- Fossel finaly editorialises about the topic. All four have different interpretations of the result that mice lacking telomerase are mostly fine until the sixth generation, and they mostly want results on the opposite case, ie when telomerase is turned on all the time on all cells.

Role of Cell Senescence in Human Aging

2011-04-04T01:07:00.004+10:00

Summary: Cell senescence is the problem, but we won't talk about cancer.

Interestingness: 7

Paper by Michael Fossel in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.

(((

This paper is mostly a defense of the senescence model of aging which consists of saying that cell senescence is the main reason for aging. The paper consists of clarifications on possible misinterpretations of the theory. The model, it says, only pertains to human aging. It says that in critical tissue, enough cells senesce for it to have organism-wide effects, either by their inability to replicate, or by their changed gene expression patterns.

The clarifications are presented by examples. One main example is that heart attacks and strokes are compatible with the theory. Damage to the endothelial cells, the surface layer, cause neighbouring endothelial cells to replicate. At some point they senesce, at which point the holes on the surface aren't fixed any more and the plasma has direct access to the subendothelial layer, triggering the rest of the effects. A bit of supporting evidence is that the places on the blood vessels at which atherosclerosis is usually formed are the same places at which telomere length of endothelial cells is shortest.

The paper has doubts about the ability of the model to explain Alzheimer's but it suggests that since astrocytes divide, measuring telomere length in astrocytes and comparing to Alzheimer's propensity would be a good test.

There is an interventionist undertone to the paper, which is why I think it is interesting. It wants to shove human telomerase (hTERT) in tissue (leukocyte stem cells, the skin of Hutchinson Gilford Syndrome patients, arterial endothelial cells) and see if that fixes them or affects longevity. It mentions unpublished experiments, at least unpublished at that time, about using young cells vs old cells vs old cells with telomerase, in forming skin layers on a naked mouse. The old cells formed skin that looked like old human skin, while the young and telomerased cells formed normal, "grossly, microscopically and genetically", looking skin.

I am a bit surprised that the paper doesn't mention cancer at all. Senescence seems like a method of cancer control so I'd expect something to be said about it. The theory is vague and broad enough to be compatible with lots of other theories of aging, but I think it is not compatible with the mitochondrial free radical theory of aging. The one presented here seems easier to test.

)))

The notion that cell senescence might, ultimately, be central to human aging has been attractive but unsubstantiated for the past four decades. Recent genetics and cell biology work has strongly supported this position. The model has been criticized, largely because few understand what the model actually says about aging. The cell senescence model (often mislabeled the "telomere theory of aging") suggests that changes in gene expression within senescent cells underlie most common age-related pathology, for example those occurring in the coronary arteries in atherosclerosis. It does not suggest that most somatic cells senesce, but rather that those cells which do senesce (e.g., endothelial cells, chondrocytes, fibroblasts, keratinocytes, microglia, hepatocytes, etc) are common denominator of human aging and age-related disease as well as the most efficient point for therapeutic intervention. The cell senescence model of human aging remains elegant and consistent with all known data on human aging and disease; an appropriate criticism is that it remains yet unproven.

Chronobiology: Time Structures, Chronomes, Gauge Aging, Disease Risk Syndromes and the Cosmos

2011-03-28T23:48:00.000+11:00

Summary: Waka waka waka wakke waka waka weh weh

Interestingness: 1

Paper by Franz Halberg, Germaine Cornéissen, Chen-Huan Chen, George S. Katinas, Kuniaki Otsuka, Yoshihiko Watanabe, Manfred Herold, Alexander Loeckinger, Alexander Kreze, Eva Kreze, Federico Perfetto, Roberto Tarquini, Cristina Maggioni, Robert B Sothern and Othild Schwartzkopff in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.

(((
This is a long sell-piece of the field of chronobiology. They want people to analyse data assuming a cyclic underlying pattern. I liked their last paper (http://readingrejuvenationresearch.blogspot.com/2010/06/circadian-hyper-amplitude-tension-chat.html), it was a bit out there, used quite unusual-to-me analysis and graphs, and had a bit of data. This one is waaaayyyyy too out there. They basically want to pump the study of all time cycles, and though I can see good reasons for circadian and yearly and all sorts of in-between rhythms being important, they suggested links between the sunspots on the sun and the levels of some type of steroids in urine based on the collections of one person for 1.5 cycles. I'm not buying this second type of cycle. I was surprised this paper was not rejected based on its literary style alone.
)))

For dealing with everyday physiology, that is, with respect to physiological variation in the normal range, the prevailing position corresponds to that in preatomic physics. The "a-tom" was then the smallest known particle that could not be further split. Breaking the atom opened the door to a new universe of particles governed by new forces and physical laws. Nuclear physics evolved and brought new knowledge, a new energy source and a wealth of practical applications. The analogy applies to the splitting of the normal range into the time structures of everyday physiology. From picking different times of day and seasons for study, a trans-disciplinary science, chronobiology, emerged. Chronobiology objectively maps chronomes (portmanteau'd from chronos = time and nomos = rule), time structures quantifying the relations among cycles and other events. The chronomes of variables in and around us intermodulate with each other; thus, we start exploring organisms as dynamic systems open to their environments near and far, and dependent upon them, beyond air and food. Entering the realm of everyday physiology allowed us to quantify, with refined indices, associations of life with remote drummers. The intermodulating feedsideward mechanisms involved in cosmophysical associations of life on earth may be in part endocrine responses to factors far beyond visible light and temperature. Pertinent knowledge may serve to optimize the quality and duration of life.

Imidazole-Containing Peptidomimetic NACA as a Potent Drug for the Medicinal Treatment of Age-Related Cataract in Humans

2011-03-27T23:18:00.002+11:00

Summary: N-alpha-acetylcarnosine probably does good things for cataract patients

Interestingness: 2

Paper by Mark A Babizhayev, Valentina N Yermakova, Anatoly I Deyev and Marie-Christine Seguin. in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.

(((
Smallish trial on 49 humans, seeing if N-alpha-acetylcarnosine (NACA) does something for the eyes of cataract patients that are not in bad enough conditiones to go to surgery for it. It seems to do things, good things.

The theory is that the NACA gets converted to L-carnosine in vivo, and this acts as an anti-oxidant preventing or reversing cataracts. Not much more is given, but inhibition of phosphatidylcholine liposomal peroxidation is mentioned. Phosphatidylcholine is a major component of the cell membrane.

They give the NACA in drops to the eyes for two years. All the improvement is seen in the first six months, and after that the levels are maintained. Control subjects deteriorate quite a lot in the period.

This paper has a very long methodology section that probably means something to ophtamologists and optometrists. It also has a lot of decent graphs in the results section.
)))

The objective of this manuscript is to test the efficacy of Nalpha-acetylcarnosine for the treatment of senile cataract in humans. It was designed as a randomized controlled trial. Forty-nine subjects-volunteers (76 eyes) with an average age of 65.3 ± 7.0 years were enrolled and randomized into two groups at diagnosis of senile cataract. Changes in lens clarity were measured and quantitated over 6 to 24 months thereafter. Patients administered 1% Nalpha-acetylcarnosine (NACA) (26 patients, 41 eyes = Group II), placebo composition (13 patients, 21 eyes) topically (two drops, twice daily) to the conjunctival sac, or were untreated (10 patients, 14 eyes); two latter groups of patients were combined into the control (reference) group I. Patients were evaluated upon entry, at every 2-month (Trial 1) and 6-month (Trial 2) intervals for best corrected visual acuity (b/c VA), by ophthalmoscopy, original techniques of glare test (Trial 1), stereocinematographic slit-image and retro-illumination photography with subsequent interactive digital image analysis and 3D computer graphics of the lens light scattering/absorbing centers. The intra-reader reproducibility of measuring techniques for cataractous changes was good with the overall average of correlation coefficients for image analytical data 0.830 and glare test readings 0.998. Group I of patients demonstrated the variability in densitometric readings of lens cloudings, negative advance in glare sensitivity over 6 months, and gradual deterioration of VA and gross transmissivity of lenses over 24 months comparatively to baseline and the 6-month follow-up examinations. As compared with baseline examination, over 6 months 41.5% of the eyes treated with NACA presented a significant improvement of the gross transmissivity degree of lenses, 90.0% of the eyes showed a gradual improvement in VA to 7-100% and 88.9% of the eyes ranged a 27-100% improvement in glare sensitivity. Topographic study demonstrated less density and corresponding areas of opacification in posterior subcapsular and cortical morphological regions of the lens consistent with VA up to 0.3. The total study period over 24 months revealed that the beneficial effect of NACA is sustainable. No cases resulted in a worsening of VA and image analytical readings of lenses in the NACA-treated group of patients. In most of the patients drug tolerance was good. Statistical analysis revealed the significant differences over 6 and 24 months in cumulative positive changes of overall characteristics of cataracts in the NACA-treated group II from the control group I. The N-acetylated imidazole-containing peptidomimetic NACA is proposed as an effective and physiologically acceptable drug for nonsurgical treatment of age-related and senile cataracts.

Neutrophil Phagocytic Function and Humoral Immune Response with Reference to Ascorbate Supplementation in Aging Humans

2011-03-22T00:06:00.002+11:00

Summary: Vitamin C supplementations makes some immune system numbers in old people resemble the ones in young people

Interestingness: 3

Paper by Muthuvel Jayachandran, Packiasamy Juliet Arockia Rani, Palaniyappan Arivazhagan and Chinnakkannu Panneerselvam in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.

(((
The methodology description is a little bit confusing, but I think they grabbed 125 20-to-30 year olds and 132 >60 year olds, measured some immune system function numbers: neutrophil phagocytic index (guessing, how easily they eat things), neutrophil avidity index (guessing again, some kind of bonding strength measurement), nitroblue tetrazolium (NBT) reduction (some kind of neutrophil phagocytic potency measurement it says), leucocyte ascorbic acid (how much ascorbic acid in the white blood cells, supposedly a good thing), immunoglobin G, M and A, complement C3 (some protein complex that punches holes in bacteria) and soluble immune complex (SIC) index (nfi).

Old people's numbers were 0.001-significantly lower for the avidity index, the NBT reduction, the leucocyte ascorbic acid, the IgG, IgM, the C3 and SIC index. Taking vitamin C for 30, 60, or 90 days didn't change the youngun's numbers, but the oldies got all those numbers within the non-0.001-significant level off the young, mostly within one standard deviation, and crossed the 0.001 level from their previous measurement.

Sounds good. Reasons not to get excited: we know vitamin C does nothing good for lifespan in humans.

)))

Abstract follows:

Age-associated deficiency of vitamin C contributes to the impaired humoral immune response, which in turn plays a role in the increased risk of illness in old age. Healthy volunteers were given vitamin C supplementation. Neutrophil phagocytic function, complement C3 concentration, and immunoglobulin status were measured at 30, 60, and 90 days. Neutrophil phagocytic function and levels of serum IgG and IgM and leukocytic ascorbate were considerably lower in the aged humans, but these decreases were attenuated by vitamin C supplementation. The level of IgA was not affected by aging. Improved neutrophil phagocytic function and humoral immune response were associated with increased vitamin C status in the aged population and might well contribute to the decreased risk of disease in the aged.

Noncorrelation Between Maximum Life Span and Antioxidant Enzyme Levels Among Homeotherms: Implications for Retarding Human Aging

2011-03-16T01:02:00.003+11:00

Summary: de Grey thinks that we need superoxide dismutase in our mitochondrial intermembrane spaces

Interestingness: 6

Paper by Aubrey DNJ de Grey in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.

(((

This is another theory/speculation paper by de Grey. He's trying to explain why there is no correlation between life span and antioxydant enzyme levels in warm blooded animals. His explanation sticks to the oxidative damage is bad, m'kay, trend and tries to fit the model to the data.

He partitions the rate of damage created by oxidation into four:

Specific metabolic rate (SMR): rate of consumption of oxygen per gram of body.
Leakiness: Proportion of oxygen that becomes superoxide.
Superoxide potency (SP): Proportion of superoxide converted into other oxide radicals (eg hydrogen peroxide) instead of being pacified by antioxidant enzymes.
Oxidisability of the tissue (OT): How easily the relevant tissue gets oxidised.

He notes that under this scheme, levels of antioxidant vitamins affect the OT and not the SP, since they act mainly to stop the chain of oxidation. SP is the rate factor that is not correlated with lifespan that is being explained in this paper.

SMR in warm blooded animals (homeotherms) is mostly determined by body size, and lifespan does correlate with body size. Lifespan depends not only on size though but seems to be well correlated with lifespan restrictions imposed by external causes. There isn't much evolutionary pressure to raise the aging-based lifespan of the animal if it is likely to die from other causes (eg getting eaten). Animals of similar weight but different chances of dying due to external causes have different lifespans (eg birds vs mammals).

In a study in primates, superoxide dismutase (SOD) did correlate with lifespan if the SOD levels were divided by the SMR when doing the calculation. Catalase, glutathione peroxidase (GP) and glutathione (G) didn't though. A less dodgy comparison, in that it didn't need the division by SMR factor, was one between rats and pigeons. Pigeons live about 8 times longer than rats even though they weight about the same. SOD levels in the pigeon were slightly higher, catalase much lower, and G and GP levels varied depending on the tissue. Another study showed similar results when looking at the canary (very low mass, very high lifespan), with not even SOD showing higher levels.

In the same studies, they showed a correlation between leakiness and rate of aging, and maybe one between OT and rate of aging. Lending support to this second correlation, de Grey mentions that fatty acids saturation in the membranes of the mitochondria and levels of non-enzymatic anti-oxidants (eg vitamins C and E) are higher in longer lived animals and these lower OT. This supposedly leaves SP as the only one out of the four factors that doesn't correlate in the predicted way with longevity.

de Grey's hypothesis to explain this is that there is no easy way for evolution to lower the SP because there are no SOD enzymes in the mitochondrial intermembrane space (MIMS) to mop up the superoxides. The selection for longer lifespan instead pushes the concentrations of non-enzymatic antioxidants (vitamins C and E) up all over the cell to get levels up in the MIMS, and the leakiness of the MIMS down which is the same mechanism that controls leakiness elsewhere in the chain. This then means that the concentrations of antioxidant enzymes in the non-MIMS regions become too high for the resulting lower radicals due to the improved leakiness and non-enzymatic antioxidant profiles, and these enzymatic antioxidant levels drift down to save resources until they match the levels that would lead to the same rate of damage as the other parts of the oxidation chain.

Since that paragraph contained the whole hypothesis I will write it again, but in expanded form. Homeotherms supposedly don't have any SODs in their MIMS but we do produce superoxides there (the evidence for that second part is probably not great). The damage caused by this, somehow (more on this later), limits our lifespan. For intelligent or otherwise flighty animals, where the external causes of dying are lower, there is a selective pressure, apparently, to raise our lifespan due to aging to match the lower external causes. Since it seems to be troublesome to introduce a SOD into our MIMS (and this supposed trouble to evolve a MIMS-SOD is the bit that to me seems weakest out of the chain of reasoning), homeotherms instead reduce the leakiness of the ATP-making mechanism, the leakiness factor, and raise the levels of non-enzymatic anti-oxidants, lowering the OT factor, to lower the total rate of aging. Now, lowering the leakiness of the process lowered the production of oxidants everywhere, not just in the MIMS, and raising the level of non-enzymatic anti-oxidants did the same everywhere, not just in the MIMS, so now, if we kept the same level of enzymatic anti-oxidants as before these last two improvements, the level of oxidants everywhere non-MIMS becomes too low for the available enzymatic anti-oxidants. By too low, he means that the bottleneck will be the MIMS oxidants, and everywhere else the oxidant damage will always be too low to matter. Since now the organism can get away with lowering the enzymatic oxidant levels in the non-MIMS sections, it does so, since it saves energy doing so.

That this non-correlation between enzymatic antioxidant levels and lifespan does not occur in flies and worms, (ie, in those species, the correlation does exist and is positive), means that the lifespan-limiting mechanism in flies and worms is different from homeotherms. de Grey suggests that this mechanism is the mutation of mitochondrial DNA (mtDNA) which tends to be attached to the inner surface of the inner membrane of the mitochondria. The mtDNA would somehow be damaged by the higher unquenched superoxide concentration across the inner membrane, in the MIMS. Old mammals have been shown to have high levels of mtDNA mutations, while this doesn't happen in flies and worms, maybe because they do not live long enough for the process of mtDNA amplification to take place. He's trying to tie it all back to his other paper (http://readingrejuvenationresearch.blogspot.com/2010/01/proposed-refinement-of-mitochondrial.html)

The suggested methods for testing the hypothesis: retarget MnSOD and CuZnSOD to the MIMS and check that they are useless there. If they are not useless, then it should have been easy to evolve those. Afterwards, retarget E Coli's iron-dependent SOD to the MIMS of mice, as has supposedly been done before in yeast, and see if that affects lifespan. That last check doesn't make sense to me. If the enzymatic anti-oxidants in the non-MIMS sections have drifted down until they are causing as much trouble as the MIMS oxidation, then lowering MIMS oxidation damage shouldn't affect the lifespan of the beasts. Doing this while raising enzymatic anti-oxidants throughout the cell might though.

In conclusion, another very interesting chain of causation hypothesis, but probably too long to have much of a chance of being correct.

)))

Abstract follows:

A series of studies over many years has conclusively disproved the hypothesis that longevity in warm-blooded animals (homeotherms) correlates with high levels of antioxidant enzymes: in fact, these variables generally exhibit a strong negative cross-species correlation. In flies and nematodes, however, substantial extension of maximum life span has resulted from genetic manipulations that increase antioxidant enzyme levels; these manipulations have always been associated with increased resistance to oxidative challenge, indicating that the life span extension is directly caused by the raised antioxidant capacity. This stark contrast merits careful analysis because it casts doubt on the value of short-lived invertebrates as models for the investigation of mammalian aging. Here is it shown that these results imply the existence, in homeotherms but not in flies or worms, of life span-limiting pathways of oxidative damage that are impervious to enzymatic antioxidants. This is shown to lend weight to the currently controversial theory that somatic mitochondrial DNA mutations contribute significantly to determining the rate of aging of homeotherms, and thereby suggests a feasible intervention to retard human aging.

Prevalence of Telomerase in Coronary Artery Atherosclerosis

2011-02-19T21:57:00.003+11:00

Summary: Telomerase detected in atherosclerotic plaque tissue, likely to be related to restenosis.

Interestingness: 3

Paper by Madhu Gupta, Marie R Shogreen, Gregory A Braden, Wain L White and David C Sane in the Journal of Anti-Aging Medicine, Volume 3, Issue 1, Spring 2000.

(((
They measured the presence of telomerase in the bits cut out of 23 people that had directional coronary atherectomy (DCA). The bits cut out are blockages of the coronary artery and the DCA cuts it out. They correlated the tissues in which they detected telomerase with those that had restenosis, which is when the blockage/narrowing of the artery reappears.

They detected telomerase in 8 out of the 23 total, in 5 out of the 7 people who later developed restenosis, and on 2 out of the 10 who didn't (p < 0.05). Results were inconclusive for restenosis in the other 6. There was no correlation between what the people had come in for and the presence of telomerase.

They mention that atherosclerotic plaques have a monoclonal population of smooth muscle cells, but I don't know what other type you could have inside one person. They offer three explanations for the 35% detection rate of telomerase, that is, how come it's not 100%:

that the tissue is maintaining its telomeres by means other than telomeres
that the tissue is senescent or closer to senescence, with some evidence coming from studies on replicative capacity of muscle cells from plaque-derived tissue compared to healthy arteries. The presence of telomerase would probably be induced by cells having replicated beyond the normal senescent stage by a viral infection or broken tumor-suppressors, and that this would activate telomerase. These cells would then be better able to cause restenosis. I have no idea how much reality there is to that idea of telomerase reactivation.
that there was no telomerase in the smooth-muscle cells at all, and instead the telomerase was detected from other cells in the tissue cut out. This could be from vascular stem cells, or from non-related cells like endothelial cells, lymphocytes or macrophages.

They also mention that the telomerase could be driving the hyperplasia not by replication but by stopping apoptosis.

)))

Abstract follows:

Telomerase is an essential enzyme for maintaining the telomeres of chromosomes and thereby enhancing the sustained replication of cells. Because atherosclerosis and restenosis are characterized by cellular proliferation, we determined whether telomerase enzyme activity was present in coronary artery tissue from 23 patients undergoing directional coronary atherectomy. Telomerase activity was determined from detergent lysates of the atherectomy tissue using an enzyme-linked immunoadsorbent assay (ELISA)-based modification of the Telomere Repeat Amplification Protocol. The presence of telomerase activity was correlated with the occurrence of coronary artery restenosis. Eight of the 23 samples (35%) were positive for telomerase. Seventeen of the 23 patients had adequate clinical follow-up to judge restenosis status. Of these, 7 had restenosis and 5 of these 7 had detectable telomerase. Of the 10 patients without restenosis, 8 were telomerase negative (p <= 0.05). We have shown, for the first time, that telomerase is found in 35% of atherosclerotic tissues. There was a strong trend toward an association between telomerase presence and restenosis in patients for whom follow-up data were available. The presence of telomerase in atherosclerotic tissue may enable a robust, sustained cellular proliferation in response to vascular injury that culminates in restenosis.

Rest of volume 2, Issue 4

2011-02-06T03:27:00.001+11:00

The rest of issue 4 of 1999 consists of:

A review of a book called Essentials of Clinical Geriatrics, 4th edition, edited by Robert L Kane, Joseph G Ouslander and
Itamar B Abrass. "Concise" 621 pages of differences between geriatric and standard medicine.

Seven article reviews by L Stephen Coles:

Gene expression profile of aging and its retardation by caloric restriction, by Cheoi-Koo Lee, Roger G Klopp, Richard Weindruch and Tomas A Prolla, in Science. Analysis of what genes change in muscle cells in old mice compared to young mice compared to old calorie restricted mice using a gene chip of 6000 genes. Lots of changes, with caloric restriction reducing the changes by 84%. L Stephen Coles thought this was a very important paper.
Can human aging be postponed?, by Michael R Rose, in Scientific American. Some pop-sci sounding piece.
Designer genomes, by Karen Hopkin, in Scientific American. Another pop-sci sounding piece about creating cells from scratch. Mentions Venter's knock out method of finding the minimal set. I didn't know he had been going at it that long.
Telomeres and telomerase in cancer, by Christopher M Counter, in Science and Medicine. Supposedly nice graphics.
Aging: The price of evolutionary success, by Robert F Rosenberger, in Science Spectra: The international magazine of contemporary scientific thought. About germ vs soma.
The hunt for the youth pill: From cell-immortalizing drugs to cloned organs, biotech finds new ways to fight against time's toll, by David Stipp, in Fortune Magazine.
Never say die, by Lisa Leff, in the Los Angeles Magazine.

Season of Birth and Human Longevity

2011-02-06T02:37:00.002+11:00

Summary: Adult women over thirty live three years longer if they were born in May or December, rather than in August.

Interestingness: 2

Paper by Leonid A Gavrilov and Natalia S Gavrilova in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

(((
Short two-page paper analysing a subset of the same data they used for their longevity vs fertility paper, ie European aristocratic families. In this case, they analysed a lot of variables until they found one that correlated with longevity.

On the relevant subsample of 4911 women, adult women over 30 born between 1800 and 1880 lived shortest if they were born in August and longest if they were born in May with the difference at about three and a half years. This is after correcting for a whole heap of variables that have nothing to do with month of birth but are related to longevity: year of birth, maternal and paternal life spans, age of parents at birth, birth order, nationality, whether the death was violent, loss of either or both parents before age twenty.

