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

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.

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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%
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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

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.

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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.
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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

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.

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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.

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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

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.

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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.
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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

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.
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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

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

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.


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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.

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Is Telomere Shortening Related to Progeria?

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.


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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

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Recovery of Circadian Body Temperature in Aged Persons

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.


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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
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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

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.


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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.
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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

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.


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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.
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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

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.

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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.
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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?

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.

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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.
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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

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

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.

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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

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)

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

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

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

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

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?

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

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

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

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

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

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

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

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.