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

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

Interestingness: 2 (but much higher back then)

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

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

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

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

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

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

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

Abstract follows:

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

Nutrition and Aging in Companion Animals

Summary: Dogs age and die.

Interestingness: 2

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

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

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

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

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

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

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

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

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


Abstract follows:

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

The Human Genome Project: Scientific Promise and Social Problems

Summary: Standard human genome project spiel before the project finished

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

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

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

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

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

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

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

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

Abstract follows:

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

Darwinian Anti-Aging Medicine

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

Interestingness: 1

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

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

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

Abstract follows:

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

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

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

Interestingness factor: 6ish

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

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

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

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

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

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

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

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

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

And then onto methods for checking that it affects aging:

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

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

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

Abstract follows:

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

A proposed refinement of the mitochondrial free radical theory of aging

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

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

Interestingness factor: 7ish

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

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

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

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

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

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

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

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

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

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

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


Abstract follows:

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

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

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

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

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

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

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

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

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

All the following were between 0.7 and 1.3:

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

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

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


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


(((Conclusion: Same as summary. Watch out for hypertension, but salt isn't the answer.)))

Abstract below:

Recently, there has been an increased incidence of diabetes mellitus in Japan, where the rate of stroke is high. We reviewed the risk factors of stroke with special reference to "Syndrome X." We reviewed a population-based cohort from 1989 through 1991 that consisted of 7,456 subjects over the age of 35 at Akita, a stroke-prevalent rural district in the northeastern part of Japan known to have the shortest longevity and the highest alcohol consumption in the country. Baseline data were obtained by a questionnaire, physical exams, and blood serum tests. Physical characteristics were similar to national norms, although the proportion of heavy (ex-)drinkers was higher (72.5% for male; 12.0% for female). The prevalence of diabetes mellitus, hypertension, and Syndrome X (defined as diabetes mellitus plus hypertension) was 3.0%, 47.0%, and 1.9%. Observed prevalence of Syndrome X was higher than the expected value. The tendency to disease-clustering was strong in young females. The risk factors of Syndrome X were high body mass index (BMI); a family history of diabetes, hypertension or Syndrome X; regular drinking; high serum GOT; and less walking activity (odds ratio: 1.15, 3.91, 1.62, 4.76, 1.35, 3.97, and 1.21). Stressful occupational environment, feelings of daily stress, a tendency to get angry, and snoring also increased risk of Syndrome X. By 1995,129 stroke cases were observed in the cohort; 123 cases were the first episode. Diabetes mellitus, hypertension, Syndrome X, high BMI, high serum GOT, and less walking activity were associated with significantly higher relative risks for stroke (odds ratio: 2.87, 3.78, 7.42, 1.07, 4.00, and 1.28). Intake of salty foods and hypercholesterolemia were not associated with a higher incidence. The population-attributable risks of stroke related to diabetes mellitus, hypertension, Syndrome X, and high serum GOT were 5.2%, 56.7%, 10.6%, and 7.8%. Syndrome X proved to have the highest relative risk of stroke. Important and controllable risk factors of Syndrome X and stroke were habitual alcohol intake with high serum GOT and less walking activity. Genetic factors were also presumably important to the prevention of Syndrome X. These factors must be considered in strategies aimed at preventing cerebrovascular aging.

Implications of Recent Work in Telomeres and Cell Senescence

Summary: Rally the troops, this is the era when shit comes to light

Paper by Michael Fossel in Journal of Anti-Aging Medicine, Volume 1, Number 1, Spring (Northern) 1998

Michael Fossel was the editor-in-chief of the journal. This is a support-building piece for the claim that modifying aging is possible and that we now actually know something about aging.

Among other things, it says that we can now insert functioning telomerase into cells, that this reverses senescence in cells (((that they stop dividing))), and that we can now test if cell senescence is an important factor in aging.

(((I won't cover these type of articles much)))


Abstract follows:

To date, although the mean human life span has been quite alterable, the maximum human life span has not. Recent work demonstrates that the maximum healthy life span of several species can be extended by dietary restriction and genetic alteration; potentially the maximum healthy human life span might be extended in a similar fashion. More dramatically, researchers have now shown that cell senescence can be reversed by transfection of the catalytic component of telomerase in normal human cells. This allows us to test the hypothesis that cell senescence underlies human aging and age-related disease. This possibility has unprecedented and profound implications for clinical medicine; it has equally unprecedented and profound—and largely unpredictable—implications for our social structures as well.