They have a graph and it doesn't look good to me. The only reasons I can think of, and that they propose, for the effect would be availability of vitamins (or calories but they are unlikely to be a problem for this group since they were all from aristocratic families) at specific points in the pregnancy or early life, but the graph is very noisy and it mostly jumps up and down. For example, the difference between July and August births is two and a bit years, and between August and September the difference is about a year and a half, with August at the minimum. The other bad months are February and March, on the other side of the year, with women born then living about a year longer than those in August. If the effect is real, then the critical periods during pregnancy must be very short.

I'm not buying any of it until it gets replicated.
)))

Adaptive Response to Swimming Exercise: Antioxidant Systems and Lipid Peroxidation

2011-02-06T02:12:00.001+11:00

Summary: Anti-oxidant enzyme concentrations go up in the blood of rats that go swimming

Interestingness: 1

Paper by M Cesquini, MA Torsoni and SH Ogo in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

(((
The abstract has everything covered. Note that these tests were on three groups of four rats each. Also, catalase was down on the endurance-trained group.
)))

Abstract follows:

Enzymatic and nonenzymatic antioxidants play an essential role in protecting tissues from oxidative damage during exercise. The present study investigated the levels of glutathione and antioxidant enzyme systems in the blood of unexercised and exercised (one bout of exhaustive swimming and adapted to swimming endurance training) rats. The hemoglobin concentration, hematocrit, and extent of oxidative injury to red blood cell (RBC) membranes were examined in the above groups of rats. The concentration of reduced glutathione (GSH) in the blood of exercised rats was about 30% higher than in the resting controls (0.40 Å [±] 0.12 GSH/Hb tetramer). Glutathione peroxidase (1.83 Å 0.24 X 102 IU/g Hb), glutathione reductase (1.73 Å 0.44 IU/g Hb), and Superoxide dismutase activities were significantly higher in both groups of exercised rats, whereas catalase activity (8.32 Å 1.04 X 104 IU/g Hb) was similar in the exercised and control animals. The hemoglobin concentration (11.8 g Hb/dL) and hematocrit (39.4%) increased with swimming exercise. Although lipid peroxidation is known to occur following physical exercise, the increased activity of the antioxidant enzymes and cell GSH levels in the present study were able to prevent lipid peroxidation of the RBC membrane. As a result, there was no significant variation in the plasma malondialdehyde levels among the three groups of rats. The redox capacity of the blood may have an important role in the organism in general since the redox status can be transferred across the RBC plasma membrane to other tissues. Exercise training is therefore beneficial to general health and protects cells against deleterious effects of reactive oxygen species produced during physical effort.

Pycnogenol Improves Learning Impairment and Memory Deficit in Senescence-Accelerated Mice

2011-01-29T19:40:00.002+11:00

Summary: Senescence accelerated mice of the memory-impairment variety do better learning with pycnogenol.

Interestingness: 2

Paper by Fujun Liu, Yongxiang Zhang and Benjamin HS Lau in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

(((
This is another one of those give substance to senescence accelerated mice (SAM) (see http://readingrejuvenationresearch.blogspot.com/2010/01/interventions-of-senescence-in-sam-mice.html), watch them act normal type papers. In this case, the substance, pycnogenol, was a commercial extract of the bark of the French maritime pine, which is made up mostly of procyanidins, which is the class of oligomers of flavonoids. The SAM chosen was SAMP8, which has mental issues. The task was learning. The SAMP8 did better when given the substance compared to controls, and about as well as the SAM resistant variety in these groups of 10 mice each. The suspected mechanism is anti-oxidant activity. Whoopee.

The interesting bit of the paper is the description of the memory experiments, which I'd heard mentioned before, as passive and active avoidance, but not described.

The passive avoidance tests are the if-you-move-I-shoot type, and they did two tests, called step-through and step-down. In the step-through test, mice are put in a bright area. There is a little tunnel to go to the dark area. Mice usually try to avoid being in a bright area, but when they go through the tunnel they get electrically shocked. If they don't go through on subsequent tests, it is assumed that they learnt. In the step-down test, they are put on a small rubber pad, surrounded by a sea of electric shock metallic mesh. If they stay on the pad for ten minutes, they "win".

The active avoidance test is, as expected, approximately the opposite. They are put in an area with two infrared beams that can be triggered. For ten seconds before the mesh below their feet becomes electrified, an alarm sounds and a light goes on, then the electricity is turned on for ten seconds. If they trigger both beams while the alarm is going on, either before or during the electric shock, the electricity is turned off. To trigger the beams they would have to run around.
)))

Abstract follows:

Pycnogenol (procyanidins extracted from the bark of French maritime pine, Pinus maritima Aiton) has been shown to be a potent free radical scavenger and an antioxidant phytochemical. The effects of pycnogenol on learning impairment and memory deficit in senescence-accelerated mouse (SAM) as a murine model of accelerated aging were determined. SAMP8, a strain of senescence-prone mice, exhibits immunodeficiency, hemopoietic dysfunction, learning impairment, and memory deficit. The effects of pycnogenol on learning performance and memory deficit were measured using step-through and step-down passive avoidance tests and shuttle box conditioned avoidance test. Oral feeding with pycnogenol for 2 months increased the retention rate in the step-through and the step-down tests and the rate of conditioned avoidance response in the shuttle box test. The latency of mice in the step-through test and the number of successful mice in the step-down test also increased with pycnogenol feeding. These results suggest that pycnogenol can improve learning impairment and memory deficit associated with aging.

Thyrotropin-Releasing Hormone Accelerates and Enhances the Age-Postponing Effects of Melatonin

2011-01-26T17:45:00.004+11:00

Summary: Thyrotropin-releasing hormone (TRH) plus melatonin increase lifespan of old mice by three months

Interestingness: 4

Paper by Walter Pierpaoli, Daniele Bulian, Gordana Bulian and Gonzague Kistler in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

(((
The sample size is small, 15 mice per group, but the effect size is interesting. The main table of results shows the following: for four groups of 15+-1 BALB/cJ female mice, 20 months old at the start of the experiment, a control group, one given melatonin, one TRH, one both, mean survival was 765+-54 days, 810+-50 days, 804+-80 days, and 861+-70 days respectively. There's also other results, with the TRH plus melatonin combination raising numbers of leukocytes and blood lymphocytes, and lowering cholesterol and triglycerides in old mice.

TRH induces release of thyrotropin, aka thyroid-stimulating hormone (TSH) which then induces the thyroid to release T3 and T4. Wikipedia has TRH being produced in the hypothalamus but the paper says it's produced by the hypothalamus and the pineal gland.

The mechanism behind this isn't precisely hypothesised but they do mention immune system upregulation. The authors hype TRH as the real reason for the supposed effects of melatonin on aging, saying that melatonin dosing stops the pineal gland making its own, so it can stay young and keep on making TRH later. TRH is also given as the explanation of why pineal gland transplantation from young to old mice, mentioned in http://readingrejuvenationresearch.blogspot.com/2010/03/perspective-on-proposed-association-of.html, increases the longevity of those mice.

)))

Abstract follows:

Studies over a period of several years have suggested an age-postponing effect of circadian nocturnal administration of melatonin and of young-to-old pineal grafting in rodents. Of the two procedures, the effect of pineal grafting was significantly more pronounced. Also, old-to-young and young-to-old pineal transplantation in normal or pinealectomized recipients suggested that the pineal itself contains the capacity to prevent or to accelerate the course of aging depending on the age of the donor and/or of a recipient when the pineal is transplanted. This observation prompted the idea that the "program of aging" might be governed by the capacity of the pineal to maintain the control of central neuroendocrine functions and to constantly synchronize the synthesis and release of hormones according to a strict circadian periodicity and seasonal rhythmicity. This report deals with the experimental evidence that, while melatonin alone exerts a low-level age-postponing activity, its age-delaying effects are greatly enhanced and accelerated when given in combination with a pineal peptide, thyrotropin-releasing hormone (TRH). This peptide may be a key element in the mechanism by which both melatonin and pineal grafting might postpone aging. In fact, as suggested by our data here, TRH could be one of the basic mediators in the brain (pineal-hypothalamic-hypophyseal axis) and in peripheral endocrine glands (e.g., the beta, insulin-producing cells in the pancreas). TRH may directly translate the light and temperature-mediated environmental stimuli into rapid energy-adapting biochemical processes which constantly monitor cell functions relating to energy production, in particular those required for thermoregulation. We show here that this energy-monitoring action of TRH is not thyroid mediated. We also show that TRH is not itself a toxic agent even when administered daily for long periods at a very high pharmacological dosage.

Effect of Carnosine on Age-Induced Changes in Senescence-Accelerated Mice

2011-01-23T16:42:00.002+11:00

Summary: Carnosine extends median survival on an accelerated-aging model of mice by about 20%

Interestingness: 2

Paper by MO Yuneva, ER Bulygina, SC Gallant, GG Kramarenko, SL Stvolinsky, ML Semyonova and AA Boldyrev in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

(((
In a study of two groups of 70 senescence-accelerated mice prone 1 (SAMP1) each, carnosine extended the time taken until half the mice in its group died. That is, on a plot of age versus percentage of animals alive, plotting both SAMP1 control and SAMP1 given carnosine groups, both curves start at 100% and drop to zero%. They reach zero at around the same age (17 months), but the control curve drops earlier, with the 50% mark being around 10 months for control and 12 months for the carnosine'd mice. Other benefits included glossier fur, less skin ulcers, and much more reactivity and passive avoidance. I don't know what reactivity is, but was in the group with passive avoidance. From wikipedia, I get that carnosine raises corticosterone. Doesn't sound good to me.

SAMP1 mice are whacked though, so again, I don't put much weight on this. SAMP1 mice are prone to amyloidoisis (http://readingrejuvenationresearch.blogspot.com/2010/01/interventions-of-senescence-in-sam-mice.html).

They don't know about the mechanism of action. They suggest a few: carnosine is a oxide radical scavenger, it prevents radical production in the first place, and it is an antiglycation agent, but maybe something else.

)))

Abstract follows:

The effect of carnosine on the life span and several brain biochemical characteristics in senescence-accelerated mice-prone 1 (SAMP1) was investigated. A 50% survival rate of animals treated with carnosine increased by 20% as compared to controls. Moreover, the number of animals that lived to an old age significantly increased. The effect of carnosine on life span was accompanied by a decrease in the level of 2'-tiobarbituric acid reactive substances (TBARS), monoamine oxidase b (MAO b), and Na/K-ATPase activity. There was also an increase in glutamate binding to N-methyl-D-aspartate receptors. These observations are consistent with the conclusion that carnosine increases life span and quality of life by diminishing production of lipid peroxides and reducing the influence of reactive oxygen species (ROS) on membrane proteins.

Impact of Dietary Restriction on Brain Aging and Neurodegenerative Disorders: Emerging Findings from Experimental and Epidemiological Studies

2011-01-22T20:01:00.001+11:00

Summary: Calorie restriction helps mice and rat models of Alzheimer's, Parkinson's and stroke. 2-doxyglucose does too.

Interestingness: 2

Paper by Mark P Mattson in the Journal of Anti-Aging Medicine, Volume 2, Issue 4, Winter 1999.

(((
Rats and mice models of Alzheimer's disease (AD) did better when they were on a calorie restriction diet (CR). The same for Parkinson's disease (PD). Also for Huntington disease (HD). Also for rats given a stroke. I don't like the models, except the one for stroke, so I don't care much about these results.

They think this effect comes from over-expression of heat shock proteins (HSP-70) when glucose goes low. When given 2-deoxygluose (2-DG), a modified glucose that competes with glucose for the energy chain enzymes but is not able to be broken down properly (http://readingrejuvenationresearch.blogspot.com/2010/07/2-deoxy-d-glucose-feeding-in-rats.html), rats and mice also did better in the AD, PD and stroke models, even though they lived under all-you-can eat buffet conditions.

Finally, some lame-sounding correlation studies between caloric intake surveys with PD, AD and stroke are listed.
)))

Abstract follows:

Although dietary restriction (DR) extends life span and reduces levels of cellular oxidative stress in several different organ systems of laboratory rodents and monkeys, its impact on the brain is unknown. As is the case with age-related disorders in other organ systems (e.g., cardiovascular disease, diabetes, and many cancers), neurodegenerative disorders such as Alzheimer disease (AD), Parkinson disease (PD), and stroke involve increased levels of cellular oxidative stress and metabolic compromise. Recent studies of experimental rat and mouse models of AD, PD, and stroke have shown that DR increases resistance of neurons to dysfunction and degeneration. DR can attenuate age-related and disease-specific deficits in cognitive and motor functions in rodents. The available data suggest at least two possible mechanisms whereby DR protects neurons. One involves decreased levels of mitochondrial oxyradical production, and the second involves induction of the expression of "stress proteins" and neurotrophic factors. The latter mechanism is supported by data showing that the neuroprotective effect of DR can be mimicked by administration of 2-deoxyglucose to animals fed ad libitum. Recent findings in epidemiological studies of human populations suggest that individuals with a low daily calorie intake have reduced risk for AD and PD. Collectively, the available data suggest that DR may prove beneficial in reducing both the incidence and severity of neurodegenerative disorders in humans.

Rest of volume 2, Issue 3

2011-01-15T23:05:00.002+11:00

The rest of issue 3 of 1999 consists of:

A review of the 28th Annual Meeting of the American Aging Association by RM Anson and MA Lane.

Two book reviews:

"Understanding the process of aging: The roles of mitochondria, free radicals, and antioxidants", edited by Enrique Cadenas and Lester Packer. Very positive.
"Towards prolongation of the healthy life span: Practical approaches to intervention", edited by Denham Harman, Robin Holliday and Mohsen Meydani. This is the collection of papers and posters for the 1997 meeting of the International Association of Biomedical Gerontology. Also very positive

The gerontology literature review:

"Human embryonic stem-cell research: science and ethics", by Shirley J Wright, in American Scientist. Ethics of stem cell research.
"Embryonic stem cells for medicine", by Roger A Pedersen, in Scientific American. Ethics of embryonic stem cells and cloning.

The usual other sections: literature watch and calendar. Web watch disappeared.

Formamidopyrimidine—DNA Glycosylase Targeted to Specific Organelles in C2C12 Cells

2011-01-13T01:20:00.002+11:00

Summary: Targeting mitochondria or nucleus with an oxidised DNA base remover

Interestingness: 3

Paper by Karah A Street, Kerrie L. Hall, Patrick Murphy and Christi A Walter in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((
The follow up paper to this one could be very interesting. This one seems to show that they could target either the mitochondria, or the nucleus with a protein, formamidopyrimidine-DNA glycosylase (Fpg), that gets rid of 2-deoxy-8-hydroxyguanine (8-OHdG), a screwed up version of the guanine base and the most common oxidised base. 8-OHdG causes the guanines (G) to be replaced by thymine (T) (by the normal repair mechanism I think). Fpg gets rid of 8-OHdG by taking out the base and leaving the ribose chain. This is supposedly a part of one of the normal DNA fixing mechanisms, called the base excision repair (BER), where one protein gets rid of a mutated base, and another goes and inserts the right base in.

So, yes, they created two DNA vectors, inserted them into some mouse muscle cells, and mostly saw what they were looking for, with the nuclear DNA being expressed mostly in the nucleus, and the mitochondrial in the cytoplasm. The levels of the molecule seemed pretty low though, and didn't correlate with the number of copies they inserted.

No assessment of the amount of 8-OHdG damage in the DNAs after transfection was done. I assume that's part of the plan for future work.
)))

Abstract follows:

Mitochondrial respiration provides a major source of energy for eukaryotic cells. However, the energy-producing processes also generate reactive oxygen species, which in turn damage mitochondrial DNA found in the mitochondrial matrix. Due to its locale, mitochondrial DNA is more susceptible to oxidative damage than nuclear DNA. While mitochondria do have some DNA repair capabilities, particularly base excision repair, oxidative damage persists in mitochondrial DNA. Correlations have been demonstrated between increasing age and increased levels of oxidative damage and mitochondrial DNA mutations. The current experiments were designed to begin to more directly delineate the role oxidative damage in mitochondrial DNA plays in aging. The mouse myoblast cell line, C2C12, was transfected with vectors, which express formamidopyrimidine-DNA glycosylase-myc fusion protein (Fpg-myc) and which contain either a mitochondrial or nuclear localization signal. Positive transfectants display expression of fpg at the mRNA level and exhibit an increase in Fpg activity in a whole-cell protein extract using a Fpg activity assay. Immunofluorescence analyses confirm that the transfected vectors have Fpg-myc appropriately targeted to mitochondria or nuclei. These cell lines with specifically targeted Fpg-myc expression provide the tools to test the effects of increasing the levels of a DNA glycosylase in mitochondria and nuclei on oxidative damage in DNA.

Centrophenoxine Slows Down, but Does Not Reverse, Lipofuscin Accumulation in Cultured Cells

2011-01-11T01:02:00.001+11:00

Summary: Centrophenoxine is not very interesting with regards to lipofuscin

Interestingness: 1

Paper by Alexei Terman and Martin Welander in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((
Lipofuscin is made up of the residues from lysosome degradation. Wikipedia claims it is the product of oxidised unsaturated fatty acids. It doesn't degrade with time in the body by itself, it just accumulates. The age-spots in old people are made of this.

Centrophenoxine is a treatement for senile dementia, which wikipedia claims improves memory and general cognition.

They tried using centrophenoxine to stop formation of, and to get rid of lipofuscin in rat heart cells exposed to high levels of oxigen (to accelerate lipofuscin production is my guess, since they only left it for a few weeks). It reduced formation by about half at what seems to me to be very high concentrations (almost a millimole), but did didly for removing already established lipofuscin particles or modifying number of autophagic vacuoles induced by leupeptin. They attribute the reduction effect on its anti-oxidant properties
)))

Abstract follows:

Centrophenoxine, a drug used in the treatment of senile dementia, has been suggested to retard, or even reverse, lipofuscin accumulation within postmitotic cells. However, a true capacity of centrophenoxine to eliminate already formed lipofuscin inclusions has not been convincingly demonstrated. Moreover, no evidence has been obtained regarding the possible mechanisms through which intracellular content of lipofuscin would be diminished by centrophenoxine. Here we show that (a) centrophenoxine at concentrations of 0.25 or 0.5 mM diminishes lipofuscin accumulation within cultured neonatal rat cardiac myocytes (by 44% or 51%, respectively, during a period of 2 weeks) when it was constantly present in the culture medium; (b) the same treatment of rat cardiac myocytes and AG-1518 human f ibroblasts, however, does not eliminate already formed lipofuscin inclusions; (c) the formation of autophagic vacuoles, and ensuing degradation of their contents, are not influenced by centrophenoxine. Thus, our results do not support the idea that centrophenoxine can reverse age-related accumulation of lipofuscin. The observed decrease of lipofuscin formation is probably due to the previously shown antioxidant properties of centrophenoxine.

Possible Influence of Metabolic Activity on Aging

2011-01-09T03:17:00.003+11:00

Summary: Details of ATP production control mechanism in mitochondria

Interestingness: 4

Paper by Bernhard Kadenbach, Elisabeth Bender, Annette Reith, Andreas Becker, Shahla Hammerschmidt, Icksoo Lee, Susanne Arnold and Maik Hüttemann in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((
This is more of a mitochondria biochem details piece, not directly related to aging. Most of it is too detailed for me to summarise or keep in memory or even follow.

Some interesting bits at the front that are not usually spelt out: out of the 13 proteins that mtDNA codes for, seven code for parts (out of 45) of NADH (nicotinamide adenine dinucleotide, protonated form) dehydrogenase (aka complex I), one for ubiquinol-cytochrome c oxidoreductase (aka complex III) (out of 11), three for cytochrome c oxidase (aka complex IV) (out of 13), and two for ATP synthase (out of some number I couldn't find). There's 5-10 mtDNA copies per mitochondrion, and 100-1000 mitochondria per cell.

It then describes two separate mechanisms of respiratory control. The first being due to the stimulation of ATP synthase by ADP triggering a lower proton motive force (deltaP) which trigger the proton pumps of the respiratory chain (NADH dehydrogenase, cytochrome c oxidoreductase and cytochrome c oxidase), kind of like an inverted system I think, with the final step pressuring the steps that come before it, but I imagine talking about the order here is completely wrong, they all happen at the same time. The second being due to the ATP/ADP ratio, with high ATP/ADP intramitochondrial ratio triggering a shut down of cytochrome c oxidase. This second method of control is bypassed by the presence of certain molecules, including 3,5-diiodo-L-thyronine, suggested as the mechanism of the short-term effects of thyoroid hormones, and palmitate (but not stearate, oleate or arachidonate).

The paper then does some studies showing that cAMP-dependent phosphorilation of complex IV enhances this ATP/ADP ratio control mechanism, and mitochondrial protein phosphatases reverse this enhancement. This second effect is shown mainly by adding a potassium fluoride which acts as a phosphatase inhibitor, and seeing the cAMP effect be stronger.

They also confirmed that it is mostly one mutant species of mtDNA that dominates a muscle fiber. They mapped a common deletion of mtDNA, probably that mtDNA4977 that was seen a couple of posts ago, and its occurrence varied between 0 and 0.06%, but corresponded with the bits of tissue that had malfunctioning complex IV.

They then speculate on how this phosphorilation/dephosphorilation mechanism is usually in balance, and is controlled by stressors and how when the ATP/ADP control mechanism is working, the proton gradient voltage is lower, and so less leakage of protons across the membrane occur, and less reactive oxide species are produced, and how this would be normally bypassed in a high caloric diet by the presence of palmitic acid, but the chain of reasoning is long and requires more concentration than I was willing to give it.

)))

Abstract follows:

The mitochondrial hypothesis on aging suggests stochastic stomatic mutations of mitochondrial DNA (mtDNA) as an important cause of respiratory-defective cells and the decline of energetic capabilities with increasing age. Reactive oxygen species (ROS), which are produced in the respiratory chain under stress conditions, are assumed to cause deletions and/or mutations of mtDNA. Using quantitative PCR, the stochastic distribution of the "common deletion" of mtDNA in human skeletal muscle tissue is shown. Recent data suggest that in vivo, under normal conditions, respiration is controlled by the intramitochondrial ATP/ADP ratio, via interaction of the nucleotides with subunit IV of cytochrome c oxidase, representing the rate-limiting step of the respiratory chain. Kinetic data are presented indicating that this "second mechanism of respiratory control" is turned on by cAMP-dependent phosphorylation of the enzyme and turned off by mitochondrial protein phosphatases. It is proposed that dephosphorylation of cytochrome c oxidase via "deleterious stress signals" results in increased mitochondrial membrane potentials and stimulated production of ROS in the mitochondrial respiratory chain. As a consequence, mutations of mtDNA would increase and aging would be accelerated. The inhibition of cytochrome c oxidase at high ATP/ADP ratios can also be abolished by low concentrations of free palmitate and high substrate pressure in the respiratory chain, supporting the notion that low caloric diet supports longevity.

Modeling the Role of Mitochondrial Mutations in Cellular Aging

2011-01-06T02:40:00.003+11:00

Summary: Model of what happens if mitochondria with damaged DNA both reproduces and degrades slower than intact mitochondria, and how it fits observed data

Interestingness: 7

Paper by Axel Kowald and Thomas BL Kirkwood in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((

They start by claiming there is a problem with the then-present theory of how damaged mitochondria are preferentially disseminated/take over cells by noting that it, the theory, is inconsistent with experimental results that show that damaged mitochondria is more prevalent in senescent cells than in dividing cells, and that the cells, or at least the muscle fibres, are taken over by one mutant type of mitochondria (by one I mean one type per case, not one common type for all cases) like we just saw in the last post http://readingrejuvenationresearch.blogspot.com/2010/12/segmental-nature-of-age-associated.html. Those are the main problems they want to see if they can patch with their model.

Their model starts at de Grey's model http://readingrejuvenationresearch.blogspot.com/2010/01/proposed-refinement-of-mitochondrial.html that basically hypothesises that mutant mitochondria produce less holes in their membranes and so are degraded less often. They justify the apparent contradiction in mutant mitochondria producing less holes with the "well known" fact that they produce more radicals by saying that most radicals are O2.- radicals but only the perhydroxy radical (HO2.-) can rip protons from lipids. Mutant mitochondria have a lower proton gradient so they produce lower amounts of HO2.- even if they produce more O2.-. Would seem good to get actual measurements, but they say that these aren't available and that they would be hard to get.

They, instead, produce a model with two assumptions: the first is that damaged mitochondria are destroyed slower than ones with intact mtDNA, and secondly, one introduced by them, that damaged mitochondria grow slower, which they justify by the energy shortage produced by the lower proton gradient. They split mitochondria into six groups, for little membrane damage, medium membrane damage and high membrane damage, each with intact mtDNA or mutant mtDNA. Radicals can increase the level of membrane damage or switch the mitochondria from an intact to a damaged mtDNA state. They give different turnover rates for mitochondria in each of the membrane damage classes, independent of their mtDNA state. The corresponding half lives for each damage class are 10, 2 and 1 week for low, medium and high damage. They used a factor of 2 as the increase in rate of free radicals that a mutant mitochondria produces compared to intact mitochondria, that mutants produced membrane damage at a rate 10 times lower than intact, and that intact grew 5 times quicker. I guess these numbers were half-guesses, and probably important in the results they got.

The model replicates the features from experiments they were looking to replicate, with one mutant taking over cells, and senescent cells having larger proportion of mutants than dividing cells, due to cell replication being a purifier of mitochondria. This purification happens because of the growth advantage of the intact mitochondria. This effect dominates when large amounts of mitochondria are to be produced, as in dividing cells, but the rate of destruction dominates when few mitochondria are being synthesised. They have some graphs showing what happens when the parameters are very different: if the mitochondria destruction rate are a bit lower, the population eventually collapses, if they are much higher, they collapse very quickly, along with other graphs showing the effects of different rates of cell reproduction and how that affects mitochondria population and stability (quick enough cell reproduction can fix higher rates of mutation).

From the model they also predict differences in importance between telomere shortening and mitochondrial damage in vivo vs in vitro. They claim that because in vitro conditions cells are replicated quickly, their collection of mitochondria will be pure through the process talked about above, so they will reach their Hayflick limit with nary an issue in their mitochondria, while in vivo, where cells replicate more slowly, mitochondrial damage will accumulate earlier and keeping telomeres long will not have an effect on cell lifespan.

(Interesting little factoid in the paper that I didn't fit in anywhere else: oxygen radicals are estimated to amount to 1-4% of consumed oxygen which sounded like a lot)

)))

Abstract follows:

The mitochondrial theory of aging suggests that an accumulation of defective mitochondria leads to loss of cell viability. The challenge is to explain how mitochondrial defects accumulate within cells, and why this process is more evident in postmitotic than in dividing cells. We describe a new mathematical model incorporating two critical features: (a) defective mitochondria are turned over more slowly than intact ones, and (b) defective mitochondria suffer a growth disadvantage. We also model the effect of cell division on the accumulation of defective mitochondria. The results support the mitochondrial theory and explain many of the observed data. The relationship of the mitochondrial theory to the suggested role of telomere loss in cell replicative senescence is discussed. We suggest that because of differences in the kinetics of their impact on cells, these two mechanisms have different relative importance for in vivo and in vitro cell aging.

Segmental Nature of Age-Associated, Skeletal Muscle Mitochondrial Abnormalities Necessitates Three-Dimensional Analyses

2010-12-14T00:41:00.003+11:00

Summary: Mitochondria with abnormal electron transport chain activity are grouped along the fibre in muscle tissue

Interestingness: 4

Paper by Nathan L Van Zeeland, Jonathan Wanagat, Marisol E Lopez and Judd M Aiken in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((
They looked at low cytochrome c oxidase (COX, complex IV) activity and high succinate dehydrogenase (SDH, complex II) activity in muscle tissue, which are supposedly common markers for age-related mitochondrial abnormalities. They are colocated with mitochondrial DNA (mtDNA) deletion (mtDNA4977). Also, muscle fibres with these abnormal mitochondrial activity are more commonly atrophied/have much lower cross-sections in rhesus monkeys. Part of the COX enzyme is encoded in the mtDNA, while all of the SDH enzyme is encoded in the nuclear DNA. (That explains why COX activity goes down, but why does the SDH activity go up?)

They measured COX and SDH activity in muscles of old (3-year old) rat and old (33 year old) rhesus monkey, making 200 slices across the muscle fibre so that they got a cross-section of the muscle at each slice. Each slice was about 10 microns thick, and they followed the muscle for about 1.6 millimetres in the monkey and 2 in the rat.

They found that the mutations were grouped along each muscle fibre. They found that in their sample, 3% of the rat's fibers had abnormal activity at some point along its length, and 0.31% of the monkey's (a 25-year old monkey though, not sure what happened to the other monkey), and contrasted these with the much lower values they would have gotten if they would have just sliced at one point (about six times lower). Through some dodgy extrapolation, they claim that 50% of the muscles fibers in the rat's case would be abnormal at some point if they had followed it through the whole length of the muscle, although they say that further studies by them point the number to be closer to 25%
)))

Abstract follows:

Age-associated electron transport system (ETS) abnormalities in skeletal muscle are distributed in a mosaic and segmental fashion; thus, histological techniques examining a single cross-section of tissue underestimate the number of fibers harboring such mitochondrial abnormalities. Analyses of consecutive cross-sections along the length of a muscle are necessary to determine the absolute number of ETS abnormal fibers within a given skeletal muscle. Two hundred serial cross-sections of old rat and rhesus monkey skeletal muscle were obtained by cryostat sectioning. Sections were stained and examined for cytochrome c oxidase and succinate dehydrogenase activity at regular intervals spanning a 1,600-micrometre region of muscle. All fibers staining negative for cytochrome c oxidase activity or hyperreactive for succinate dehydrogenase activity were then followed along their lengths to determine the extent of the ETS abnormal regions. ETS abnormalities in both animal models were found to be distributed in localized regions of individual muscle fibers (i.e., segmental). Examination of fibers along their length lead to a fourfold increase in detection of rat muscle fibers bearing mitochondrial abnormalities. In situ histological techniques that examine numerous sections at multiple positions along the length of skeletal muscles are particularly well suited for determining numbers and assessing the cellular impact of skeletal muscle fibers harboring age-related mitochondrial abnormalities.

RNA Oxidation in Alzheimer and Parkinson Diseases

2010-12-06T21:45:00.002+11:00

Summary: RNA is oxidised in some of Alzheimer's, Parkinson's and Down syndrome patients' neurons

Interestingness: 2

Paper by Akihiko Nunomura, George Perry, Jing Zhang, Thomas J Montine, Atsushi Takeda, Shigeru Chiba and Mark A Smith in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((
They measured 8-hydroxydeoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG) as markers for DNA and RNA oxidation respectively in an unknown number of brains of postmortem Alzheimer's (AD), Parkinson's (PD) and Down syndrome (DS) patients. They found more 8-OHG in some parts of the brains of some types of disease, and less in others, but the parts of the brain still don't mean much to me. In any case, here they are:

More oxidation in the cytoplasm than in the nucleolus and nuclear envelope in the neurons of AD and DS, clean in controls
No difference in cerebellum between AD, DS and controls
RNA oxidation was the main thing being detected in AD and DS
Less oxidation with increased amyloid beta (AB) and neurofibrillary tangles (NFT)
Increased oxidation in substantia negra in PD, dementia with Lewy bodies (DLB), and multiple system atrophy-Parkinsonian type (MSA-P). More in PD than other two
Both RNA and DNA oxidation in PD, DLB and MSA-P
No increase in RNA oxidation in PD in cerebellum or cerebral cortex, but increase in cerebral cortex for DLB

They think the source of oxidation is damaged mitochondria spewing hydrogen peroxide, and it transforming to hydroxyl radicals through the Fenton reaction in the cytoplasm. They don't know what effect oxidation has on RNA's functionality or if it is important. Probably some translation issues with wrong base pairing.
)))

Abstract follows:

In Alzheimer and Parkinson diseases, oxidative alterations, affecting lipids, proteins, and DNA, have been described. Using an in situ approach to identify 8-hydroxyguanosine, an oxidized nucleoside, we recently identified RNA as a major target of oxidation in Alzheimer and Parkinson diseases as well as Down syndrome, where premature Alzheimer-like neuropathology is invariably found. RNA oxidation is localized to the neuronal populations potentially affected in these diseases. Together with the known mitochondrial dysfunction in Alzheimer and Parkinson diseases, the cytoplasmic predominance of neuronal 8-hydroxyguanosine supports mitochondria as the most likely source of reactive oxygen responsible for RNA oxidation. The consequence of oxidatively damaged RNA is not fully understood; however, the potential of oxidized RNA to cause errors in translation indicates a metabolic abnormality in neurodegenerative diseases.

Mitochondrial DNA Oxidation

2010-12-06T01:30:00.003+11:00

Summary: Most of the oxidising damage in mitochondrial DNA (mtDNA) is in bits/fractions of mtDNA, not in the circular form. And iron relaxes mtDNA loop and increases its replication.

Interestingness: 5

Paper by Christoph Richter in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((
This paper starts by describing how mtDNA gets oxidised: superoxide radicals (O2-) are formed "when cytochrome oxidase is blocked, when cytochrome c is detached from the inner mitochondrial membrane, " ... and " when mitochondrial oxidative phosphorylation is inhibited". The superoxide radical then gives the electron to a water molecule, which forms hydrogen peroxide (H2O2), which then forms hydroxyl radical (OH.) in the presence of iron or copper (Fenton reaction). The hydroxyl radical is the bastard that then goes and reacts with everything.

It then mentions radical nitrogen species, usual description of mtDNA (16.3 kb pair coding for 13 peptides, 22 tRNAs and 2 rRNAs), how people started thinking of mtDNA damage as important for diseases, measurement of mtDNA damage (usually measuring 8-hydroxyguanine and strand breaks), sidetrack into azidothymidine (AZT, the anti-AIDS drug) causing problems in mitochondria, and Friedreich's ataxia (FA) probably being a problem with oxidation damage in mitochondria.

Now, interesting bit, measurements of amount of oxidative damage in mtDNA differ depending on methodology. Detection of 8-hydroxydeoxyguanosine (8-OHdG) gives big numbers (4 modifications per mtDNA molecule) while numbers from repair enzymes (dunno how it works) give much lower numbers. High number doubted also from seemingly high number of working mitochondria. They do analysis of mtDNA from rat's livers, detecting 8-OHdG. They get 0.051 picomole per microgram of DNA for circular mtDNA, which they say is about one 8-OHdG mutation every two mtDNA molecules, 0.014 picomole per microgram of DNA for nDNA, which is contamination in the sample, but 0.741 picomole per microgram in low molecular mtDNA, ie fractions of floating mtDNA. They don't know what the fractions of mtDNA are doing or why they are so highly oxidised. It could be that they are being actively degraded, or they could be new chunks being made. Having found these fragments, he then hypothesises that these fragments integrate with nDNA, and that this is the main mechanism of aging of mtDNA oxidation damage.

The part that follows is also interesting. Experimenting with iron overload into the mtDNA of rat's livers in vitro they find that it (iron, in the form of Fe3+ gluconate), relaxes mtDNA from the standard supercoiled form to the open circular form. Anti-oxidants prevent some of the change but not all. The iron forms colloids that bind to mtDNA, and there may be a purely physical mechanism of relaxation. They then repeat the experiment in vivo also observing more relaxed circular DNA compared to controls, as well as increased mitochondrial surface and volume density, increased intracellular ferritin and hemosiderin, and higher replication of mtDNA.

It then switches to mtDNA damage prevention, mentions caloric restriction as reducing 8-OHdG counts, AZT leading to higher urinary 8-OHdG but vitamins C and E reducing those levels in AZT-taking people (I thought vitamins C and E didn't enter the mitochondria). Finishes by looking at future studies, evidence that mtDNA inserts in nDNA are more common in tumours, Drosophila overexpressing superoxide dismutase and catalase having increased lifespan, and some wacky suggestion of using bacteria to transfect genes into mitochondria.

)))

Abstract follows:

Mitochondrial diseases have been known for more than three decades. A refinement of the free radical theory of aging states that oxidative damage to mitochondria, particularly to mitochondrial DNA (mtDNA), is responsible for aging. About 10 years ago, oxidative damage to mtDNA was first reported, and human diseases were related to mutations of mtDNA. Subsequent reports suggested that oxidative mtDNA damage is more pronounced in old individuals and during certain diseases. Studies of animal models indicated that oxidative mtDNA damage can be ameliorated by dietary antioxidants and caloric restriction, an established method to increase life span. More recent data indicate that fragmented mtDNA is the predominant carrier of oxidized mtDNA bases and that fragments constitute a substantial amount of the total mtDNA. This article discusses the emerging relationship among mtDNA oxidation, diseases, and aging, and suggests experiments by which such a relationship can be further substantiated.

Area-Specific Differences in OH8dG and mtDNA4977 Levels in Alzheimer Disease Patients and Aged Controls

2010-12-01T00:28:00.001+11:00

Summary: Mitochondrial DNA in the brain gets damaged at different rates across brain regions depending on type of damage, age, and Alzheimer's diseasedness.

Interestingness: 1

Paper by AMS Lezza, P Mecocci, A Cormio, M Flint Beal, A Cherubini, P Cantatore, U Senin and MN Gadaleta in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((
They track two different common mutations to mitochondrial DNA (mtDNA) in post-mortem brains of 14 people, 8 with Alzheimer's, 6 control. One type of mutation is a deletion of 4977 bases in the mtDNA, which, going by the large amount of google results, seems to be quite a common thing to check for. The other is a product of oxidation, 8-hydroxy-2'-deoxyguanosine (OH8dG).

It seems like very little data to be taking the conclusions seriously, but the abstract is a good summary of the results. If nothing else, it seems that Alzheimer's disease patients have more oxidised mtDNA than non-Alzheimer's disease patients.
)))

Abstract follows:

The levels of mitochondrial DNA (mtDNA) 4977-bp deletion (mtDNA4977) and 8-hydroxy-2'-deoxyguanosine (OH8dG) have been measured in different brain areas of aged controls and Alzheimer disease patients. An area-specific distribution of the OH8dG level among three cortices and the cerebellum in aged controls as well as in Alzheimer disease patients has been found. It seems that in control subjects the age-related oxidative damage to mtDNA, represented by OH8dG content, shows a faster increase in the temporal and parietal cortices than in the frontal and in the cerebellum. In Alzheimer disease patients, where the OH8dG values are always higher than those of the control counterparts, such an area-specific distribution is maintained, but with a less significant difference among the cortices. The mtDNA4977 levels, on the other hand, are very different between frontal and parietal cortices on one side and temporal cortex and cerebellum on the other, both in control subjects and in Alzheimer disease patients. In general, it seems that the lowest mtDNA4977 levels coexist with the highest OH8dG contents in controls and, even more, in Alzheimer disease patients. This suggests that oxidative stress takes place both in aging and in Alzheimer disease, where it is amplified; however, mtDNA4977 level correlates with OH8dG content only in the frontal cortex of controls.

Free Radical Theory of Aging: Increasing the Average Life Expectancy at Birth and the Maximum Life Span

2010-11-21T02:46:00.001+11:00

Summary: The founder of the free radical theory of aging again summarising the results that back the theory, and theorising on what could help slow down this process.

Interestingness: 2

Paper by Denham Harman, MD, PhD, in the Journal of Anti-Aging Medicine, Volume 2, Issue 3, Fall 1999.

(((This is a rewrite of the paper two issues ago, summarised here: http://readingrejuvenationresearch.blogspot.com/2010/09/aging-minimizing-free-radical-damage.html, with better editing and slightly abridged (no cool graphs). It was more interesting the first time around, but this version is more polished.

This one puts more emphasis on substances that could slow down the aging process. There are a couple mentioned in this one that weren't mentioned in the first one, but nothing particularly intesting.
)))

Abstract follows:

Continued improvements in general living conditions—e.g., better nutrition, medical care, and housing—during the past two millennia have increased average life expectancies at birth from about 30 years in ancient Rome to almost 80 years in the developed countries with no change in the maximum life span. Current average life expectancies at birth will be increased little by further improvements. The rate of accumulation of damage inflicted on us by our inherent aging process limits average life expectancy at birth under optimal living conditions to around 85 years and the maximum life span to about 122 years. The inherent aging process is caused by chemical reactions that arise in the course of normal metabolism. Attempts to significantly increase average life expectancies at birth and the maximum life span in the future, unlike in the past, will require an understanding of aging. The free radical theory of aging postulates that this process is caused by free radical reactions, largely initiated by superoxide radicals arising from the mitochondria at an increasing rate with age. Some measures based on the free radical theory of aging may further increase the life span without interfering with the activities of normal life include: (a) caloric restriction, (b) compounds that decrease O2 access to "electron-rich areas" of the mitochondria, and (c) substances that help to minimize mitochondrial damage. The foregoing are discussed briefly along with the amelioration of damaging reactions in early life that predispose to life-shortening diseases. The feasibility of the measures suggested above needs to be evaluated. This task should be both interesting and rewarding.

Rest of volume 2, Issue 2

2010-11-13T22:28:00.001+11:00

The rest of issue 2 of 1999 consists of:

Some book reviews:

"Gray dawn: How the coming age wave will transform America and the world", by PG Peterson. Populist-sounding book warning that the US is getting old. Not reading it going by that review.
"Living to 100: Lessons in living to your maximum potential at any age", by TT Perls, M Hutter Silver, JF Lauerman and M Hutter-Silver. Book about how life at 100 can still be good. Feel-good book? Not reading it going by that review.
"Life without disease: The pursuit of medical utopia", by WB Schwartz. Using genes to predict and prevent disease. Sounds populist. Not reading it going by that review.
"The causes of aging", by AP Wickens. Sounds like introduction to biology of aging. Maybe ok.
"Super T: The complete guide to creating an effective, save, and natural testosterone enhancement program for men and women", by K Ullis, J Shackman, and G Ptacek. Guide on how to use testosterone as a supplement. Even though it sounds like marketing crap, it could be interesting.

The gerontology literature review:

"The centenarians are coming", by CG Wagner, in The Futurist. Usual Futurist content. Sounds similar to the "Living to 100" book above.
"Longevity: The ultimate gender gap", by HB Simon, in Scientific American. Reviewer didn't like it and mostly gave differing explanations and recommendations for the reasons of why men and women have different life expectancies. I don't like the alternative explanations offered.
"Aging: A message from the gonads", by DL Riddle, in Nature. Burning bits of somatic gonadal tissue in some worms extended their lifespan by 60% compared to standard. Paper-suggested theoretical background: fecundity and longevity are inversely proportional, controlled by hormones. IGF-1 signals lots of food. Interesting. (Further below *).
"Analysis of telomere lengths in cloned sheep", by PG Shiels, AJ Kind, KHS Campbell, D Waddington, I Wilmut, A Colman, and AE Schnieke, in Nature. Dolly, and two other cloned sheep, have 20% shorter telomeres than expected for their age. Theorised that telomere length not reset. Other people (that the reviewer contacted?) not convinced the result is not a fluke, or just experimental error (supposedly hard to distinguish telomeres 19kB long from ones 24 kB long)

The usual other sections: web watch, literature watch and calendar.

* On reading the article/letter, the description above is a bit wrong. The note is a theoretical justification for the gonad ablation result from another group. The 60% longevity expansion effect only happens when they get rid of the germline precursor cells (that generate sperm and eggs) and leave the gonad precursor cells alone, but not when they blast both sets. He interprets this as sperm shortening life and gonads extending it (I didn't get the teleological reasoning). There's more gene analysis ending with DAF-12 and DAF-16 upregulation extending lifespan, maybe through catalase upregulation, and DAF-2 shortening it by inhibiting DAF-16.

How Human Longevity and Species Survival Could Be Compatible with High Mutation Rates

2010-11-10T01:34:00.003+11:00

Summary: Hypothesising that humans select against deadly mutations primarily at the zygote stage.

Interestingness: 4

Paper by Leonid A Gavrilov and Natalia S Gavrilova, in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.

(((
Another short note, this one on how come the human race still exists considering the large amount of mutations that occur during each generation. They quote a number from a different study claiming 1.6 new harmful mutations per person, per generation. Their suggested mechanism on how to select against deadly combinations is by being very sensitive at the zygote stage, so having the deaths happen early. Their evidence for this is that the time lag between marriage and first child is around 16-19 months, giving time for about 7-10 failures. Doesn't sound like impressive evidence to me, but the idea is appealing anyway. They don't offer a mechanism as far as I can see on how the zygote is made so sensitive to deadly mutations.

)))

Is Telomere Shortening Related to Progeria?

2010-11-10T00:39:00.003+11:00

Summary: Telomere shortening probably doesn't cause Hutchinson-Gilford progeria

Interestingness: 6

Paper by W Ted Brown in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.

(((
This is a short note speculating on whether progeria is caused by telomere shortening. The author says unlikely. Hutchinson-Gilford progeria is a fucking rare disease (1 in 8 million) of the type that pop up through a dominant spontaneous DNA mutation. Progerias are diseases that look like accelerated aging. This one starts being noticeable in toddlers between one and two years old, then they start looking old very quickly, going bald and losing subcutaneous fat, and have an expected lifespan of 13 years. 80% of them die of heart attacks and congestive heart failure, but they don't seem to get cancer, cataracts, osteoporosis or Alzheimer's like regular old people.

Fibroblast cultures extracted from progeria patients have an almost normal lifespan, but one paper reported shorter telomeres in them. Studies from Werner's syndrome, a different progeria that hits during early adulthood, give mixed results for shorter telomeres, but maybe some indication of faster telomere shortening.

Mice with telomerase knocked out don't show too many problems and in one study, could reproduce for at least six generations. By the sixth generation, their telomeres were much shorter and there were a lot of chromosome fusions. Other studies on these telomerase knockouts showed slightly lower lifespan, lower wound healing capacity, and more cancer. From this, he says it seems unlikely that telomere shortening would cause progeria. From what I remember, though, mice have way longer telomeres than humans to begin with, which would hide the effect a bit, but he didn't discuss that

)))

Recovery of Circadian Body Temperature in Aged Persons

2010-11-01T01:30:00.003+11:00

Summary: Some body temperature measurements of old people, with some rising

Interestingness: 1

Paper by Iwao Hirosawa, Susumu Iwamoto, Junko Yoneda, Yasuhiko Wada and Akio Koizumi in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.

(((
They measured the temperature of 10 old people that were put into aged care, mostly after having a stroke. They measured many times a day for about a year. In their analysis, they split the people into two groups, the first one, consisting of four people, in which their temperature went up after they entered the care place, and the other of the remaining six, whose temperature didn't go up. Their summary says that maybe the people in the first group were under caloric restriction prior to entering, which got fixed once entering, thus raising their temperature. From the weight numbers, they were probably all borderline CR anyway (40 kg for women, 43 for men, 1.40 and 1.49 metres. Small people). The graphs are not clear to me. It isn't clear either whether the rise in temperature for those four people was a good or bad thing.