Interventions of Senescence in SAM Mice

Summary: Description of effects of many substances on various diseases on mice that age fast.

Paper by Masanory Hosokawa, Makiko Umezawa, Keiichi Higuchi and Toshio Takeda in Journal of Anti-Aging Medicine, Volume 1, Number 1, 1998.

(((bias: I don't pay much attention to mice as models of aging. I pay even less attention to accelerated-aging mice as models of aging. They seem too far removed. I also know squat about the subject)))

Most of the paper describes the Senescence accelerated mouse prone and resistant (SAMP and SAMR) variety of mice developed since the late 60s. They are closely related, and are both relatively normal until they reach maturity (((don't know when that is, but they become fertile at around 45 days))). After maturity, SAMR continues a relatively normal mouse life, but SAMP deteriorates rapidly in many different ways. Median life-span of SAMR mice is about the same as normal long-lived mice, although not the ones in their lab, which lived for around 19 months. Median life-span for SAMP mice varied between about 7 and 14 months depending on the sub-variety. They also use a degree-of-senescence score that is just how fucked they think the mouse is, and note a factor of 1.5-3.5 greater degree of senescence in SAMP mice over SAMR at 8 months of age. SAM mice, both varieties, tend to die from contracted kidneys, abscess formation (((balls of pus!?))), pneumonia and lymphomas (((not similar to the profile in humans))). The idea is that the SAMP is just an accelerated decline version of the SAMR.

It then describes a few sub-variants of the SAMP mice that are specially prone to osteoperosis, learning and memory problems, amyloidosis (((insoluble protein clumps in various organs))) and immune system decline.

It finishes with things they tried that helped with each one of those. Caloric restriction helped with the lifespan and the amyloidosis of SAMP mice (no measurement numbers given) (((Most interesting for me is that it didn't extend the SAMR lifespan))). Summary of the rest of the benefits found is as follows (no numbers are given for any of these):

Soy bean protein instead of casein for amyloidosis, aged garlic extract helped survival ratio of the sub-variety with problems with memory and immune-system (SAMP8). Toki-Shakuyaku-San (TSS) and Boui-Jiou-Tou (BJT) extended median survival of the amyloidosis prone mice (SAMP1). Deer antler (((!?!))) orally increased testosterone, decreased malondialdehyde (((a oxidative stress marker))) in the liver and brain, increased RNA and protein in the liver, increased liver super-oxide simutase, decreased monoamine oxidase B in liver and brain in SAMP8 males. Alpha-phenyl N-tertiary-butyl nitrone (PBN, a spin-trapping agent) (((free-radical capture))) increased lifespan of SAMP8. Acidic fibroblast growth factor (aFGF) protected the impairment of delayed type hypersensitivity reaction in SAMP8.

The osteoperosis-prone variety (SAMP6) was helped by mixing its bone marrow with those of another sub-variety, or getting bone marrow-derived factors from that other sub-variety, or by giving it calcium, parathyroid hormone or estrogen.

(((I'll skip the substances that helped memory and learning since I consider them even less relevant to humans than the others, but there's a lot of them, so read the article if you are interested)))


(((Conclusion: mice with mutations that make them age fast can be successfully helped with lots of substances. I wouldn't expect much of it to transfer to humans)))


Abstract follows:

The Senescence-Accelerated Mouse (SAM) strain was established in the Department of Senescence Biology, Chest Disease Research Institute, Kyoto University, as a novel murine model of senescence acceleration and age-associated disorders. This strain is actually a group of related inbred strains (recombinant inbred strain-like) including nine strains of accelerated senescence-prone, short-lived mice (SAMP) and three strains of accelerated senescence-resistant, long-lived mice (SAMR). Each SAMP strain shows relatively strain-specific age-associated pathologies. These characteristic pathological phenotypes are similar to those often observed in elder humans. They include senile osteoporosis, osteoarthritis, age-related deficits in learning and memory with/without forebrain atrophy, presbycusis, senile amyloidosis, age-related impairment of the immune response, and so on. The common aging characteristic of SAMP strains is senescence acceleration after normal development and maturation. We have made attempts to intervene the senescence acceleration and specifically in these pathologies: senile osteoporosis and the age-related deficits in learning and memory. These attempts, including caloric restriction, administration of nutrients, chemicals and traditional herbal medicines, show beneficial effects on the aging process of these mice. Similar interventions may prevent or control the onset and progress of age-associated disorders in other species and may have clinical relevance for humans.

Growth Hormone: A Physiological Fountain of Youth?