There is some further analysis of seasonal changes split across time of day, but I don't understand what it showed
)))

Abstract follows:

The human diurnal body temperature rhythm does not differ significantly between aged and young subjects; the amplitude and mean level, however, decrease with age. In order to know whether the core body temperature of disabled elderly persons was influenced by environmental factors, we measured the tympanic temperature of nursing home patients. In 4 of 10 tested patients, there was a statistically significant upward shift of the core body temperature within 1 month of admission (P < 0.05). This restoration of body temperature was observed to occur without any relationship to the season of admission. The amplitude of circadian body temperature did not change. There were significant seasonal variations in the diurnal body temperature range between summer and winter, especially between 0900 and 1100 hours in 5 persons with, and without, an upward shift of body temperature. The persons who recovered their body temperatures were thought to have been had lower-than-normal-body temperature for age prior to admission. Body temperature recovery after admission may have been caused by an improvement in energy intake and nutritional balance.

Prevalence and Risk Factors of Cognitive Deficits and Dementia in Relation to Socioeconomic Class in an Elderly Population of India

2010-10-31T17:32:00.001+11:00

Summary: Study of dementia and pre-dementia in India, how it relates to behavioural and economic factors, difficulties of doing such research, all with expected results

Interestingness: 1

Paper by RB Singh, R Singh Rao, AS Thakur, S Srivastav, MA Niaz and SN Shinde in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.

(((
The abstract is a perfect summary of the results. The paper mainly describes the process of the survey and how it had to be changed to make it work in India. The results are pretty much what I expected, except for the alcohol intake correlation.

It comes with an appendix with the questions in the survey. That bit is fun, even though the results are a little bit troubling.
)))

Abstract follows:

We attempted to find the association between age-related cognitive deficits or dementia and socioeconomic class or other risk factors, using a cross-sectional random survey of 595 elderly subjects ages 50-84 years in an urban population of Moradabad, India. The prevalence of cognitive deficit was 18.6% and was significantly higher in men than women (22.3% vs 14.6%; P < 0.05). There was a greater prevalence of cognitive deficits in lower socioeconomic classes. The prevalence of cognitive deficit, including dementia, has become a public health problem in India and is significantly associated with lower socioeconomic class, higher age, smoking, malnutrition, and alcohol intake in men.

Estrogen and Brain Aging

2010-10-31T17:09:00.001+11:00

Summary: Description of mostly suggestive data about the effects and importance of estrogen on aging in the brain

Interestingness: 1

Paper by Mahendra K Thakur in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.

(((
The most interesting part of the paper is a mention of a result in some other paper that women receiving estrogen replacement therapy (ERT) are 40% less likely to have Alzheimer's disease (AD) than women not receiving ERT.

The rest is a description of the changes in neurotransmitter and receptor densities in the brain as it ages, how estrogen might affect those neurons that produce and receive those neurotransmitters, mainly going by rat studies, results of women's mental scores going down when taking medication that suppresses estrogen production, and how those scores are rescued when taking ERT. I'm not good at absorbing the neurotransmitter information, so I glazed over a lot of it. Nerve growth factor seemed to be mentioned a lot.

There was also mention of estrogen as an antioxidant and its relation to AD. My biases prevailed and I discounted all of it before it even hit my long term memory.
)))

Abstract follows:

Recent research findings have made it clear that the female sex-steroid hormone estrogen has several functions other than regulation of sexual and reproductive behavior. In addition to this hormone's well-known influence on bone and the heart, this hormone exerts a wide variety of effects on the brain, including both development and function. The current interest in aging of the brain derives, in part, from the enormous and global increase in the proportion of elderly people. Old age is associated with several health problems including a general decline in mental function, especially in dementia, and specifically Alzheimer's dementia (AD). To focus on this issue, it is essential to understand the changes taking place in the aging brain and the role that estrogen plays in this process. This article reviews the data on the involvement of estrogen in the aging brain and discusses the potential consequences of estrogen replacement therapy.
Free first page

Is There a Reproductive Cost for Human Longevity? and Human Longevity and Reproductive Success: Response to Gavrilov and Gavrilova

2010-10-24T00:53:00.002+11:00

Summary: Critique and response of a study of an implicit tradeoff between number of offspring and mortality.

Interestingness: 1

Paper by Leonid A Gavrilov and Natalia S Gavrilova in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.
Response by Rudi GJ Westendorp and Thomas BL Kirkwood in the same issue.

(((
This is a critic of a paper that appeared in Nature about a trade off between number of offspring and longevity among the Brittish aristocracy going back to the year 740. Reasonable sounding critique, and reasonable sounding response. The abstract below is a good summary of the critique. The reply shows that adjusting for each of the items in the critique doesn't change the resultant mortality increase associated with having 2 or more children (1.15), and that they get different results from other studies because they restricted themselves to a homogenous group.
)))

Abstract of first paper follows (second one lacked an abstract):

This is a critical review of the recent claims by Westendorp and Kirkwood that human longevity is achieved at the cost of reproductive success. The criticism could be summarized in four statements. (1) Declaring that long-lived women have less progeny and older age at first childbirth, the authors failed to adjust the data for the age at marriage—the most important explanatory variable both for the number of children and for the age at first childbirth; (2) they also overlooked another important confounding variable—the husband's fertility; (3) the authors used the data that are inappropriate for fertility studies—extremely ancient and incomplete genealogies with many underreported records for daughters that led to incorrect estimates for the number of progeny and for the age at childbirth; and (4) the authors presented their study as completely new for humans and did not quote the opposite results from the earlier study by Le Bourg et al. where no trade-off between human longevity and fertility was observed. They also ignored findings of Bideau and of Knodel that the most fertile women live longer than the remainder or at least not shorter contrary to the author's claims. Thus, the conclusions of Westendorp and Kirkwood are inconsistent with the existing knowledge and should be reanalyzed using more appropriate methods and data.

Importance of T-Cell Replicative Senescence for the Adoptive Immunotherapy of Cancer in Humans?

2010-10-24T00:19:00.002+11:00

Summary: Review of replication of T-cells in vitro

Interestingness: 3

Paper by Graham Pawelec in the Journal of Anti-Aging Medicine, Volume 2, Issue 2, Summer 1999.

(((
This is another paper on T-cell senescence (previous one here: http://readingrejuvenationresearch.blogspot.com/2010/06/immunosenescence-analysis-and-genetic.html). It focuses on in-vitro studies, saying they are clinically important since that is how immune therapies will likely work best (eg training T-cells on tumor cells outside the body and then reinserting them) to work around the low immune responses of old people. I think their main area of investigation is trying to optimise the conditions under which T-cells replicate the longest.

It says the average number of population doublings (PD) of a T-cell in vitro before it becomes senescent, when externally stimulated, is 17, but 33 for cells that manage to get "established" (ie they get to a million cells). Seems like a very arbitrary cutoff but it better matches the numbers in the previous paper (25-40). The longest living ones reach 80 PDs on average and their record is around 170. They don't know why the large variability exists. The age of the person they were taking from doesn't seem to be one of the important variables. Longevity of CD34+ stem cells differentiated in vitro is no different to that of mature CD3+ cells.

They then switch to the link between telomeres and senescence. Fibroblast telomere length is directly proportional to replicative capacity. They say that this might apply to lymphocytes since the telomere lengths of human blood cells ex vivo are related to donor age, and the rate of telomere shortening with each doubling is about the same as for fibroblasts (120 bp per cell doubling). To me this would contradict what they said before that the replicative longevity was not related to the age of the donor, unless they mean blood cells other than T-cells.

In experiments by other people (Weng, Levine, June, et al) they found that CD4+ memory cells have shorter telomeres than naive cells, and that the difference is independent of the age of the donor. Telomere length decreases during autocrine replication of both of these and naive cells have higher replicative longevity than memory cells. The authors of this paper say this might not give the same results if externally stimulated replication was being used, since this can go on for way longer than the capacity for the cells to secrete interleukin-2, which triggers replication under autocrine replication, and that it doesn't necessarily follow that telomere length is the determining cause of senescence. Telomerase activity is upregulated in T cells when stimulated with CD3 and CD28 simultaneously but this might not happen optimally under various experimental setups, and might not happen optimally in-vivo due to decreased expression of CD28 with age. This, they say, might be the driving mechanism to senescence.

From small experiments they ran on oldish (<35 PD) and older (>43 PD) CD4+ cells, they noticed an upregulation of three mitotic inhibitors (p16-INK4alpha, p21-WAF, and p27-kip1) which suggest that upregulation of mitotic inhibitors might be an alternative hypothesis as the cause of senescence.
)))

Abstract follows:

Replicative senescence may compromise T cell-dependent immune responses to intermittent or chronic antigenic stimulation. While the impact of senescence in vivo remains hard to ascertain, clonal cultures of T cells in vitro provide models for longitudinal studies of aging in well-defined populations. Functional and phenotypic studies as well as investigations into average and maximal longevity of T cells can be performed conveniently with these cloned cells (the former in fact only with cloned cells). Many of the age-associated alterations observed during culture in vitro have also been noted ex vivo in T cells from the elderly.

Moreover, under circumstances where large numbers of antigen- and function-specific T cells may be required, for example for adoptive immunotherapy, the in vitro longevity of the cells may be critically important to successful outcome. These considerations are discussed in the following commentary in the context of immunotherapy of cancer.

Rest of Volume 2, Issue 1

2010-10-17T14:09:00.001+11:00

The rest of issue 1 of 1999 consists of:

A report on the 51st annual meeting of the gerontology society of America.

A review of:

Brocklehurst's TextBook of Geriatric Medicine and Gerontology, 5th edition, by R Tallis, H Fillit and JC Brocklehurst (one-stop shop for gerontology, glowing, must have).
Darwin's Spectre: Evolutionary Biology in the Modern World, by MR Rose (popular science of effects of evolution on aging)
A Means to an End: The Biological Basis of Aging and Death, by WR Clark (good)
Age Right: Turn Back the Clock with a Proven Personalized Anti-Aging Program, by K Ullis and G Ptacek (information from sports medicine about aging)
Aging in the Thrid Millenium, by EL Schneider (a paper in Science)
Nutrition and longevity: The Johns Hopkins White Papers, by S Margolis and LB Wilder (summary of benefits and risks of various suplements and foods)

Some announcements of research grants by the American Federation of Aging Research.

The usual other sections: web watch, literature watch and calendar.

The Telomere Shortening Signal May Be Explained by a Fountain Mechanism Modulating the Expression of Eukaryotic Genes

2010-10-17T02:42:00.003+11:00

Summary: Speculation on the mechanism involved in telomere-shortening bringing about cell senescence

Interestingness: 4

Paper by AM Olovnikov in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.

(((
This dude hypothesised that telomere shortening was the trigger for cell senescence and the existence of telomerase back in the 70s. He now gets to publish whatever he wants about telomeres like the hypothesis in this paper. By the present time (2010) biologists probably know if the theory has any merit but I don't, so to me it's still interesting. The idea is more about basic cell biology than about aging. Its only link with aging is that it explains cell senescence via telomere shortening.

The theory tries to explain how it is that telomere shortening causes senescence. It proposes that some bits of RNA bind to and open Ca2+ and Zn2+ channels on the nuclear membrane, and that the influxes of these ions into the nucleus are critical to the transcription of some/most genes. When telomeres shorten, they would physically pull genes near the telomeres out of the areas where these ion influxes happen and therefore they would stop being transcribed, or at least their transcription patterns would be significantly altered. From what I can tell, the specific bits of RNA, which he calls fountain RNAs (fRNAs), and the importance of the ions to transcription are both speculation.

He says that the location and orientation of the chromosomes between G1 and S phase are nonrandom. The telomeres attach to the nuclear membrane, and the bits of attachment are a reinforced section of the membrane that lack the ion channels in question. As the genes near the telomeres get pulled in closer to the membrane, they would also miss out on the ions.

The fRNAs would be composed of two sections, one that would bind to a section of the genome close to the genes that are going to be induced by the ions, and the other section to the ion channels. The sections of the genome to which the fRNA binds to are called converters. The section of the fRNAs that bind to them would vary depending on which section of the genome the fRNA is meant to stimulate. The other section of the fRNA that binds to the channels, in order to open them, would be constant per channel type, Ca2+ and Zn2+ (although the choice of these two doesn't seem central to the theory, and Mg2+ is listed as another option), but the fRNA wouldn't be able to bind to the channel without having first bound to its converter. The activation of the bits of DNA that code for the fRNAs themselves, called modulators, could themselves be controlled by the ionic fluxes so all sorts of feedback loops and modulation of gene expression would exist.

I had problems distinguishing which bits of the paper were speculation and which parts are presented as evidence. From what I can tell, the following are some of the snippets given as supporting evidence for the theory:

Ca2+ can increase both transcriptional activity and mRNA stability, increases promoters and RNA levels
There are Ca2+ releasing channels in the inner nuclear membrane and the nuclear envelope has a store of Ca2+
Zn2+ involvement in zinc fingers, and their involvement in everything DNA
Explains the long spacers between genes as spacers decoupling the ionic activation between the genes

)))

Abstract follows:

We propose a possible mechanism for the telomere shortening signal. The suggested solution of this as yet unsolved enigma—how cell senescence is causally linked to telomere short-ening—is based on a "fountain theory" of modulation of eukaryotic gene expression, in which gene expression is modulated by ionic channels of the inner nuclear membrane. These Ca2+ and Zn2+ channels are opened transiently through the action of a special small nuclear RNA (the fountain RNA or fRNA) on the ionic channels as conformational changes of the fRNA and channel-forming protein occur. Specific Ca2+ and Zn2+ ion channels allow these ions to pass from the perinuclear lumen to the nucleoplasmic gene surroundings. The resultant change of ionic concentration in close vicinity to certain genes, in turn, will alter some in- properties (e.g., mRNA stability, transcript maturation, chromatin configuration, transcriptional activity, and so forth).

Such fRNA-dependent ionic "fountains," may serve as a major mechanism regulating quantitative gene (phenotypic) expression in eukaryotes. We suggest that among metal-activated transcription factors, zinc-finger nuclear proteins evolved, and they are used in the nucleus as an alternative, noncalcium, path of gene-activity modulation, by means of fRNA-dependent channels, increasing the versatility of a fountain system.

We further propose that telomeres are anchored—in a compacted state—to special reinforcing shields, which are parts of the nuclear lamina along the inner nuclear membrane. This may be particularly true between Gl and S phases of the cell cycle, when chromosomes have nonrandom allocation within a nuclear space and telomeres are compacted and serve as "spacers" between the subtelomeric chromosome and the inner nuclear membrane. Each reinforcing shield would cover a portion of the inner nuclear membrane and, in doing so, prohibit the action of fRNA-dependent ion channels, causing an ionic "dead zone" in the nuclear membrane located immediately beneath the shield. When telomeres are long (e.g., in young cells), subtelomeric genes are located at a relatively greater distance from such dead zones; when telomeres shorten and reach the critical threshold, subtelomeric genes become closer to the dead zone and are deprived of contact with active ion channels. Shortening of the telomere—and therefore of the distance of subtelomeric genes from the dead zone—alters subtelomeric gene expression, decreases the functional capabilities of the cell, and results in cell senescence.

In some species, such subtelomeric genes may encode the fRNAs themselves, in addition to structural genes. If modulator genes—coding for fRNAs—require the ion fountains for optimal expression, then other structural genes (in turn modulated by such genes) will inevitably show senescence-associated gene expression as the telomere shortens. Such an alteration of gene expression, and the consequent dysfunction in cellular homeostasis, are typical of senescing cells.

Enhanced Cholinergic Function in Aged Rats Treated with TJ-23

2010-09-27T00:30:00.002+10:00

Summary: Toki-shakuyaku-san (TJ23) given to old rats maybe increases acetylcholine churn in their striata.

Interestingness: 1

Paper by Midori Hiramatsu, Makiko Komatsu, Toshimitsu Yuzurihara, Kazuko Saitoh, Atsushi Ishige and Yasuhiro Komatsu in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.

(((
TJ-23 is a mix of herbs common in Japan. In a previous paper it was given to senescence accelerated mice to extend median lifespan. The authors gave them to adult (6 months) and old (24 months) rats. Old rats given TJ23 had increased choline acetyltransferase (enzyme that metabolises acetylcholine) activity in their stratium compared to controls. Old control rats had lower activity than adult rats. Activity in the cortex, hippocampus, midbrain, pons-medula oblongata and cerebellum didn't change between adult and old, TJ-23ed or control.

Muscarinic receptor binding (MRb) in the stratium also increased in old TJ-23 compared to control, and in both compared to adult. MRb was also higher in old cortices compared to adult. No changes elsewhere.

Finally, acetylcholinesterase (catabolyses acetycholine) was also higher in old TJ-23ed stratia compared to controls, and in both compared to adult. No changes elsewhere.

I don't think any of this means much. The authors claim antioxidant effect of TJ-23 is helping.
)))

Abstract follows:

A traditional herb ("Toki-shakuyaku-san" or TJ-23) has been reported to cause clinical improvement in patients with Alzheimer's dementia. To investigate possible neuronal mechanisms, we looked at its effect on cholinergic functions in the cortex, hippocampus, striatum, midbrain, pons-medulla oblongata, and cerebellum of rats. In the aged (compared with the adult) rat brain, we found that choline acetyltransferase (CAT) activity was decreased in the cortex and striatum; acetylcholinesterase activity was decreased in the hippocampus, mid-brain and pons-medulla oblongata and increased in the striatum; and muscarinic receptor binding was increased in the cortex and striatum. In the striatum of aged rats, TJ-23 resulted in increased choline acetyltransferase activity, muscarinic receptor binding, and acetylcholinesterase activity. TJ-23 has a significant effect on cholinergic function in the striatum of aged rats.

Characterization of the Age Changes in Brain and Liver Enzymes of Senescence-Accelerated Mice (SAM)

2010-09-25T21:14:00.001+10:00

Summary: Some enzymes and neurotransmitters have different activity in mice models of accelerated aging.

Interestingness: 1

Paper by E Bulygina, S Gallant, G Kramarenko, S Stvolinsky, M Yuneva and A Boldyrev in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.

(((
In senescence accelerated mice, prone 1 (SAMP1) compared to senescence accelerated mice, resistant 1 (SAMR1):

Mono-amine oxide b (MAOb) activity in the brain goes up as it ages. In SAMR1 it stays put.
Glutamate binding in N-methyl-D-aspartic acid (NMDA) receptors starts much lower in young mice, but climbs to be much higher as it ages
Na/K ATPase activity in the brain goes up as it ages.
Cytochrome P450 activity in the liver is consitently higher

In all of the above, young is 4 months, age tracking goes from 8-12 months. SAMP1 mice die around then.
)))

Abstract follows:

The comparative neurochemical characteristics of brain and liver membranes of senescence-accelerated mice, prone (SAMP1) and senescence-accelerated mice, resistant (SAMR1) strains were evaluated using males and females of several ages. Abnormal N-methyl-D-aspartic acid (NMDA) binding and monoamine oxidase b activity in SAMP brain membranes may promote increased accumulation of reactive oxygen species (ROS) in neurons. Na/K-adinosine triphosphatase (ATPase) and liver cytochrome P450 activities are greater in SAMP1 neurons than in SAMR1 neurons, which may reflect an adaptive tissue response to ROS accumulation.

Noradrenergic Function in the Pancreatic Islets of Streptozotocin-Diabetic Aging Rats

2010-09-20T01:52:00.001+10:00

Summary: Destroying beta-cells in the pancreas has mostly the same effects in young and old rats, but not exactly the same.

Interestingness: 1

Paper by Asha Abraham and Cheramadathikudyil S Paulose in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.

(((This is the first of most likely most of papers in which I give up even attempting a half-assed summary)))

(((After chemically destroying the beta cells in the pancreas of young and old rats and thus making them "diabetic", they measured higher glucose concentrations, higher noradrenaline receptors, higher noradrenaline concentration in the pancreas and higher binding constants of noradrenaline receptors in both young and old diabetic rats. cAMP concentration went way up in the young and a bit down in the old. This might mean something. Their guess is alpha2-adrenergic receptors get more sensitive during old age, beta-adrenergic in young rats. Alpha2-adrenergic receptors inhibit insulin release. Beta-adrenergic increase cAMP)))

Abstract follows:

We studied age-related changes in the noradrenergic function in the pancreatic islets of streptozotocin diabetic male Wistar rats. Blood glucose, norepinephrine content, noradrenergic receptor binding, and cyclic adenosine monophosphate (cAMP) content were analyzed in the pancreatic islets of these rats. In the present study, the pancreatic islets of diabetic young and old rats showed a significant increase in noradrenaline content accompanied by a significant increase in Bmax and Kd for noradrenergic receptors compared with age-matched controls. The cAMP content increased significantly in diabetic young rats, whereas, in old rats a significant decrease was seen when compared with age-matched controls. These data demonstrate that the cAMP system is inhibited in the pancreatic islets of diabetic old rats, whereas it is stimulated in diabetic young rats. This might play a role in the early recovery shown by streptozotocin-treated young rats. Also, changes in the noradrenergic function in the pancreatic islets occurring during aging might account for the increased risk of diabetes mellitus with age.

Aging: Minimizing Free Radical Damage

2010-09-12T22:53:00.005+10:00

Summary: The founder of the free radical theory of aging summarising the results that back the theory, some nice graphs, and other interesting bits of speculation.

Interestingness: 6

Paper by Denham Harman, MD, PhD, in the Journal of Anti-Aging Medicine, Volume 2, Issue 1, Spring 1999.

(((This is a summary of the current state of the free radical theory of aging (FRTA) by the guy that is introduced as the father of the FRTA. I didn't like the way it was written. I'm going to skip big chunks of it)))

(((The paper starts with a series of mortality curves over age across time for women in Sweden from the 1750s to 1992. These are cool, even if I've seen them before. They show the mortality following Gompertz function with mortality going up exponentially after around age 50 with a doubling time of about 7 years. The slope of this exponential is the same in all curves. While mortality is much lower across all ages as we get closer to the present, the line goes exponential at a younger and younger age, so that the difference in mortality at ages 70 onwards is not that big across history. So, for example, the curve for the 1900s and 1920s seem to hit the exponential proper only at age 60, while the curve for 1992 seems to be on the exponential from age 40. The left hand side of the curves, that is, the bits before we hit the exponential growth, have declined massively across history. The text mentions that in that 1992 curve, only 1.1% of all females in Sweden die before age 28 (the date at which he puts the exponential rise starting) )))

(((It continues with a couple of life expectancy graphs from the 1950s to the present for male and females in Sweden, Switzerland, the USA and Japan. The first three going up by 1-2 years per decade and Japan by 3 years per decade, from a lower base. I don't really understand what these graphs or the previous mortality curves have to do with the main theme of the article, but I like them anyway)))

The free radical theory of aging (FRTA) says that all aging and death in all living things is based on the initiation of free radical reactions, the rate of which is determined by genetics and environment. This theory was later extended (((modified?))) to say that in mitochondria-containing living things, it is the rate of initiation of free radical reactions (FRR) in the mitochondria that determines their lifespan. FRRs can be classified into initiation, a propagation chain, and termination. An antioxidant usually refers to a compound that breaks the propagation chain, or, in general, any substance that delays or inhibits oxidation in low concentrations.

The major sources of radical reactions are:

Respiratory chain
Phagocytosis
Prostaglandin synthesis
Cytochrome P-450 system
Nonenzymatic reactions of O2
Ionising radiation

Defenses against damage caused by FRR are:

Antioxidants. eg: tocopherols, carotenes
Heme-containing peroxidases. eg: catalase
Glutathione peroxidase
Superoxide dismutases (SOD)
DNA repair mechanisms

By the FRTA, slowing down FRRs would increase longevity. Studies backing this up include:

Overexpression of superoxide dismutase and catalase in fruit flies extended life span by a third.
Longer-lived strains of fruit flies, flatworms and bread mold have higher antioxidant enzyme activity than short-lived strains
Addition of 2-mercaptoethylamine (2-MEA), an antioxidant, to food increased average lifespan of LAF1 mice by 29.2% (((no idea what the characteristics of LAF1 mice are)))
2-MEA addition to food of mice mothers before mating increased lifespan of their offsprings by 15% and 8% to male and female offsprings respectively

Decreasing initiation rates of endogenous FRRs would also lead to increased longevity. The rate can be reduced by caloric reduction, compounds that compete with O2 for access to electron-rich areas of the mitochondria, compounds that bind to the respiratory chain and stop the reaction with O2, and genetic regulation of mitochondrial superoxide creation. Cutting caloric intake of rats by 40% increased average lifespan by 40% and maximal life span by 49% (((Those numbers are higher than I'm usually accustomed to))). The study also suggests a lower rate of aging for rats under caloric restriction (((ie a lower gradient on the semilog plot of age vs mortality))) (((I think the suggested link is lower amount of products to oxidise => lower total load of FRR in mitochondria))).

Only study showing antioxidant to extend maximal lifespan of mice is 2-MEA, added at 0.25% w/w to the diet of BC3F mice extended mean and maximal lifespan by 13% and 12% respectively. The study hasn't been replicated. The reason that most antioxidants fail to extend lifepan is that they have toxic effects on mitochondria at lower concentrations than those needed to slow down FRRs significantly.

The paper continues by listing the possible effects of the FRTA on specific diseases. They are:

Cancer, listing epidemiological studies suggesting vitamin C and fruits and vegetables having lower incidence
Atherosclerosis, caused by lesions that would result in higher localised concentrations of oxidation products, and oxidation of polyunsaturatid lipids, and mentioning a study of vitamin E supplementation showing a decrease of 40% in coronary artery disease (((never heard of that one. will have to look it up)))
Hypertension, mentioning a study of SOD targeted to endothelium cells lowering blood pressure in spontaneously hypertensive rats, but not in normal rats
Alzheimer's disease, listing mutations in mtDNA, mutations in amyloid precursor protein (APP), and increases in levels of APP and SOD in Down's syndrome (((I don't get how the last two are meant to relate to FRTA)))
Immune deficiency, saying some antioxidants increase immune responses
Autoimmunity, with ethoxyquin fed to a mice used for studying autoimmune disease (NZB) increasing lifespan by 32%

The gender mortality gap is also supposedly explained by the FRTA via two different effects: one is the lower stores of iron in women prior to menopause leading to less FRRs catalysed by iron, and the second (((something I don't even understand enough to describe))).

The paper finishes by claiming that a large part of the increase in lifespan in the USA since the 1960s could be attributable to the widespread use of multi-vitamins by the population (((yeah riiiiiight))).

Abstract follows:

Aging is the accumulation of changes that increase the risk of death. The major contributors after age 28 years are the endogenous chemical reactions that, collectively, produce aging changes that exponentially increase the chances for disease and death with age. These reactions constitute the "inborn aging process." This process is the major risk factor for disease and death of the 98% to 99% of cohorts still alive at age 28 in developed countries, where living conditions are now near optimum.

The Free Radical Theory of Aging (FRTA) and, simultaneously, the discovery of the ubiquitous, important involvement of endogenous free radical reactions in the metabolism of biologic systems, arose in 1954 from a consideration of aging phenomena from the premise that a single common process, modifiable by genetic and environmental factors, was responsible for the aging and death of all living things. The FRTA postulates that the single common process is the initiation of free radical reactions. These reactions, however initiated, could be responsible for the progressive deterioration of biologic systems with time because of their inherent ability to produce random change. The theory was extended in 1972 with the suggestion that the life span was largely determined by the rate of free radical damage to the mitochondria.

The FRTA suggests the possibility that measures to decrease the rate of initiation and/or the chain length of free radical reactions may, at least in some cases, decrease the rate of reactions that produce aging changes without significantly depressing those involved in maintenance and function. Many studies support this possibility.

Applications of the FRTA have been fruitful. For example, it is a useful guide to efforts to increase the life span, and it provides plausible explanations for the aging phenomenon (e.g., the association of disease with age as well as insight into pathogenesis; the gender gap; the association between events in early life and late onset disease; and the shortening of telomeres with cell division). Further, it is reasonable to expect on the basis of animal and epidemiologic studies that the increasing population-wide use of antioxidant supplements and ingestion of foods high in antioxidant capacity over the past 40 years have helped to increase the functional life span of the population by contributing significantly to the decline in "free radical" diseases, to increases in the fraction of elderly, and to the decline in chronic disability in this group.

Rest of Volume 1, Issue 4

2010-08-14T23:01:00.002+10:00

The rest of issue 4 consists of:

A review of a book called Mitochondrial DNA Mutations In Aging, Disease And Cancer, mostly positive.

Three article reviews:

Aging health risks and cumulative disability, by Vita AJ, Terry RB, Hubert HB, and Fries JF. Gives evidence in support of the compression of morbidity hypothesis, showing lower disability rates for people with lower health risks in the 8 years to the 75 year mark, but similar life expectancy at age 85 if they get there.
Telomerase and the Aging Cell: Implications for Human Health, by Fossel M. Review of experiments upregulating telomerase in-vitro.
Fantastic Voyage in the San Francisco Magazine, by Berger K. About Geron.

The usual other sections: web watch, literature watch and calendar.

Risks of Testosterone Treatment in Elderly Men

2010-08-14T22:22:00.002+10:00

Summary: The risks of testosterone supplementation aren't a big deal either.

Interestingness: 1

Paper by Peter J Snyder, MD in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is a subset of the previous paper, focusing on risks.)))

Higher testosterone concentration seems to be related to higher probability of having prostate cancer. In one study, testosterone measurements for about 22000 men were taken and those men were tracked for the following ten years. 222 of those men that developed prostate cancer were age matched with 444 non-prostate cancer men. Men with the highest quartile of testosterone concentration were twice as likely to have developed cancer as those in the lowest quartile. Those with the highest quartile of sex hormone binding globulin (SHBG) which binds testosterone were half as likely to have developed as those in the lowest quartile.

Prostate cancer is testosterone dependent (((not shown))). Autopsies of 249 men showed 41% of those in their 50s and 63% of those in their 60s had occult (((unknown))) prostate cancer (((hardcore numbers))).

Prostate size also seems to be dependent on dihydrotestosterone, which is created from testosterone by 5alpha reductase. Blocking of 5alpha reductase with finasteride reduced prostate size, increased maximal urinary flow rate and decreased symptoms of benign prostatic hyperplasia (BPH) (((enlarged prostate))) compared to placebo.

Testosterone probably lowers high density lipoprotein (HDL) concentrations. In one study, inhibiting testosterone release with an antagonist of gonadotropin-releasing hormone (GnRH) raised HDL, but blocking testosterone release and injecting testosterone simultaneously didn't.

Testosterone replacement in hypogonadal men also increased apnea episodes and increased concentration of haemoglobin in small studies.

(((Summary: Testosterone wasn't good to begin with)))

Abstract follows:

As men age, serum testosterone concentrations fall, and they experience decreases in energy, bone mineral density, and muscle strength, which at least in part may be due to the fall in testosterone. Consequently, testosterone treatment has been considered for aging men. The possible benefits of testosterone treatment of aging men should be balanced, however, by its possible deleterious effects, including an increase in the prevalence of prostate cancer, benign prostatic hyperplasia, sleep apnea, lipid abnormalities, erythrocytosis, and hypercoagulability, all of which to some degree are testosterone dependent.

Androgens in Aging Men: Do Men Benefit from Testosterone Replacement?

2010-08-09T21:19:00.003+10:00

Summary: Shit-all good comes from testosterone supplementation in old men.

Interestingness: 1

Paper by Carrie J Bagatell, MD and William J Bremner, MD, PhD in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is the male equivalent of the previous two posts. Testosterone supplementation is much less used than estrogen and thus much less is known about it. This paper is short on numbers and graphs, so not much to report)))

Total and free testosterone levels decline during aging in men. Young men with low gonad activity (((and therefore low testosterone levels))) show lower muscle mass and higher fat content than men with normal activity. Supplementing with androgens in those men increases muscle mass, decreases fat content, increases libido and frequency of erections and ejaculation (((don't know if enough to put them back to standard levels))). This increase in sexual function does not work with older men though (((that seems to be the summary of the whole paper: it works for hypogonodal young men, it doesn't work for old men))), and most older men with erectile dysfunction do not have low levels of testosterone. Use of gonadotropin-releasing hormone analogs (GnRH) triggers a similar condition to having low gonad activity (((makes no sense to me with that name))). When this is done in older men (((prostate cancer??))), it triggers lower bone density.

In a very small study, long term use of testosterone increased libido (((partially contradicting the previous paragraph))). It did not help cognition in a different study. Improvement in hand grip strength was noted in many studies. No benefit in bone density or good bone markers were noted on older men under androgen supplementation.

Risks also don't appear to be a big deal: decreases in high-density lipoprotein (HDL) in young men and some worries about it contributing to the growth of prostate cancers exist. In older men, hematocrit and hemoglobin fraction increase a lot, with 25% of test cases developing polycythemia (((disease of the blood where too high a fraction of the volume of blood is made up of red blood cells))).

The authors think that selective androgen receptor modulators would be useful, and some are being studied in primate models (((but I fail to see the benefits))).

(((There's too few benefits shown by testosterone to pay much attention to it)))

Abstract follows:

Most cross-sectional studies and one recent longitudinal study suggest that testosterone levels in healthy men decline slowly and that this decline begins during middle age. The decline in "free" or unbound testosterone is greater than the decline in total testosterone levels. Physiologic sequellae of lower testosterone levels may include a decrease in muscle mass, increase in body fat, decreased bone density, and a variety of changes in sexual function. Long-term studies of androgen replacement are currently in progress. Short-term studies suggest that, for some men, androgen replacement may increase libido and muscle strength and decrease abdominal fat. The available data suggest that androgens do not generally worsen symptoms of prostatic hypertrophy or stimulate the development of prostate cancer. Lipid profiles may be slightly improved during androgen replacement, but the long-term effects of androgens on the cardiovascular system are unknown. Hematocrit and hemoglobin frequently rise in response to androgen administration. In most men, these increases are small, but in some men they can be significant. Liver toxicity can occur with use of alkylated androgens, but it is extremely rare with the use of testosterone esters. Men receiving androgens should have periodic monitoring of their prostate, serum prostate-specific antigen level, lipids, hematocrit, and liver functions. Future androgens, with minimal effects on the prostate, may become available for clinical use.

Hormones and Breast Cancer

2010-08-08T23:43:00.003+10:00

Summary: Estrogen replacement hormones cause breast cancer

Interestingness: 2

Paper by Graham A Colditz, MD, Dr.Ph, FAFPHM in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is a subset of the previous one, with a few more details. This summary is going to be very short)))

Higher levels of estrogens in postmenopausal women are associated with higher incidence of breast cancer and lower breast cancer survival. In a smallish study, 130 women, risk of breast cancer was 3.2 (1.4-7.0) times higher among postmenopausal women in the highest quartile of estrogen levels compared with those in the lowest. Other studies give similar results. Yet other studies suggest that risk of breast cancer is associated linearly with accumulated cell divisions in breast epithelial cells.

Since women with the lowest levels of postmenopausal estrogen are more likely to get hormone replacement therapy (HRT), the effect of HRT on breast cancer will be partially hidden if not correcting for this factor. Also, because lower age of menopause is associated with a much lower risk of breast cancer, women on HRT have a lower risk of breast cancer than non-users of the same age (((that only makes sense to me if the non-user hasn't undergone menopause, or is it that the effect of later menopause enough to override total accumulated effect of HRT of all practical time spans?))). A large meta-analysis, of a total of 50000 breast cancer cases and 100000 non-breast cancer cases, estimates risk of breast cancer increases 2.3% (1.1-3.6) per year on HRT. Most studies in the meta-analysis were only using estrogens (((but other parts of the paper claim that progestins wouldn't help and might worsen the risk))). From the meta-analysis, they estimated that for every 1000 postmenopausal women who start HRT at 50, six more will get breast cancer if they use it for ten years, and 12 more if they use it for 15.

(((Summary: again, not particularly influential in life expectancy. Also, I think I remember some big study that came up in the last couple of years, maybe 2008, that most likely supercedes anything in the last couple of posts. This is the main reason I gave both these papers a low interestingness rating. The CHD benefits, if I remember correctly, turned out not to be real)))

Abstract follows:

The role of estrogen replacement therapy in the cause of breast cancer continues to be debated. This article reviews the literature on hormones and breast cancer, including articles on cell proliferation, endogenous hormone levels, epidemiologic studies, and the risk of breast cancer. A cause of cancer is defined as a factor that increases the probability that cancer will develop in an individual. A causal relationship between female hormones and breast cancer is consistently suggested by several lines of argument, especially the relationship between duration of use and risk of breast cancer, dose-response with endogenous hormone levels, and biologic plausibility. The magnitude of the increase in risk of breast cancer caused by using hormone replacement is comparable to that seen in delayed menopause. The positive correlation between endogenous hormone levels and risk of breast cancer supports a causal relationship between exogenous hormone use and breast cancer. The increase in risk of breast cancer with increasing duration of use, which does not vary substantially across studies, offers further evidence for a causal relationship. The reduction in mortality rate with short-term use of hormones, although strongest among women with risk factors for cardiovascular disease, adds complexity to the risk-to-benefit trade-off associated with long-term hormone use. All evidence supports a causal relationship between both endogenous estrogens and the use of estrogens and progestins, and breast cancer incidence in postmenopausal women. Hormones act to promote the late stages of carcinogenesis among postmenopausal women and to facilitate proliferation of malignant cells. Strategies for relief of menopausal symptoms and long-term prevention of osteoporosis and heart disease that do not cause breast cancer are urgently needed.

Estrogen Therapy For Menopause

2010-08-07T22:45:00.002+10:00

Summary: Review of health benefits and risks of estrogen on post-menopausal women

Interestingness: 2

Paper by Kathryn A Martin MD in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((This paper is a dense but nicely written review of the effects of estrogen on post-menopausal women. It is hard to summarise since it already is a summary. I'm going to pick out interesting snippets)))

The postmenopausal ovary produces almost no estrogen. Estrogen in postmenopausal women is mainly produced by conversion of androstendedione (((don't know where that happens))). Average age of menopause is 51 (((or was back then, and probably in the USA. Last third of their life spent with assumedly little estrogen, although there is no plot or numbers of levels of estrogen in the paper))).

Some problems associated with this drop in estrogen are vaginal dryness, pain during sex and symptoms similar to urinary tract infection. Hot flushes are also experienced by 75% of women which commonly leads to insomnia and its derivative problems. Osteoporosis is also common, and the risk of coronary heart disease (CHD) goes up by a lot (((doesn't say))). Estrogen in hormone replacement therapy (HRT) helps with the flushes, and the vaginal and urinary tract problems. It also stops the osteoporosis and decreases the risk of CHD (((by 50% it seems from later in the paper))) when given in doses equivalent to 625 micrograms in conjugated form, or equivalent. Although a 15-year study on postmenopausal women did not notice any difference between estrogen and non-estrogen users with respect to cognitive function, a meta-analysis of epidemiological and control studies claims the risk of dementia for estrogen users to be 0.71 (0.53-0.96) compared to non-users (((but the paper abstract discourages that conclusion))).

Five types of HRT are used:

estrogen only (625 micrograms conjugated)
cyclic combined: estrogen (625 micrograms conjugated) for days 1-25 of the month, medroxy-progesterone acetate (MPA, a progestin), 5mg, days 13-25. This is the most popular option.
continuous combined: estrogen (625 micrograms conjugated), and MPA (2.5 mg) without breaks.
other estrogen preparations: Different variants all equivalent to the 625 micrograms of conjugated estrogen. Some as vaginal creams.
low dose contraceptives: these are mostly used by women around menopause time

Risks of HRT when supplying only estrogen include increased risks of gallstones, endometrial hyperplasia and cancer (((uterus))), and breast cancer. The increase in uterine cancer can be cancelled by adding in progestin, but it doesn't seem to help with the breast cancer. Breast cancer risk is a factor of 1.35 (1.21-1.49) compared to baseline after 5 years of HRT.

Estrogen raises high density lipoprotein (HDL) and decreases low-density lipoprotein (LDL), but progestin has the opposite effect (((although it later says that women under the combined therapy had HDL levels similar to women only taking estrogen, and that the protective effects against CHD were similar in both groups))). Estrogen suppresses platelet function and is a potent vasodilator. It also improved 10-year survival of women with narrowing of their coronary arteries. On a different study though, HRT did not improve survival of women with CHD and risk of events (((heart attacks?))) was higher during the first year compared to placebo.

Some new substances can act as estrogen agonists in some tissue and estrogen antagonists in others. Raloxifene, for example, appeared, in one study, to have an estrogen agonist effect with respect to osteoporosis and lipid profile, but antagonist with respect to breast and endometrial tissue. Even though it affected lipids in a positive way, it did not show improvement with respect to artherosclerosis.

(((Summary: I don't think it'd have a major effect on longevity)))

Abstract follows:

The medical management of menopause continues to be a topic of controversy. Although many of the benefits of estrogen therapy have been well established (treatment of estrogendeficiency symptoms, prevention of osteoporosis, and prevention of coronary heart disease), the potential risks of breast cancer are of great concern. Although many postmenopausal women are candidates for hormone replacement therapy (HRT), many choose not to take it because of fear of breast cancer or concerns about potential side effects and continued menstrual bleeding. Therefore, making choices about potential therapies after menopause can be a difficult one for both women and their health care providers. An important principle of HRT is the notion of short-term versus long-term use, as the goals of both therapy and riskbenefit profiles are different. Although most perimenopausal and postmenopausal women are candidates for short-term HRT (with the exception of those with a history of breast cancer), no general consensus is found regarding who should or should not receive long-term HRT. Other new areas of clinical investigation in the field of menopause and HRT include the possible impact of estrogen on cognitive function, the role of exogenous androgen replacement for libido, and the role of a new class of drugs known as "selective estrogen receptor modulators" (SERMs). Given this rapidly changing field, it is likely that the medical management of menopause will continue to evolve in the coming years.

2-Deoxy-D-Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction

2010-07-13T22:21:00.002+10:00

Summary: There's almost nothing interesting to say about 2-deoxy-D-glucose yet.

Interestingness: 1

Paper by Mark A Lane, Donald K Ingram and George S Roth in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((The previous paper was about the effects of calorie restriction (CR). This one is by the same group of people, about a potential CR mimic (ie a substance that has similar effects to practicing CR). I assume there will be many more of these type of papers through the rest of the journal history)))

Since CR is unlikely to be taken up by a large proportion of the population, it'd be good to find substances that trigger the same effects. While the mechanism by which CR extends lifespan is unknown, there are many hypotheses, including reduced oxidative stress, elevated glucocorticoids, reduction in body temperature, and altered glucose metabolism. This study looks at this last one by introducing a substance into rats diet, 2-deoxy-D-glucose (2DG), that is a competitive inhibitor of glycolysis. 2DG is phosphorylated by hexokinase (((energy-consuming step))), but the process stops there (((no energy released))).

120 rats were split into four groups of 25 and one group of 20, the smaller group acting as a control, three other groups being fed 0.2, 0.4 and 0.6 percent 2DG, and the final group matched to consume only as much food as the group taking the smallest amount out of the rest (((to control for direct CR effects I think))). The study lasted 24 weeks and started when the rats were 6 weeks old.

Since four rats died in the first 5 weeks in the high dose group, the diet was modified to be one week of 0.6% 2DG intermixed with a week free of 2DG (((hack))). There was one death in each of the two other dose groups but they were not attributed to 2DG.

In all but two of the 2DG rats, autopsies of rats killed at the half way point and at the end of the study showed vacuoles in their heart (((holes of fluid?))). Food intake was slightly (5%) lower in the 2DG rats throughout the study. Weight was also a lot lower throughout in the higher 2DG dose rats, and in the pair matched (((about 10% from the graph))), and a little lower in the 0.4% group (((5% or so))), with very low variance. Temperature was also lower in the two higher dose groups (((by about 0.25 degrees from the graph, even though the text says 0.5 degrees))), but variance was higher. Finally, insulin levels were lower in the 0.4% dose group at both autopsy points (((by about 25% with respect to controls))), but no statistical effect on glucose (((but still a bit lower))).

(((0.6% kills, and 0.2% has no effect, and they all leave holes in the heart. The supposedly beneficial effects in the 0.4% group are not impressive (lower weight, slightly lower temperature, lower insulin) and were matched by the pair-matched group in all but temperature. Lifespan data would be nice, but until then there's nothing to see here)))

Abstract follows:

Calorie restriction (CR) extends the life span, slows the rate of aging, and delays the onset of many age-related diseases in short-lived laboratory species, primarily rodents. Although it is unknown if CR extends the life span in long-lived mammals, findings emerging from CR studies in rhesus monkeys agree with the extensive rodent literature that suggests this intervention can have beneficial effects in primates. Even if CR is shown to extend the life span in long-lived species, it is unlikely that the 30% to 40% reduction in intake used typically in this paradigm would become a widespread practice in humans. An alternative strategy may be to design interventions that "mimic" biologic effects of CR but do not significantly reduce food intake. The present study was designed to test the hypothesis that administration of a glucose analogue, 2-deoxy-D-glucose (2-DG) would mimic certain effects of CR. Specifically, we administered three doses (0.2%, 0.4%, and 0.6% w/w) of 2-DG in the diet to male Fischer-344 rats. Rats fed 0.4% 2-DG weighed slightly less than controls and exhibited significant reductions in body temperature and fasting serum insulin levels. Our findings suggest that it might be possible to design interventions to mimic certain metabolic effects, and perhaps other beneficial effects of CR such as life span extension and retardation of physiologic aging.

Calorie Restriction in Nonhuman Primates: Implications for Age-Related Disease Risk

2010-06-27T16:58:00.004+10:00

Summary: Calorie restriction (CR) probably reduces diabetes and heart disease markers in rhesus monkeys. It also probably maintains DHEAS levels.

Interestingness: 3

Paper by Mark A Lane, Angela Black, Donald K Ingram and George S Roth in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((I had already read a follow up paper published in 2010, so I knew the movie continued to go relatively well, but not fantastically so. That detracted from the excitement. This paper focuses on the effects of CR on diabetes and cardiovascular disease, and by measuring biomarkers in the latter case. Mortality would have been more interesting, but most likely the numbers would have been too low at such an early stage of the study. In any case, since CR seems to be the only "easy" intervention to make a difference for now, it's still a relatively interesting read.)))

Calorie restriction (CR) (((lowering food calorie intake by about 30% while maintaining good nutrition))) extends lifespan in lots of short-lived species, including rotifers (((little water animals, about half a milimetre long))), water fleas (((same))), fish, spiders, hamsters, mice and rats. Doing the relevant controlled experiment in humans would be tricky and take a long time. Doing it on rhesus monkeys is a close approximation and until animal-liberationists bomb them, less problematic.

Four experiments are reviewed. Two proper long-term randomised control studies on groups of 200 and 80 monkeys, the first one (NIA) in its 12th year, starting on sets of 1-2 year olds, 3-5 year olds and of > 17 year old monkeys, and the second one (UW) on 8-14 year old monkeys (((lifespan of rhesus monkeys is around 40 years))). One of the others (BGWF) is a short term (4 years) study on the cardiovascular effects of CR on 32 8-year old crab-eating macaques, the study being in its second year. The final study (UMB) is on 8 weight-stabilised rhesus monkeys which by coincidence happened to have a food regime similar to CR monkeys.