Summary: Need more data. Doesn't look encouraging.


Paper by Jason Wolfe in Journal of Anti-Aging Medicine, Volume 1, Number 1, 1998, published by Mary Ann Liebert Inc (it always is, so consider that your final notice)

This is a review paper of the use of growth hormone with respect to preventing/reversing aging. The idea of why it's worth trying is simple: growth hormone (GH) triggers building of protein and growth of tissue in general. It generates muscle, grows your thymus (immune system trainer/storage) and shrinks adipose tissue (fat). Old people become smaller and their tissues shrink. They are also made of fat (40% in over 75s vs 20% in the young and spritely). Their growth hormone levels, coincidentally, drop like a bitch (14% per decade, dunno if that's simple or compound interest).


GH is triggered/upregulated by growth hormone releasing hormone (GHRH). It is also thought to act mostly through the upregulation of IGF-1 (Insulin-like growth factor). (((Since mutations in IGF-1 receptors in mice lead to big life extension effects, and caloric restriction is also probably related to lowering IGF-1 levels, this seems like a big no-no))).


Early smallish experiments injecting GH into over 60 year olds increased muscle mass sometimes, by a little bit, decreased fat content and increased bone density. No cognitive benefits though, and raised blood glucose levels. The effect on muscle mass was also 10 times smaller than doing exercise.

Studies then tried raising GH by going upstream and injecting GHRH (((mainly because it's a simpler/cheaper molecule I think))), but while it triggered GH, they weren't seeing the increases in IGF-1 that they wanted, unless they injected twice a day. Also, IGF-1 trended back to pre-injection levels during the study.

Finally, some small synthetic molecule was found by accident to raise GH levels. It was modified so that it could be sniffed or eaten which is a big benefit over injections. It raises GH, raises IGF-1, doesn't do anything crazy.

(((Conclusion: no obvious data with regards to longevity. The samples were way too small and young to look for mortality differences. All studies here I think were on quite small groups (20 people or less). No obvious benefits with respect to immune system. If it does turn out to be beneficial, the synthetic seems like a nice thing to have. The author is much more upbeat than this though)))

Abstract follows:

During childhood and early adult life, growth hormone (GH), secreted by the anterior pituitary, is involved in the growth of bones and muscles and other organs as well. Aging is characterized by a decrease in muscle mass and bone strength and an increase in adipose, similar to the effects of pathological hyposecretion of GH in the young. Aging is also accompanied by a gradual decrease in the output of GH, like the drying of an internal fountain, until in the eighth decade of life, it is secreted at less than one-fifth of the "youthful" level.

The GH hypothesis of aging posits that with the availability of human recombinant growth hormone and human recombinant insulin-like growth factor-I, which mediates most of the effects of GH, the GH hypothesis has become testable. Initial experiments involving short term administration of GH in a group of elderly men did indeed show modest improvement in lean body mass and adipose tissue. These studies are sometimes—and incorrectly—taken as proof of the correctness of the growth hormone hypothesis of aging. Subsequent year-long studies have shown GH therapy causes significant adverse effects. Other concerns of long-term treatment include possible diabetogenic effects, potential for increased risk of cancer, and high costs (>$10,000/yr). IGF-I, which mediates most of the effects of GH, is also being explored experimentally, but its role as a growth factor raises fears about tumor induction.

Methods being explored to raise GH levels more physiologically include: GHRH, the GH— releasing hormone produced by the hypothalamus; GH-releasing hexapeptides (GHRPs) which stimulate GH secretion via a novel receptor whose normal function is unknown; and orally active aromatic compounds, developed synthetically which mimic the effects of GHRPs. Because of the unknown long-term effects of elevated GH in the elderly, mimetics should be carefully restricted to clinical trials and temporary needs.

And so it begins

This is my experiment with blogging. It is also my experiment with reading a journal on a regular basis. I've got access to a very extensive e-journal collection that includes "Rejuvenation research". I'm not a doctor, nurse or biochemist, but I've had an interest in Not Dying Yet for a while now, and find reading about anti-aging fun, so I plan to read it from the beginning, I'm OCD like that, when it was called the "Journal of Anti-Aging Medicine" back in '98, and make my way forward, writing summaries of the bits I find interesting.

The posts title will just be the title of the papers, the content will be my interpretation or the bits I care about. I'll follow a BruceSterlingesque commenting style, in that if I'm saying something not taken from or not related to the paper, it will be inside (((triple parenthesis))). This will not, as far I can tell, be an entertaining blog.