From the NIA study, the following effects are seen on the monkeys:
Decreases in:

Body weight

Fat and lean mass

Trunk to leg fat ratio

Fasting glucose/insulin

Metabolic rate (short term)

Body temperature

Triglycerides

IGF-1/growth hormone

IL-6

Rate of decline of DHEAS

Lymphocyte number

Increases in:

Insulin sensitivity

HDL_2B

Time to sexual maturation

Time to skeletal maturation (((table says opposite on these last two, but text is clearer)))

No changes in:

Metabolic rate (long term)

Locomotion

Testosterone

Estradiol, LH, FSH, Progesterone

Wound closure rate

Clonal proliferation

Beta-galactidase senescent cells

Lymphocyte calcium response

All of these agree with rodent CR studies, in the cases where the rodent data is available, except for the lymphocyte calcium response.

(((That could really do as a summary, but the paper had another eight pages to go)))

With regards to diabetes and glucose regulation, there is another handy table summarising all the studies:

Both big studies agree in all of the following results:

Decrease in fasting glucose

Decrease in fasting insulin

Decrease in insulin response

Increase in insulin sensitivity

No increase in glucose tolerance

The small coincidental study disagrees with regards to fasting glucose and glucose tolerance, and the short term study with respect to fasting insulin.

The effect of CR on cardiovascular disease doesn't appear to be as clearly beneficial. While triglyceride levels decreased the effect on LDL, HDL and total cholesterol was not statistically significant. By analysing HDL fractions, an increase in HDL_2B levels was measured. In the female subset of monkeys, lower total cholesterol and blood pressure was measured in CR monkeys compared to control monkeys. Lower arterial stiffness was also measured in male CR monkeys.

(((A graph at the end shows lower rate of decline of DHEAS (dehydroepiandrosterone-sulfate) in male CR monkeys, which would probably be the most interesting part of the paper. The framing of the graph seems a bit too purposeful though (why only show 3 years between 6 and 9 years of age?) )))

Abstract follows:

Calorie restriction (CR)—undernutrition without malnutrition—ranks among the most reproducible and widely used research paradigms in gerontologic research. This intervention is the only manipulation that has been shown consistently to extend the life span, delay onset and slow tumor progression, and retard physiologic aging in many systems. A large body of literature exists documenting these remarkable effects in such diverse short-lived species as rotifers, water fleas, fish, spiders, hamsters, and laboratory mice and rats. However, it is not known if CR has similar effects in longer-lived species more closely related to humans. Two major studies in rhesus monkeys, one at the National Institute on Aging and the other at the University of Wisconsin, were begun several years ago to address this question. Two similar studies focusing mostly on disease end points such as obesity, diabetes, and cardiovascular disease are also underway at the University of Maryland and Bowman-Gray School of Medicine. These studies have clearly shown that most physiologic responses assessed in monkeys on CR parallel the extensive literature on rodents. This article focuses on data related to various risk factors for age-associated diseases, in particular diabetes and cardiovascular disease. Although it will be several more years before definitive results regarding life span are available, emerging data from the monkey studies strongly suggest that CR alters several disease risk factors and may affect postmaturational aging in some systems. Therefore, it is likely that this nutritional intervention will result in at least moderate increases in the primate life span related to amelioration of certain age-related diseases and their complications.

Immunosenescence: Analysis and Genetic Modulation of Replicative Senescence in T Cells

2010-06-20T16:21:00.001+10:00

Summary: T-cell senescence might be an important part of aging.

Interestingness: 4

Paper by Rita B Effros and Hector F Valenzuela in the Journal of Anti-Aging Medicine, Volume 1, Issue 4, Winter 1998.

(((These people want to try out upregulating telomerase in old T-cells)))

A major part of the function of T- and B-lymphocytes is based on replication. When differentiating from hematopoietic stem cells, the molecules or particles which the future mature lymphocytes are sensitive to (aka antigens) are encoded by a few sequences of DNA which are combined in random fashion. This makes the system potentially sensitive to hundreds of millions of different antigens. When an antigen is bound by a lymphocyte, the lymphocyte starts replicating, making identical clones (ie their receptor which sensed the antigen is not modified). When the antigen is no longer found in the environment, most of the lymphocytes disappear, but a few memory lymphocytes with the particular receptor remain so that the system can be revved up faster the next time that specific antigen is in the system.

Senescent T-cells can be generated in vitro by repeatedly exposing them to interleukin-2 (IL-2), a T-cell specific growth factor. After about 25-40 replications, they become senescent (ie they stop replicating). Fibroblasts (connective tissue cells) also become senescent after about 21 replications.

The receptor CD28 is not expressed in 95% of CD8+ senescent T-cells, and in all CD4+ senescent T-cells. Without CD28 costimulation, antigen binding doesn't lead to cell replication. CD28 signal transduction upregulates IL-2. It is also hypothesised to upregulate telomerase activity. Telomerase is very active in lymphocytes under certain conditions: in developing T-cells in the thymus and in lymphoid organs, when stimulated with mitogens (particles that upregulate replication), or by combination of antibodies to CD3 and CD28. When CD28 binding is inhibited, telomerase remains inactive even if there is strong stimulation of its T-cell antigen receptor (TCR). Even though telomerase is sometimes active in T-cells, senescent T-cells have short telomeres typical of other senescent cells. When split into CD28+ and CD28- T-cells, CD28- cells have shorter telomeres and lower replicative capacity when stimulated.

In vivo, CD28- T-cells are 1% fraction of neonates' total T-cells, 30% of (average) 78 year olds, 40% of people over 100, and 50% of HIV patients. Telomere lengths also shorten in peripheral blood lymphocytes as age increases. This loss of CD28 and shortening of telomeres is more pronounced in CD8+ cells, which specialise in anti-viral and anti-tumor activity, than in CD4+ cells (((doesn't this contradict the earlier numbers of 95% in CD8 and all in CD4?))). This could be due to infections by viruses that do not disappear (eg Epstein-Barr, varicella) or by repeated infections (eg influenza).

As people age, memory T-cells become a larger fraction of all T-cells. Senescence is also more common among memory cells. Non-senescent T-cells in old people respond to activation as strongly as those in young people.

During normal immune system activity, once the antigen dissapears from the system, most T-cells die by apoptosis. Senescent cells respond to apoptotic signals much less strongly, especially among CD8+ cells. These leftovers memory T-cells could be crowding out the production of new more useful T-cells. In calorie restricted mice, apoptotic response is maintained at youthful levels.

Abstract follows:

Immunosenescence, which constitutes one of the most dramatic physiologic changes associated with aging, may account for the increased susceptibility to infections and the high incidence of cancer in the elderly. A novel facet of T-cell biology has been recently identified that may exert a considerable impact on immune control over infections and cancer during aging. Cell culture studies have shown that after repeated rounds of antigen-driven proliferation, T lymphocytes eventually reach replicative senescence, an irreversible nonproliferative state associated with the loss of expression of a critical T-cell signaling molecule. Identification of this unique, cell-specific marker of senescence has facilitated the documentation and analysis of replicative senescence within the immune system in vivo during aging. This article summarizes the features of T-cell replicative senescence and highlights several genetic strategies that may reverse the process. The ability to manipulate T-cell replicative senescence may ultimately provide a fresh therapeutic approach to extend the years of immunologie "coverage" in the elderly.

Rest of Volume 1, Issue 3

2010-06-06T23:22:00.000+10:00

The rest of the third issue consists of a favorable review of a popular science book about aging by Ben Bova, a summary of a telomeres and telomerase conference, an overview of the Gordon conference on aging, a review of a paper on the reasons for longer female longevity compared to male longevity, and the usual literature and web watch.

The review of the paper on longer female longevity doesn't mention anything new (hypotheses: estrogen as protective substance, less risky behaviour, two X chromosomes acting as backup, blood loss through menstruation lowering iron load)

The Gordon conference is an interesting idea. People show unpublished material, with the condition that noone else is meant to publish about it. Because of this condition though, the overview was very high level.

Interesting bits from the telomerase conference:

Three models of the link between telomeres and cell senescence: short telomeres trigger a DNA-damage response; proteins that bind to longer telomeres get released, regulate transcription somehow; the area around the telomeres are tightly bound and therefore those genes suppressed when the telomeres are long, so when they shorten they become active.
90% of all malignant tissue has active telomerase
T cells replicated to exhaustion lack expression of CD28. T cells lacking expression of CD28 become increasingly prevalent in vivo during aging.

Circadian Hyper-Amplitude-Tension (CHAT): A Disease Risk Syndrome of Anti-Aging Medicine

2010-06-06T21:33:00.000+10:00

Summary: Large circadian changes in blood pressure are possibly a very high risk factor for ischemic stroke. More data needed.

Interestingness: 2

Paper by Franz Halberg, Germaine Cornélissen, Julia Halberg, Henry Fink, Chen-Huan Chen, Kuniaki Otsuka, Yoshihiko Watanabe, Yuji Kumagai, Elena V. Syutkina, Terukazu Kawasaki, Keiko Uezono, Ziyan Zhao and Othild Schwartzkopff in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.

(((Back from hiatus. I found this paper more interesting than the usual, mainly because I hadn't heard about the topic before. Wikipedia calls the main author of this paper the founder of (American) chronobiology, and this paper seems to be part of the field. I'd never heard of it until now. The graph is full of what now would be considered retro-graphs which do help a lot)))

(((The language used in the paper is a bit salesmanish. It stresses two cases in which circadian hyper-amplitude-tension (CHAT) was diagnosed, with one case being treated, and the other not, and the large amount of money lost in treating the negative outcomes of the second case. I wouldn't be surprised if the field is considered quackish by academics)))

(((Switching back to paper mode))) The paper highlights the negative effects of having a high range (or double amplitude) (ie maximum value minus minimum value) in the smoothed measurements of blood pressure across the day. This is not about the difference between systolic and diastolic pressure but about comparing systolic vs systolic, or diastolic vs diastolic, throughout the day, and determining whether the differences are too high. The treatment recommended, briefly, consists of relaxation techniques and timed doses of anti-hypertension drugs.

To measure the double amplitude, a sine wave is fitted to the raw measurements which are taken across many days (((the more days the merrier it seems, but the ones mentioned seemed to fluctuate between 2 and 20 days))). (((least square error regression of the following formula:

(image taken from http://www.cbi.dongnocchi.it/glossary/Cosinor.html). The MESOR is the midline-estimating statistic of rhythm (some kind of mean), and the acrophase would be a phase adjustment. I think the MESOR, the amplitude, the period and the acrophase are fit simultaneously, but the period seems "seeded" to 24 hours))). Two separate curves are created, one for systolic and one for diastolic pressure. The MESOR is the value halfway between the peak and trough, and the double amplitude is the difference between the peak and trough of these curves. If the double amplitude measurement exceeds the 95th percentile for the person's particular age/gender bracket, that person is diagnosed with CHAT.

The main evidence presented as to the importance of CHAT is a study of 297 people who had their blood pressure monitored continuously for 48 hours, and then their incidence of negative vascular events recorded for six years (((Not sure what. Stroke and heart attacks I presume, but what else?))) The relative risks of the following conditions were calculated (Approximate 95% CI range in brackets):

BMI > 25kg/m^2: 0.6 (0.2-2.1)
High cholesterol: 1.0 (0.4-3)
Male: 1.7 (0.55-4.8)
Drinking: 2.5 (0.9-7.5)
Family history: 2.6 (0.6-11)
Smoking: 2.7 (1.0-8)
Age > 60: 4.7 (1.6-12)
Systolic MESOR > 130mmHg: 4.1 (1.0-16)
Systolic CHAT: 6.2 (2.2-15)
Diastolic CHAT: 8.2 (3-20)

(((The numbers of incidents were clearly quite low if the CI bars are so wide)))

Focusing on ischemic strokes, the relative risk of people with CHAT compared to people without CHAT are also much higher than 1.0 when partitioning the people into MESOR buckets, for every bucket, although in this case the CI ranges are even wider and include 1.0 in most cases. These high risk factors also remain when any of the other individual risk factors mentioned in the previous list are absent, and all with estimates higher than 5.0. Again, the ranges are big, but in this case, they do not touch 1.0.

Other studies cited are ones in which: 424 people that were measured for 24 hours, in which CHAT was related to higher left ventricular mass index; 18 11-14 year olds and the relation between CHAT and betamimetics received while in the womb; and a study of 40 rats in which CHAT preceded high MESOR by weeks.

Conclusion: More data would be nice to get so that the confidence interval ranges are tightened, and so that the findings don't feel like searching for the impressive statistic among a bunch of numbers. The relative risk values cited for stroke are impressive though. It could be a fun project over a week to check for CHAT.

Abstract follows:

Serial measurements, taken around the clock in the laboratory and clinic, can be analyzed by computer-implemented curve-fitting to assess the approximate 24-hour (circadian) variation, among other rhythmic and chaotic components of the time structure (chronome) of any variable. This approach is particularly important to quantify blood pressure variability, which renders even the most accurate single measurement into a snapshot on a roller coaster. A seemingly acceptable blood pressure can be particularly misleading when accompanied by the recommendation of another check-up in 2 years, which is the official position of the World Health Organization. An overswinging of the blood pressure along the 24-hour scale may then be missed. This excessive circadian amplitude, called "circadian hyper-amplitude-tension" (CHAT), constitutes a new disease risk syndrome, warranting screening, diagnosis, and treatment. With or without the midline-estimating statistic of rhythm (MESOR) (i.e., the [chronome-adjusted] mean value), the circadian double amplitude, a measure of the extent of predictable change within a day, is a predictor of vascular disease risk. An excessive amplitude (above the upper 95% prediction limit of healthy peers matched by age, gender, and ethnicity) is associated with an elevated left ventricular mass index in a retrospective chronometa-analysis of data from 424 patients and with an increase in morbid events in a prospective 6-year study on 297 patients, following-up on ancillary clinical studies and on results obtained on the laboratory model of the stroke-prone spontaneously hypertensive rat. CHAT is associated with a 720% increase in risk of ischemie cerebral events. It represents the greatest increase in risk, compared with 310%, 370%, 160%, 170%, and 150% in relation to a high blood pressure, old age, a family history of high blood pressure, and/or of other vascular disease, smoking and alcohol consumption, respectively. To identify CHAT and for other diagnostic and therapeutic reasons, single measurements should be replaced by an around-the-clock profile, for a week or longer, if need be, at the outset. The profile is preferably obtained by automatic monitoring with ambulatorily functional instrumentation. When such a monitor is unavailable, self-measurements at 3-hour intervals during waking and one around midsleep are acceptable. The midsleep measurement is taken with minimal disturbance, preferably by a companion, while the patient sleeps with a cuff on the arm. When no companion is available, the patient can set an alarm clock to take the self-measurement. Treatment should be timed with individualized guidance by a blood pressure profile (chronotherapy). The same profile also serves to assess the treatment effect with a control chart to validate the reduction of an excessive amplitude, the lowering of the blood pressure, or both when elevated. Controlled clinical trials assessing long-term outcomes are overdue. By monitoring for only weeks, the recognition and treatment of blood pressure overswinging along the 24-hour scale—a must in anti-aging medicine—may prevent postcatastrophic care for years.

A Perspective on the Proposed Association of Melatonin and Aging

2010-03-27T17:57:00.007+11:00

Summary: Melatonin is another substance that we need more data on but doesn't look all that promising.

Interestingness: 1

Paper by Russel J Reiter, Dun-Xian Tan, Seok Joong Kim, Javier Cabrera and Daniele D'Arpa in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.

(((Melatonin is a molecule produced by the pineal gland that regulates the circadian rhythm. It puts you to sleep. It gets produced in the darkness, and bright light interrupts its production)))

Melatonin is another hormone which the body produces less of as it gets older. A graph with a linear best fit seems to indicate that peak melatonin concentration drops by about half between the ages of 20 and 70, although the text mentions a pronounced drop between the ages of 40 and 60. It also mentions factor of two differences between young people of the same age (((which makes it a bit less important in my eyes))). Production of melatonin in calorie-restricted rats drops slower than in normal rats (((probably more of an endorsement of calorie restriction as a method to slow aging than support for melatonin being important in the process)))

(((The paper now switches to melatonin as an anti-oxidant, which doesn't interest me much))) Melatonin mops up hydroxy radicals, peroxyl radicals, and neutralises single oxygen atoms and peroxynitrite anions (ONOO-). It also stimulates activity glutathione peroxidase and glutathione reductase (((dunno how))) which neutralise hydrogen peroxide. The paper stresses the effectiveness in protecting against lipid peroxidation.

Switching to direct aging studies, it mentions a study where the pineal glands of young rats were transplanted into old rats and these older rats were judged to have become younger, a result which the authors of this paper say is hard to accept since the pineal gland stops producing melatonin after the nerves are destroyed (((edit: the author of that paper seemed unhappy with these comments on this paper, and wrote to the editor in the next issue. They do not think the effect is mediated by restoring melatonin levels. Maybe I'll read their paper))) (((edit 2: paper seems reasonable. Part of it is the drugging of the water with interesting results. The pineal transplantations are into the other mice's (not rats) thymus, because they are supposedly similar tissue. Tiny samples, 15 mice transplanted with pineal glands total, but quite a strong effect (810 days vs 747 days mean survival on mice operated on in the 20th month). Probably completely unrelated to melatonin though.))) (((For reference, other paper is "Pineal Control of Aging: Effect of melatonin and pineal grafting on aging mice" by Walter Pierpaoli and William Regelson)))

Studies of long term melatonin administration in rats have had inconclusive results. Drugging the drinking water extended lifespan when it was given during the night but not during the day. Injecting melatonin directly extended lifespan when done in the morning, but not in the afternoon. (((These studies were done on groups of 10 and 15 mice respectively. The second one focuses on the effect of injections of lithium chloride, and melatonin has no effect on top of lithium chloride. The effects look sort of interesting to me, but this paper doesn't think much of them)))

Abstract follows:

Melatonin, the chief secretory product of the pineal gland, has been proposed to have some functional association with aging. Certainly, melatonin production in vertebrates, including humans, wanes with increasing age. This age-related drop in melatonin has been inferred to be consequential in terms of accelerating some aspects of aging, although the experimental evidence for this is not compelling at this point. There are several functional aspects of melatonin that make it of interest to gerontologists. Thus, the cyclic production of melatonin is reflective of the biological clock, and circadian disturbances in general are a feature of aging. These alterations may impact the rate of aging. Also, melatonin is an antioxidant and, as such, it reduces free radical damage. A primary theory of aging is accumulated oxidative damage, and any molecule, such as melatonin, that retards the accumulation of that molecular damage may forestall some aging processes. The experimental data are incomplete, however, and the specific association of the diminished melatonin cycle with aging or age-related diseases remains suggestive but unproven.

Effectiveness of Growth Hormone (GH) Secretagogues in Diagnosing and Treating GH Secretory Deficiency in Aging Men

2010-03-20T17:42:00.003+11:00

Summary: Growth hormone releasing peptide (GHRP) increases effect of growth hormone releasing hormone on inducing growth hormone release, even when not given immediately prior. GHRP probably blocks somatostatin. Levels of GHRP's natural equivalent probably drop during aging.

Interestingness: 1

Paper by Richard F Walker and Barry B Bercu in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.

(((Yet another growth hormone paper. This one at least is neatly done, sticking to only one specific issue and comes with an easy conclusion)))

(((In this study, the older group is a bunch of people between 37 and 68, the younger group is between 16 and 21. The results seem to only refer to the male subsets. These groups are tiny, with six people in some, and three in others)))

Old people release way less growth hormone (GH) than young people when given GH releasing hormone (GHRH), but they release about the same GH when given GH releasing peptide (GHRP) (((an artificial peptide found to release GH, not found yet in the body naturally))) in older as in younger people. The amount released due to GHRP is much higher than that produced when GHRH alone is given. The relative effect of GHRP is much higher in older people: young people released 1.5 times as much GH when given GHRP compared to GHRH, but older people released 20.5 times as much when given GHRP compared to GHRH. When given less GHRP, less GH is released (((this is part of what they want to show, making the connection that older people probably have lower levels of GHRP or equivalent))).

GHRP only enhances the effect of the present GHRH though. If GHRH receptors are blocked with antagonists, GHRP doses don't lead to increased GH release. Giving GHRH and GHRP combined also leads to greater release than the sum of the releases when given separately. This is consistent with GHRP acting as a functional blocker of somatostatin.

Giving older people GHRP for 10 days, and then giving them GHRH the day after, released much more GH than without the 10 days of preparation. Since GHRP is metabolysed in minutes, this means that GHRP is not just acting directly ((("GHRH signal transduction" is what the paper calls it))) (((the increases in these priming examples are much lower than the immediately-prior dosing though)))

Abstract follows:

This study was conducted primarily to determine the utility of recombinant growth hormone releasing hormone (GHRH) and xenobiotic GH-releasing peptide (GHRP) administered sequentially or in combination, as diagnostic agents for pituitary-based, GH secretory dysfunction in aging men. The secondary purpose was to test the hypothesis that loss of sensitivity to stimulation with GHRH during aging results, at least in part, from reduced exposure of the pituitary gland to the yet unknown, endogenous compound whose activity is stimulated by GHRP. Increases in serum GH following GHRH administration were significantly lower in older men than they were in adolescent and young adult men. In contrast, changes in serum GH following GHRP were comparable in the younger and older men. Because robust GH secretion in response to administration of exogenous GHRH or GHRP is interpreted as representing adequate concentrations of complementary endogenous GHRP and GHRH, respectively, the data suggested that older subjects were deficient in endogenous GHRP. Accordingly, it was of interest to determine whether priming with GHRP would restore the response to GHRH in these men. Ten consecutive days of priming with GHRP caused the responses to GHRH challenge to be significantly improved compared with responses observed before priming. GH secretion following co-administration of GHRH and GHRP were comparable in both age groups. The results of this study suggest that functional elements of pituitary somatotrophs directly related to expression of GHRH activity are intact during aging, but lose their effectiveness in part because of complementary secretagogue (endogenous GHRP analogy) deficiencies. Whereas priming with GHRP demonstrates the plasticity of GHRH signal transduction mechanisms in aging men, the data do not allow determination of whether GHRH or GHRP receptors or second messengers for either or both of these secretagogues become down-regulated. Future studies are designed to make these determinations and to further investigate and confirm the validaity of using GH scretagogues to reactivate the GH axis in the elderly.

The Involvement of Protein Kinase C-βII in Glucose-Induced Rat Vascular Smooth Muscle Cell Proliferation

2010-03-13T17:50:00.002+11:00

Summary: Protein kinase C beta 2 has something to do with cells entering S-phase, at least for vascular smooth muscle cells from rats' aortas.

Interestingness: 1

Paper by Mayumi Yamamoto, Niketa A Patel and Denise R Cooper in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.

(((All that growth hormone has destroyed my wishes to summarise everything. I'm going to stick to the ones I find interesting, and only write brief highlights of the rest, like in the case of this one)))

(((The abstract says about everything I would write about this paper and is way clearer because I don't understand the result presented)))

Protein kinase C - beta II (PKC-B2) overexpression slowed down replication of vascular smooth muscle cells (VSMC) extracted from rats' aortas (((VSMC proliferation is likely a bad thing for atherosclerosis))). High glucose levels downregulate PKC-B2 in the short term (((but raise it long term))) and speed up VSMC replication. CG53353 is a PKC-B2 inhibitor (((but adding it doesn't seem to speed up replication of VSMC))). It makes the cells ignore the glucose levels with regards to replication speed. Glucose usually speeds up the rate at which cells enter S-phase (((DNA-replication step of cell replication))). This is consistent with PKC-B2 being a controller of when cells go into S-phase (((but the picture seems confusing to me. Why doesn't adding CG53353 raise VSMC replication? It does on cells that overexpress PKC-B2, but not in standard ones. Why?)))

Abstract follows:

The protein kinase C (PKC)-βII modulates glucose-induced cell proliferation in A10 cells, a clonal cell line of vascular smooth muscle cells (VSMC) from rat aorta, which were studied by overexpressing PKC-βII and using a PKC-βII specific inhibitor (CG53353). PKC-βII overexpression was verified by the fourfold increase of PKC enzyme activity and PKC-βII immunoreactivity. Overexpression of PKC-βII attenuated A10 cell proliferation and DNA synthesis through the suppression of cell cycle progression inhibiting the entry of cells into the S phase. High glucose (25 mM) increased and accelerated cell proliferation, DNA synthesis, and the percentage of cells entering the S phase in A10. High glucose down-regulated PKC-βII in A10 cells during the first cell cycle after cell synchronization. CG53353 inhibited glucose-induced cell proliferation and DNA synthesis specifically. These results suggest that PKC-βII has inhibitory functions as a cell cycle checkpoint mediator during the late G1 phase and may regulate the S phase entry. High glucose down-regulates endogenous PKC-βII, which alters its normal role in cell cycle progression, and results in stimulation of VSMC proliferation through acceleration of the cell cycle. CG53353 might release cells from the PKC-βII regulated checkpoint of the cell cycle.

Use of Growth Hormone for Treatment of Anatomic and Physiologic Decrements Associated with Aging

2010-03-08T11:49:00.003+11:00

Summary: Effects of growth hormone on cardiovascular health and its periphery. Not much there.

Interestingness: 1

Paper by Bengt-Åke Bengtsson, Gudmundur Johannsson, and Jörgen Isgaard, all of them MD, PhD, in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.

Case studies show improvements in heart function in heart failure patients when given growth hormone (GH). Placebo-controlled studies fail to replicate those effects. In rats, insulin-like growth factor 1 (IGF-1) lowers heart cell apopstosis after induced heart attacks.

Like in the previous paper summarised, they note the similarities between GH deficiency and Syndrome X (insulin resistance plus hypertension) (abdomen/visceral obesity, insulin resistance, high triglycerides, low levels of high density lipoprotein (HDL), hypertension, high plasma fibrinogen, high plasminogen activator inhibitor (PAI-1) activity, premature atherosclerosis and high cardiovascular disease mortality), and also the association between higher abdominal/visceral fat and lower secretions of GH and subsequent IGF-1. In some trials, massive weight loss restores normal levels of GH secretion, but in others it doesn't.

In GH-deficient people, GH supplementation does lots of good things (lower visceral fat, lower diastolic blod pressure, total cholesterol, and low density lipoprotein (LDL), and raises HDL).

In GH sufficient people, it doesn't help the obese lose weight, but in a nine-month study by the authors on obese men, it lowered total body fat, abdominal fat, total cholesterol, triglycerides, it improved insulin sensitivity and lowered diastolic blood pressure, but plasma fibrinogen levels increased. Hypothesis given for the effects are:

Higher insulin sensitivity: lower fatty-acid exposure by the liver through lower abdominal fat. Or increased glucose transport by the skeletal muscles
Lower total cholesterol: more liver LDL-receptors
Lower triglycerides: increased insulin-stimulated glucose uptake
Lower diastolic blood pressure: reduced peripheral vascular resistance through increased insulin-sensitivity or through IGF-1 action on the vascular wall with increased levels of nitric oxide.

Concludes with a section about end-stage renal failure patients and a 6-month study by the authors showing increased muscle mass and strength, and increased albumin concentration in these patients when given a low dose of GH.

Abstract follows:

There are striking similarities between Syndrome X or "the metabolic syndrome" and untreated GH deficiency in adults. The most central findings in both these syndromes are abdominal/visceral obesity and insulin resistance. Other features common to both syndromes are lipid abnormalities, increased prevalence of hypertension, elevated levels of plasma fibrinogen and plasminogen activator inhibitor (PAI)-l activity, premature atherosclerosis, and increased mortality from cardiovascular disease. GH treatment can improve several of the aberrations that GH deficiency has in common with Syndrome X. Recently, we have shown that nine months of treatment in a randomized, double-blind, placebo-controlled trial in middle-aged men with abdominal/visceral obesity reduced their total body fat and resulted in specific and marked decrease in both abdominal subcutaneous and visceral adipose tissue. Moreover, insulin sensitivity and lipoprotein profile improved, and diastolic blood pressure decreased.

A number of experimental and clinical studies suggest a potential role for GH as an addition to conventional therapy for the treatment of congestive heart failure (CHF). Recently, patients with heart failure due to idiopathic dilated cardiomyopathy showed a positive response to GH addition. However, so far, no placebo-controlled study with GH addition to standard optimal therapy in patients with CHF has been able to confirm these findings. Elderly patients on chronic hemodialysis are in a chronic catabolic phase with low lean body mass. We have recently performed a randomized double-blind placebo-controlled trial with GH in elderly on chronic dialysis. Six months of treatment improved lean body mass, muscle strength and walking capacity.

Neuroregulatory Pathophysiology of Impoverished Growth Hormone (GH) Secretion in the Aging Human

2010-03-01T01:28:00.000+11:00

Summary: Review of possible regulatory causes of the decrease in growth hormone with age. I don't know if it comes to any conclusion, but it seems to suggest that there is too much somatostatin being secreted and either too little growth hormone releasing hormone or some other hypothetical growth hormone releasing peptide.

Interestingness: 2

Paper by JD Veldhuis in the Journal of Anti-Aging Medicine, Volume 1, Issue 3, Fall 1998.

(((This issue seems to consist mostly of the papers from the conference on endocrine and molecular interventions in aging reported on in the previous issue. Could get heavy)))

(((First repeat subject: growth hormone. Not one I find particularly interesting)))

Giving growth hormone (GH) to people with GH deficiency helps with many of their problematic psychological symptoms (reduced energy and sense of well-being, social isolation, depressed mood and increased anxiety) and physical symptoms (reduction in lean body mass, bone mineral density, basal metabolic rate, strength, glomerular filtration rate (((kidneys))), increase in body fat and cholesterol). Old people share many of the same problems. Maybe GH would be good for them too. (((The underlying drive in the paper is that increasing growth hormone would be a good thing. Considering the correlation between GH and IGF-1, and it and shortened lifespan, I think the assumption nowadays would be the opposite))). There are some side effects with GH supplementation (fluid retention, myalgia (((muscle pain))), arthralgia (((joint pain))), carpal tunnel syndrome, gynecomastia (((man-boobs))), glucose intolerance) but maybe by triggering it with growth hormone releasing hormone (GHRH) or growth hormone releasing peptides (GHRP) to secrete in its usual pulse-like manner the side-effects can be reduced or eliminated (((as in the previous GH post)))

GH secretion goes down by 50% every seven years in healthy men after hitting 20 years of age (((That's quite a different number from the 14% every decade cited in the previous paper. The graph shown purportedly showing that decline has 21 data points, a line of best fit that looks like it's not going down by half every 7 years after age 35. It also looks like if you were to take the 6 data points of men under 30 out, you'd be left with a horizontal line of best fit))). In pre-menopausal women, the rate of decline is half as fast but it becomes the same as men's after menopause. It is also lower to begin with (((The graph showing young male and female declines of total GH concentration (it integrates concentration over 24 hours) also seems remarkably dodgy for women. Taking out one outlier out of the 32 data points would seem to make it almost flat. Also, these declines are modeled as linear, which doesn't merge with the exponential declines in secretion. I think I'm missing something in the difference between secretion amounts and total concentrations))). The reason for the difference between the sexes is unknown but probably related to estradiol stimulating GH production.

There's also an exponentially declining link between BMI and GH, with a 1.5 kg/m^2 increase leading to a halving of secretion. (((Accompanying dodgy graph, but this one seems reasonable, except for what seems to me to be too little data to be doing exponential regression))) (((Personal hypohypothesis aside: could this be related to why higher BMI doesn't lead to higher mortality even in the presence of the high heart disease risk?))). This interacts with the age link since there's an increase in BMI with age as well. Abdominal fat also dampens the normally strong link between testosterone serum levels and GH secretion, although this dampening isn't as strong in women. The action of testosterone also seems to be by conversion to estradiol.

There are other covariates with age that might influence GH secretion such as fitness, disturbed sleep, different diet, medication, and illness. Little is known about these to be able to differentiate among causes of decline.

I'll skip for a bit to the model of influences presented later since it helps. The model suggested involves a lot of negative feedback loops to stop GH and IGF-1 from being too high. So GH induces IGF-1 which switches GH off. GHRH induces GH secretion, so both GH and IGF-1 turn GHRH off. Somatostatin turns off GH and GHRH secretion so GHRH, GH and IGF-1 all raise somatostatin secretion. Then there are substances that act on GHRH and somatostatin separately. GHRH is raised by GABA-B, galanin, alpha2-adrenergic and the suggested GHRP. Somatostatin is raised by B-2 adrenergic, but lowered by dopamine, serotonin (1-D), L-arginine, muscarinic cholinergic neurotransmission, and the imagined GHRP.

(((The backing of the above confuses me a bit, and is really not very useful, but here it goes))) Pyridostigmine, a cholinergic agonist, given over two days doubles the daily GH secretions by increasing the amount secreted in the pulse, not by increasing rate of pulsing. This link is attenuated with increased body fat. The equivalent of pyridostigmine in sheep stimulates GHRH and triggers a large GH secretions. The paper then suggests that pyridostigmine limits somatostatin, and that this suggests that the reduction in GH with age is due to both an increase in somatostatin and a lack of GHRH.

Alpha-2 adrenergic agonists increase GH in lots of mammals, including the human, partly by increasing GHRH secretion, and possibly by reducing somatostatin. Clonidine, an alpha-2 adrenergic agonist, is a weak GH inducer in humans though. Beta-2 adrenergic agonists lower GH production, and that's believed to be through somatostatin because they lower GH even in the presence of GHRH.

Dopamine is also a GH secretion inducer, but not much is known about how it changes with aging or across sexes. Also, serotoninergic (5-HT) stimulate GH by reducing somatostatin. Galanin also, being more effective in women than in men and the effect decreasing with age. Same with GABA-B, which works better in older women than in men. Corticotropin releasing hormone, leptin and neuropeptide Y are also mentioned as requiring more study (((but I assume they are also inducers of GH secretion)))

(((Back to the main thread))) Most external drivers of higher GH secretion are dampened with age, including GHRH, GHRP, opiates, GABA agonists, fasting, galanin, sleep, exercise,pyridostigmine, L-arginine, clonidine and L-dopa, but some are not, eg insulin-induced hypoglycemia, and combining L-arginine and GHRH or GHRP. This is consistent with somatostatin excess being one of the main culprits in the decline of GH with age since L-arginine hammers somatostatin. But since L-arginine alone doesn't restore the levels of GH fully, too much somatostatin is probably not the only cause, and there is likely a shortfall in GHRH and/or GHRP as well. Combinations of GHRH, synthetic ligands for the GHRP receptor and L-arginine are very effective at raising GH and IGF-1 secretion.

Finally, the level of randomness in the network of hormones around GH increases with age. This is common in many other hormonal networks, and is also triggered by fasting in the GH network by lowering IGF-1. This also needs more study.

(((That was a painful paper. I know too little about the subject. The graphs didn't inspire much confidence. Growth hormone isn't that interesting to me. Too many details that I'll forget by next week.)))

Abstract follows:

A central enigma in neuroendocrine pathophysiology is the virtually uniform, but mechanistically incompletely explicable, attenuation of secretory and trophic activity of the growth hormone (GH)—insulin-like growth factor type I (IGF-I) axis in healthy aging in mammalian species, including the primate and human. Indeed, in humans, the calculated daily GH secretion rate falls approximately 50% every 7 years beginning at age 18 to 21, but this diminution in GH secretion is approximately twofold less rapid in premenopausal women. In contrast, the magnitude of relative GH deficiency appears to be similar in individuals of older (e.g., postmenopausal) age of either gender. Interpreting the mechanisms that underlie such marked attenuation of secretory activity of the GH-IGF-I axis is confounded by endocrinemetabolic covariates that accompany healthy aging, such as an accumulation of (visceral) adiposity, a decline in physical fitness, a reduction in sex steroids, disruption of slow-wave sleep, and concurrent illness and medications. Available clinical investigations point to a partial endogenous GHRH deficiency state, in this so-called somatopause. An important additional age-related fall in brain cholinergic activity (which regulates somatostatin secretion) is likely, thus arguing for combined hypothalamic somatostatin excess and GHRH, GHRP, or both deficiency. This article also evaluates the novel hypothesis that the GH impoverishment of aging is marked by disrupted network function of the GH-IGF-I feedback axis. Given this background, available and new technologies applied in patient-oriented investigations will likely unravel further the presumptively multiple mechanisms that subserve the hyposomatotropism of healthy aging, and begin to address the relative risks and benefits of restoring secretory activity of the aging GH-IGF-I axis.

Rest of Volume 1, Issue 2

2010-02-08T01:45:00.002+11:00

The rest of the second issue consists of two book reviews: Biology of Aging: Observations and Principles which sounds pretty good, and Successful Aging, which doesn't. Then a report of the International Symposium on Endocrine and Molecular Interventions in Aging, a review of some popsci article and the usual literature and web watch.

Genetic Diagnosis of Werner's Syndrome, a Premature Aging Disease, by Mutant Allele Specific Amplification (MASA) and Oligomer Ligation Assay (OLA)

2010-02-08T01:32:00.000+11:00

Summary: How to detect the mutations that cause most of the cases of Werner's syndrome.

Interestingness: 1

Paper by Takehisa Matsumoto, Zenta Tsuchihasi, Chie Ito, Kumiko Fujita, Makoto Goto and Yasuhiro Furuichi in the Journal of Anti-Aging Medicine, Volume 1, Issue 2, Summer 1998

(((This is a methodology paper, which means I am even less able to understand and dissect than usual. Naively, it seems that nowadays they'd just use a gene chip. I'll mostly cover the introduction in this one, since I assume we'll see Werner's again)))

This paper is about methods of picking up the mutations that cause Werner's syndrome. Werner's syndrome is a very rare disease that looks a lot like accelerated aging. There's only been 1100 cases reported since it was first described in 1904 and 800 of those have been in japan.

After a mostly normal pre-adult life, people with the disease get gray hair or go bold, get cataracts, their voice gets hoarse and their testosterone levels drop in their 30s, their skin grows thick and tight, they get diabetes, skin ulcers, atherosclerosis (((thick artery walls))), and cancer. Their lifespan is of 46 years (+- 12 years).

The gene that is mutated to cause Werner's syndrome is WRN, which codes for a RecQ DNA helicase, which are enzymes that unwind DNA for things like genomic repair. Most of the mutations lead to the protein not being able to be imported into the nucleus, making it useless.

Since most symptoms don't appear until adulthood, and to detect carrier status, this paper investigates ways to detect it through DNA testing. They try mutant allele specific amplification (MASA) and oligonucleotide ligation assay (OLA).

(((From what I gather, MASA is doing PCR amplification with primers that work well for the mutant sequence but badly for the standard sequence. This then shows up in a gel as a band in the right place for the case of the mutant strand, and nothing at all in the case of the standard gene being present. PCR amplification is also run with primers that work for the standard sequence and not for the mutant sequence to be able to differentiate the homozyguous mutant cases from the heterozyguous cases)))

(((The OLA method seems more complicated. This explanation is likely to be dodgy. There's three different probe strands of DNA that get created: one that is complementary to the mutant variant, ending right up on the mutant bit; another that is complementary to the standard variety, also ending up right in the bit that it differs from the mutant variety. Both of these strands also have a molecule attached on one end, biotin, that reacts with streptavidin that coats the lab plates, so that they can be trapped to the plate. These are called the capture probes. Only one type of strand is used per plate.

The third strand is complementary to the bit of DNA starting right after the bit where the codes differ, and it also has attached a marker to it, something that changes colour when a specific enzyme, alkaline phosphatase, is added. This is called the reporter probe.

The sample strands of DNA from the human, mutant and normal, are amplified through PCR and added in to the wells. The mutant DNA anneals (wraps with) the mutant capture probe strand perfectly, and almost perfectly with the standard capture probe strand. DNA ligase is also added in, and this joins these annealed bits to the reporter probe, but, here's the trick, it only joins them if the annealing is perfect (why?? does the loose end impair the enzyme from attaching?). So, after the unattached reporter probes are washed away, the situation in a well with mutant capture probes would be as follows: if you added mutant sample strands you get mutant sample strands attached to mutant capture probe strands and reporter strands, but if you added standard sample strands you get mutant capture probe strands attached to standard sample strands but no reporter probes. And vice-versa on the wells with the standard capture probes. Then you add the alkaline phosphatase and you see colour that tells you were the reporter probes are.)))

The meat of the paper is a description of how each of these methods was used in detail (((the sequences of the primers, and bits like 'the 40 microlitres of 0.1% of Triton X-100 was added ...'))) which are not summarisable or particularly interesting. They do mention that MASA is better for proving which particular mutation is carried, but that OLA is easier to use for epidemiological studies because a lot of test sequences can be tested at the same time in a plate.

Abstract follows:

Two genetic diagnostic systems were established to detect gene mutations that cause Werner's syndrome (WS), a premature aging disorder. The mutant allele specific amplification method permits a definition of the types of mutation of the gene (WRN) responsible for WS in WS patients or patients suspected of having WS. By contrast, the oligomer ligation assay method allows the analysis of many DNA samples, which can fit into a large epidemiologic study to investigate the spread of a certain WRN mutation in a given population using a small amount of genomic DNA extracted from a volunteer's blood. In this report, we describe in detail the two diagnostic systems for three representative mutations: 1, 4 and 6, which include about 90% of WRN mutations occurring in Japanese WS patients. Similar systems could also be applied for other WRN mutations endemic to other countries.

Extension of Life Span in Normal Human Cells by Telomerase Activation: A Revolution in Cultural Senescence

2010-01-31T01:01:00.000+11:00

Summary: Expressing the protein related to telomerase extends the telomeres and replicative lifespan of human cells.

Interestingness: 2 (but much higher back then)

Paper by Homayoun Vaziri in the Journal of Anti-Aging Medicine, Volume 1, Issue 2, Spring 1998.

(((This paper also feels old nowadays. Telomerase hype killed the excitement)))

(((I won't skip the introduction this time))) The bits at the end of the chromosomes are called telomeres. With each division of the cell, these are shortened. When they are too short, the theory goes, the cell decides to stop dividing, so that the real DNA doesn't get damaged. As evidence, tumours and other immortal cell lines maintain long telomeres somehow, and the correlation between telomere length and replicative lifespan of human fibroblasts is high. If we could activate the system that lengthens telomeres (called telomerase) the hypothesis could be tested in a causative manner.

So that's what they tried and that's what they got: activating hTERT (human telomerase reverse transcriptase) in human cells lengthens telomeres and enhances the replicative lifespan of the cell. (((That's really it for the paper. The rest is fluff because otherwise this would be too short))) It later cautions though, that this can't rule out that hTERT might be extending the replicative lifespan of the cell by a different mechanism than extension of the telomeres (ie that even though it extends telomeres, this might not be what is extending the lifespan, but some other unrelated function of hTERT is).

The rest of the paper is about how this can be used.

For research, once a cell with properties that are wanted are found or created, they can be made to express hTERT leading to an (((infinitely??))) replicative cell line. Same thing for gene therapy, introduce a cell that expresses the protein you want, add hTERT, and it will last longer. As an example of gene therapy, it gives Duchenne muscular dystrophy, even though it gives good reasons why this most likely wouldn't help (((maybe they were running trials for it at the time))). That it might help with HIV, on the hunch that the short telomeres on CD8+CD28- T-cells indicate immunosenescence, even though it might raise the likelihood of leukemia and lymphoma. Similarly for cancer, that it could prevent a hypothetical immunosenescence after chemotherapy, by extracting CD34- cells and introducing hTERT into them and reinserting the cells into the body.

It finishes by suggesting that it is p53 that acts as the detector of short telomeres that triggers senescence in the cell. (((There's a diagram of proposed gene activation in the paper that would be laborious to describe)))

Abstract follows:

Normal human cells have a limited life span in culture, exhaust their replicative potential after a fixed number of doublings, and enter a phase of cell cycle arrest termed "senescence." Senescent cells are metabolically active cells, known to up-regulate several cyclin-dependent kinase inhibitors and to be arrested primarily at the G1 phase of cell cycle. Telomere loss due to incomplete replication of the ends in normal somatic cells is thought to be the signal which initiates the senescence cascade. Lack of telomere maintenance in somatic cells may be caused by the absence or the low enzymatic activity of telomerase, the enzyme responsible for synthesis of telomeric DNA that counteracts the end-replication problem. Previous attempts to increase the life span of human cells involved inactivation of tumor suppressor genes such as p53 were not a viable method of life span extension because of significant risk of genomic instability. Extension of the life span of normal cells with minimal risk of genetic instability may be achieved by manipulation of the most upstream signals that initiate the senescence cascade. We and others have recently shown that reactivation of telomerase in normal human cells leads to restoration of the length of telomeric DNA and to a highly significant increase in cellular life span. These data provide strong evidence consistent with the telomere hypothesis and indicate that elongation of telomere length by genetic manipulation might render normal human cells virtually immortal. These findings indicate that telomere shortening and senescence act as a tumor suppressor mechanism and establish a solid genetic link between telomeres, cellular aging, and immortalization.

Nutrition and Aging in Companion Animals

2010-01-30T16:42:00.001+11:00

Summary: Dogs age and die.

Interestingness: 2

Paper by Michael G Hayek and Gary M Davenport in the Journal of Anti-Aging Medicine, Volume 1, Issue 2, Summery 1998.

(((This isn't a paper about dogs and cats as models of human aging. It is about dogs and cats aging and what we can do to slow the process down, but its mostly a descriptive article. It does often refer to studies in humans mostly for confirmation that the effect is similar in both)))

(((This paper is supposedly about companion animals but almost all the data refers to dogs)))

After the usual why-this-is-important section, there's a long list of median ages of dogs by breed from cases collected during the '80s. They range from 3.5 years for the Rottweiler to 9.3 for the miniature Poodle, with most breeds around the 6-7 year mark. There is an inverse relation between dog breed size and its life expectancy. Cats seem to have a uniform life expectancy, independent of breed.

The rest of the paper goes through some components of the dog that deteriorates/changes as it ages:

Aging dogs have lower number of white blood cells and immature neutrophils and higher counts for mature neutrophils and concentration of immunoglobulin G. They have decreased response to stimulation of T- and B-cell division.

Aging dogs and cats also have a higher percentage of body fat compared to young dogs and cats, going from 18% to 27% in dogs, 30% to 35% in cats, and a corresponding loss of muscle mass. It then says something about higher protein intake leading to higher protein turnover needed for good immune system function but I'm confused by the text. It does seem to recommend higher protein intake for the elderly (dogs and humans).

No change in nutrient absorption occurs in the aging dog. They do become worse at maintaining glucose levels and at desaturating fatty acids.

(((Conclusion: too much of a mish-mash of bits of data for me. It recommends specific dietary changes from these bits of data but I don't see much evidence in the text to quote them)))

Abstract follows:

The aging process is associated with alterations in a variety of physiological systems and metabolic processes. These alterations are not well-defined in companion animals. Understanding these age-associated changes will aid in designing nutritional interventions specific for the geriatric population of companion animals. In the dog, age-associated physiological changes include a decline in the cell-mediated parameters of the immune response and alterations in body composition (i.e., increased body fat and decreased lean body mass). Metabolic changes include decreased ability to utilize glucose and alterations in the elongation of omega-3 and omega-6 fatty acids. Nutritional interventions such as antioxidant vitamins, adequate dietary protein, and adjusted levels of long chain fatty acids have the potential to slow the aging process in these animals.

The Human Genome Project: Scientific Promise and Social Problems

2010-01-28T22:26:00.000+11:00

Summary: Standard human genome project spiel before the project finished

Interestingness: 1 now, but it would have been exciting back then

Paper by Paul H Silverman in the Journal of Anti-Aging Medicine, Volume 1, Issue 2, summer 1998.

(((This paper seems very old now. The genome project got a lot of coverage in the intervening 12 years, and we've read the contents of this paper another hundred times)))

We'll finish the human genome project by 2005 (((ha))). Many diseases related to aging have genetic risk factors, but genes only account for about 35% of life span variance.

Mutations in a gene in C Elegans double their normal life span. That gene (daf-2) is the homolog of the human insulin and insulinlike growth factor. Maybe the system is conserved.

Genetic diagnosis of diseases will be awesome. Already used for IVF to filter out cystic fibrosis.

Genetic therapy will also be awesome, and there are a hundred human trials underway. (((and then that dude died)))

Lots of legal and ethical issues to be sorted (((etc)))

Abstract follows:

The Human Genome Project, initiated in 1990, has progressed rapidly in the development of sequencing and bioinformatic technology. It is anticipated that the 3 billion nucleotide sequence of the human genome will be completed by 2005. In the meantime, new genes and their function are being identified, leading to the new field of functional genomics. The genomic information has stimulated the development of commercial firms focused on diagnostics and on gene therapy. Many diseases, including cancer, genetic disorders and some infectious diseases, are being treated with gene therapy in human trials. The predictive quality of DNA diagnostics is raising concerns about third party coverage for pre-existing conditions.

Darwinian Anti-Aging Medicine

2010-01-25T00:32:00.002+11:00

Summary: Aging is due to evolution and studying aging should take that into account

Interestingness: 1

Paper by Michael R. Rose in the Journal of Anti-Aging Medicine, Volume 1, Issue 2, Summer (Northern) 1998.

Aging is due to lack of evolutionary pressure for continuing to live on creatures past the age of helping their offspring. Studies should take this into account. Fruit flies and mice have been evolved to live longer, and these are good specimens to study to see what differs from their wild varieties.

(((I didn't think there would be enough disagreement on the subject to warrant writing this article. As it is admitted in the article, there isn't much in practice to be done differently based on this knowledge)))

Abstract follows:

Two new movements vie for the attention of mainstream medicine: anti-aging medicine and Darwinian medicine. Each is based on the rejection of one of the major assumptions of medical practice and medical research. Anti-aging medicine rejects the basic assumption of conventional medicine that the deterioration accompanying increasing chronologic age is an unchangeable absolute.1 Instead, anti-aging is based firmly on the hope that medical research will discover practical means to intervene in human aging processes, not just individual degenerative diseases, so that the limits of the healthy human life span can be progressively increased. Darwinian medicine rejects the assumption that the scientific foundations of medicine are to be found in the swatch of biologic disciplines ranging from biochemistry to organismal physiology, and no further.2 Proponents of Darwinian medicine argue that numerous concrete benefits can be obtained from reforming, or at least expanding, medicine so that it takes into account the many insights derivable from such fields as population genetics, molecular evolution, quantitative genetics, evolutionary ecology, and the like. These two new perspectives on medicine intersect in a small field that I call "Darwinian anti-aging medicine." Defining this approach to medicine is the concern of the present article.

A Mechanism Proposed to Explain the Rise in Oxidative Stress During Aging

2010-01-24T22:50:00.009+11:00

Summary: Longish speculative chain on how cells dominated by mutant mitochondria, even though they are rare, can cause system wide oxidation damage. The speculation sounds speculative.

Interestingness factor: 6ish

Paper by Aubrey de Grey, published in Journal of Anti-Aging Medicine, Volume 1, Issue 1, Spring 1998. (((can be gotten from http://www.sens.org/files/sens/AdGpubs.htm)))

(((A long theoretical piece. I'm not going to do it justice. Reading about glycolysis and the Krebs cycle helps)))

The previous blog reviewed the article that forms the basis for this paper. Assuming that mutant mitochondria take over individual cells, how can they affect the rest of the body, if, as this paper points out, they seem to only make up about one percent of tissue cells?

The hypothesis starts with an explanation of how these cells survive at all. It uses data gathered from experiments with cells that lack mitochondrial DNA altogether (p0 cells), that can survive if supplemented with pyruvate or a whole bunch of other molecules.

The problem to solve for them, aside from the lower amounts of energy available, is how to restore levels of NAD+ that get converted to NADH during glycolysis. The proposed solution is that they do this by reduction of extracellular molecules through an enzyme that sits on the membrane called plasma membrane oxidoreductase (PMOR) that exist in every cell. That is, they do this by exporting electrons. Evidence presented is that succinate dehydrogenase is upregulated in these p0 cells, and that since it is part of the Krebs cycle that consumes pyruvate, it shows that the main alternative method of exporting those electrons (by reducing pyruvate to lactate with NADH and then exporting the lactate) is probably not being used. (((Which doesn't show me how some other third method is not what is really going on)))

Those exported electrons primarily go to vitamin C in extracellular fluid, but once you run out of that, they'd go to oxygen, creating superoxide radicals. Most of this would be cleaned up by superoxide dismutase, but some would escape and react with the iron in haemin (((non-protein bit of haemoglobin))) (other iron options are well protected) which would then oxidase LDL particles. This last part, the oxidation of LDL particles by haemin, seems to have some evidence behind it.

The oxidation of some LDL would raise the intake of somewhat oxidised LDL by all cells in the body, which would raise the amount of oxidation damage that all cells have to deal with. Since this mechanism would be going on constantly, ie those mutant mtDNA cells would be constantly spewing electrons, quite a lot of oxidised LDL would be created.

The paper then moves onto methods of testing the suggested chain of events:

Seeing if cells that do not have a functioning electron transport chain (by assessing cytochrome c oxidase activity) have high PMOR activity.
Seeing if there's high levels of superoxide near cells with busted mitochondria
Checking if LDL is highly oxidised near mutant cells
Checking if oxidised LDL particles stress normal cells anti-oxidant system.

And then onto methods for checking that it affects aging:

Restoring the function of the mutant mitochondria by importing the proteins encoded by the mitochondrial DNA and seeing what happens (((hard project)))
Targeting those zombie cells controlled by mutant mitochondria and destroying them, then seeing what happens. (((I like it)))

(((Conclusion: The chain of events suggested here sounds much more dubious to me than the one suggested in the previous article. The electrons from NADH might be used some other way inside the cells, or the electrons might be quenched in some benign way outside the cell, or oxidation of LDL might not have any major effect on aging (outside of the effects on cardiovascular disease). The tests seem simple enough though, and they'll pop up regardless, if they haven't already. It would be good if this was correct since killing the mutant cells doesn't sound insanely hard to me. Easier than curing cancer since these cells don't reproduce, as determined by the method that they come into existence)))

(((This is the last paper that I'll write about in the first issue. The rest consists of some futurist speculation, a meeting report and literary review. While interesting, they are already in summary form)))

Abstract follows:

Most phenotypes of aging in vertebrates may be caused by a progressive decline in the ability of antioxidant defences to maintain cellular and systemic homeostasis. This is due both to a diminished efficacy of those defences and to an enhanced level of pro-oxidant toxicity; the imbalance between the two has been termed oxidative stress. However, the cause of this increasing imbalance remains obscure. This article proposes a mechanism by which spontaneously mutant mitochondrial DNA (mtDNA), despite being present only in very small quantities in the body, may be the main generator of oxidative stress. Mutant mtDNA is distributed very unevenly within a tissue: some cells apparently contain no wild-type mtDNA whatever. Those cells must rely on glycolysis for ATP production; furthermore, they require a system to stabilize their NAD+/NADH ratio. This can only be achieved by an efflux of electrons from the cell, most probably mediated by the plasma membrane oxidoreductase (PMOR). It is proposed that the required rate of electron efflux from these anaerobic cells exceeds the local electron-accepting capacity of "safe" acceptors in plasma such as dehydroascorbate, with the result that reactive species, such as Superoxide, are formed. This leads to increased oxidation of lipids in the plasma, notably of low-density lipoprotein (LDL) particles, which are subsequently imported into mitochondrially healthy cells. This oxidized lipoprotein must be destroyed by the recipient cells' antioxidant defences. That task diverts the cell from the degradation of pro-oxidants that it is itself generating; thus, it imposes oxidative stress on the cell. As the number of anaerobic cells in the body rises, so does oxidative stress in all cells. The consistency of this hypothesis with known facts is discussed, and technically feasible tests are suggested both of the proposed mechanism and of its overall contribution to mammalian aging, including plausible interventions to retard the process.

A proposed refinement of the mitochondrial free radical theory of aging

2010-01-17T19:47:00.008+11:00

(((This isn't really part of the series. I was reading "A Mechanism Proposed to Explain the Rise in Oxidative Stress During Aging" in the series but it assumes that the reader is familiar with this paper. Since I found it interesting, I'm writing a summary of this one as well)))

Summary: Hypothesis is that cells get filled up with mutant mitochondria. This is because their membrane gets destroyed at a slower rate due to them being slower in producing free radicals. This leads to them not being destroyed by the cell recycling mechanism.

Interestingness factor: 7ish

Paper by Aubrey de Grey, published in BioEssays, 1997, volume 19, issue 2. (((can be gotten from http://www.sens.org/files/sens/AdGpubs.htm)))

(((Harder to summarise theoretical papers, since most of it tends to be important for the theory to hold)))

The paper makes the case that the replication of mutant mitochondria fills up cells with mostly useless mitochondria that do not feed the cell enough ATP, and that this is important for mammalian aging. I'll focus on the description of the mechanism of how mutant mitochondria supposedly get selectively replicated and come to represent most/all of the mitochondria in a cell, since that's the bit that's relevant to the paper in the Anti-Aging journal. I'll mostly ignore the importance of this to aging.

(((Reading up on mitochondria, and http://en.wikipedia.org/wiki/Electron_transport_chain#Electron_transport_chains_in_mitochondria helps)))

Mitochondria reproduce more frequently that the cells that contain them, especially if those cells don't replicate at all
(senescent). Their DNA (mtDNA) is not as well protected as nuclear DNA and is close to the reactive molecules that they produce. There are 13 genes in mtDNA that are not duplicated in the nuclear DNA and so are essential to the functioning of the mitochondria. They include proteins that form part of the respiration chain and the ATP generation. Therefore point mutations in those parts of their DNA would interfere with those functions. If there was a selective process which would preferentially replicate these mitochondria over the non-mutant ones, then mutants would dominate the cell and all/most mitochondria in the cell would have non-working or slow ATP production.

(((The most speculative part is the following))) Mitochondria damage their cell membrane in the production of the proton gradient. The process creates radical molecules that attack the lipids in their inner membrane. If the membrane is damaged enough small molecules from the interior of the mitochondrion will leak into the cytoplasm. The cell uses these as markers of damaged mitochondria and destroys it (by lysosomal degradation). Because the mutant mitochondria have faulty electron transport chains, their membrane degrades slower. This means they are left alive and reproduced when the cell thinks it needs more ATP (cell has to pick from the mitochondria that are alive). (((Tada!)))

Evidence offered for this theory: 1) Mitochondria in cells tend to share the same mutations, and these are different from the mutations in the cell next door. 2) Mutations that affect the ATP synthetising enzymes do not become popular among cells, because their transport chain is intact and therefore their membranes are just as damaged as non-mutant mitochondria (((this is offered as a prediction in the paper but he claims the result is provisionally known to be true)))

Refutations of potential counter-arguments. (((I'm restricting to only the ones that refer to the spread of the mitochondria again)))

1) Objection: Mitochondria have many copies of mtDNA, single mutation in one copy won't make much of an impact. Counter-counter: Some mutations will hang around and become homozyguous in all copies of a mitochondrion by genetic drift. Also, even arecessive mutation would have some small effect on electron transport and the mitochondrion only has to survive a little bit longer than the rest to be replicated.

2) Objections: Membranes get repaired. Counter-counter: Not all damage can be fixed.

3) Objection/question: Does a mitochondria with a damaged electron transport chain mechanism actually cause less damage on their inner membrane? Counter-counter: Yes. Three paths of lipid peroxidation: perhydroxy levels lower on the outside of an inner membrane of a slowly respiring mitochondrion, so will levels of ubisemiquinone. Metal-catalysed pathway still just as active probably (((I'm just parroting this bit. No idea if it's complete nonsense)))

Abstract follows:

Over recent years, evidence has been accumulating in favour of the free radical theory of aging, first proposed by Harman. Despite this, an understanding of the mechanism by which cells might succumb to the effects of free radicals has proved elusive. This paper proposes such a mechanism, based on a previously unexplored hypothesis for the proliferation of mutant mitochondrial DNA: that mitochondria with reduced respiratory function, due to a mutation or deletion affecting the respiratory chain, suffer less frequent lysosomal degradation, because they inflict free radical damage more slowly on their own membranes. Once such a mutation occurs in a mitochondrion of a non-dividing cell, therefore, mitochondria carrying it will rapidly populate that cell, thereby destroying the cell's respiratory capability. The accumulation of cells that have undergone this transition results in aging at the organismal level. The consistency of the hypothesis with known facts is discussed, and technically feasible tests are suggested, of both the proposed mechanism and its overall contribution to mammalian aging.

Diabetes and Hypertension (Syndrome X) as an Increasing Risk Factor for Cerebrovascular Aging in Japan

2010-01-16T21:02:00.006+11:00

Summary: Diabetes, hypertension and high serum GOT highly associated with stroke. High cholesterol, salt intake, calorie intake, smoking, alcohol consumption and family history were not associated with stroke.

Paper by Y Wada, M Tsukada and A Koizumi in Journal of Anti-Aging Medicine, Volume 1, Issue 1, Spring 1998.

This is a standard epidemiological study that follows about 7500 over 35 year olds from the Akita prefecture in Japan for 3 to 5 years (((I can't tell exactly. They measured them between '89 and '91 and followed the death registry till '94))) looking for correlations between a number of health and behavioural measures, and stroke. They observed 123 strokes. There were also 94 strokes among their subjects prior to enrolment but they excluded those people and their strokes from the analysis with respect to stroke.

Akita is the high stroke, high alcohol consumption region of Japan. Going by the characteristics table in the paper, the men smoke and drink, and the women do neither. About 3% of the people in the study had diabetes, about half had hypertension and about 2.5% had both. The researchers focused a bit on that combination of diabetes and hypertension called Syndrome X (((which I think is commonly called metabolic syndrome nowadays))), and set it up as another variable to measure correlation.

Results of relative risk of stroke expressed as odds ratio were as follows:

(trait - what is ratio measuring - odds ratio (95% confidence interval)

Hypertension - yes/no - 3.78 (2.4 - 5.97)
Diabetes - yes/no - 2.87 (1.51 - 5.44)
Both (Syndrome X) - yes/no - 7.42 (3.16 - 17.42) (((ratio is people with both to people with neither)))
serum GOT - >40 IU/L / 8-40 - 4.00 (2.00 - 8.00)
age class - >60 / 50-59 / <>

All the following were between 0.7 and 1.3:

Hypercholesterolemia (> 220 mg/dl)
BMI
Father, mother or sibling with diabetes, hypertension or stroke
Miso soup intake
Salty food intake
Changes in habits of food intake or salt intake
Drinking habit
Smoking habit
Physical inactivity

Notes regarding models:
Gender, age, diabetes and hypertension were regressed together.
All other variables were adjusted for age and gender only.

(((Serum GOT (aspartase aminotransfarase) is used as a marker for liver damage, but can also be due to heart damage (or kidney, or brain, or muscle in general). They seemed to take it as a marker for alcohol related liver damage)))

They also calculated relative risks of syndrome X of those same variables. (((I don't consider them as interesting)))

(((Conclusion: Same as summary. Watch out for hypertension, but salt isn't the answer.)))

Abstract below:

Recently, there has been an increased incidence of diabetes mellitus in Japan, where the rate of stroke is high. We reviewed the risk factors of stroke with special reference to "Syndrome X." We reviewed a population-based cohort from 1989 through 1991 that consisted of 7,456 subjects over the age of 35 at Akita, a stroke-prevalent rural district in the northeastern part of Japan known to have the shortest longevity and the highest alcohol consumption in the country. Baseline data were obtained by a questionnaire, physical exams, and blood serum tests. Physical characteristics were similar to national norms, although the proportion of heavy (ex-)drinkers was higher (72.5% for male; 12.0% for female). The prevalence of diabetes mellitus, hypertension, and Syndrome X (defined as diabetes mellitus plus hypertension) was 3.0%, 47.0%, and 1.9%. Observed prevalence of Syndrome X was higher than the expected value. The tendency to disease-clustering was strong in young females. The risk factors of Syndrome X were high body mass index (BMI); a family history of diabetes, hypertension or Syndrome X; regular drinking; high serum GOT; and less walking activity (odds ratio: 1.15, 3.91, 1.62, 4.76, 1.35, 3.97, and 1.21). Stressful occupational environment, feelings of daily stress, a tendency to get angry, and snoring also increased risk of Syndrome X. By 1995,129 stroke cases were observed in the cohort; 123 cases were the first episode. Diabetes mellitus, hypertension, Syndrome X, high BMI, high serum GOT, and less walking activity were associated with significantly higher relative risks for stroke (odds ratio: 2.87, 3.78, 7.42, 1.07, 4.00, and 1.28). Intake of salty foods and hypercholesterolemia were not associated with a higher incidence. The population-attributable risks of stroke related to diabetes mellitus, hypertension, Syndrome X, and high serum GOT were 5.2%, 56.7%, 10.6%, and 7.8%. Syndrome X proved to have the highest relative risk of stroke. Important and controllable risk factors of Syndrome X and stroke were habitual alcohol intake with high serum GOT and less walking activity. Genetic factors were also presumably important to the prevention of Syndrome X. These factors must be considered in strategies aimed at preventing cerebrovascular aging.

Implications of Recent Work in Telomeres and Cell Senescence

2010-01-13T01:04:00.003+11:00

Summary: Rally the troops, this is the era when shit comes to light

Paper by Michael Fossel in Journal of Anti-Aging Medicine, Volume 1, Number 1, Spring (Northern) 1998

Michael Fossel was the editor-in-chief of the journal. This is a support-building piece for the claim that modifying aging is possible and that we now actually know something about aging.

Among other things, it says that we can now insert functioning telomerase into cells, that this reverses senescence in cells (((that they stop dividing))), and that we can now test if cell senescence is an important factor in aging.

(((I won't cover these type of articles much)))

Abstract follows:

To date, although the mean human life span has been quite alterable, the maximum human life span has not. Recent work demonstrates that the maximum healthy life span of several species can be extended by dietary restriction and genetic alteration; potentially the maximum healthy human life span might be extended in a similar fashion. More dramatically, researchers have now shown that cell senescence can be reversed by transfection of the catalytic component of telomerase in normal human cells. This allows us to test the hypothesis that cell senescence underlies human aging and age-related disease. This possibility has unprecedented and profound implications for clinical medicine; it has equally unprecedented and profound—and largely unpredictable—implications for our social structures as well.

Interventions of Senescence in SAM Mice

2010-01-10T23:19:00.005+11:00

Summary: Description of effects of many substances on various diseases on mice that age fast.

Paper by Masanory Hosokawa, Makiko Umezawa, Keiichi Higuchi and Toshio Takeda in Journal of Anti-Aging Medicine, Volume 1, Number 1, 1998.

(((bias: I don't pay much attention to mice as models of aging. I pay even less attention to accelerated-aging mice as models of aging. They seem too far removed. I also know squat about the subject)))

Most of the paper describes the Senescence accelerated mouse prone and resistant (SAMP and SAMR) variety of mice developed since the late 60s. They are closely related, and are both relatively normal until they reach maturity (((don't know when that is, but they become fertile at around 45 days))). After maturity, SAMR continues a relatively normal mouse life, but SAMP deteriorates rapidly in many different ways. Median life-span of SAMR mice is about the same as normal long-lived mice, although not the ones in their lab, which lived for around 19 months. Median life-span for SAMP mice varied between about 7 and 14 months depending on the sub-variety. They also use a degree-of-senescence score that is just how fucked they think the mouse is, and note a factor of 1.5-3.5 greater degree of senescence in SAMP mice over SAMR at 8 months of age. SAM mice, both varieties, tend to die from contracted kidneys, abscess formation (((balls of pus!?))), pneumonia and lymphomas (((not similar to the profile in humans))). The idea is that the SAMP is just an accelerated decline version of the SAMR.

It then describes a few sub-variants of the SAMP mice that are specially prone to osteoperosis, learning and memory problems, amyloidosis (((insoluble protein clumps in various organs))) and immune system decline.

It finishes with things they tried that helped with each one of those. Caloric restriction helped with the lifespan and the amyloidosis of SAMP mice (no measurement numbers given) (((Most interesting for me is that it didn't extend the SAMR lifespan))). Summary of the rest of the benefits found is as follows (no numbers are given for any of these):

Soy bean protein instead of casein for amyloidosis, aged garlic extract helped survival ratio of the sub-variety with problems with memory and immune-system (SAMP8). Toki-Shakuyaku-San (TSS) and Boui-Jiou-Tou (BJT) extended median survival of the amyloidosis prone mice (SAMP1). Deer antler (((!?!))) orally increased testosterone, decreased malondialdehyde (((a oxidative stress marker))) in the liver and brain, increased RNA and protein in the liver, increased liver super-oxide simutase, decreased monoamine oxidase B in liver and brain in SAMP8 males. Alpha-phenyl N-tertiary-butyl nitrone (PBN, a spin-trapping agent) (((free-radical capture))) increased lifespan of SAMP8. Acidic fibroblast growth factor (aFGF) protected the impairment of delayed type hypersensitivity reaction in SAMP8.

The osteoperosis-prone variety (SAMP6) was helped by mixing its bone marrow with those of another sub-variety, or getting bone marrow-derived factors from that other sub-variety, or by giving it calcium, parathyroid hormone or estrogen.

(((I'll skip the substances that helped memory and learning since I consider them even less relevant to humans than the others, but there's a lot of them, so read the article if you are interested)))

(((Conclusion: mice with mutations that make them age fast can be successfully helped with lots of substances. I wouldn't expect much of it to transfer to humans)))

Abstract follows:

The Senescence-Accelerated Mouse (SAM) strain was established in the Department of Senescence Biology, Chest Disease Research Institute, Kyoto University, as a novel murine model of senescence acceleration and age-associated disorders. This strain is actually a group of related inbred strains (recombinant inbred strain-like) including nine strains of accelerated senescence-prone, short-lived mice (SAMP) and three strains of accelerated senescence-resistant, long-lived mice (SAMR). Each SAMP strain shows relatively strain-specific age-associated pathologies. These characteristic pathological phenotypes are similar to those often observed in elder humans. They include senile osteoporosis, osteoarthritis, age-related deficits in learning and memory with/without forebrain atrophy, presbycusis, senile amyloidosis, age-related impairment of the immune response, and so on. The common aging characteristic of SAMP strains is senescence acceleration after normal development and maturation. We have made attempts to intervene the senescence acceleration and specifically in these pathologies: senile osteoporosis and the age-related deficits in learning and memory. These attempts, including caloric restriction, administration of nutrients, chemicals and traditional herbal medicines, show beneficial effects on the aging process of these mice. Similar interventions may prevent or control the onset and progress of age-associated disorders in other species and may have clinical relevance for humans.