GH Secretagogues in Aging

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

Interestingness: 2

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

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

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

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

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

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Abstract follows:

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

Rest of volume 3, Issue 1

The rest of issue 1 of 2000 consists of:

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

Role of Cell Senescence in Human Aging

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

Interestingness: 7

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

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

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

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

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

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

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

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

Summary: Waka waka waka wakke waka waka weh weh

Interestingness: 1

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

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This is a long sell-piece of the field of chronobiology. They want people to analyse data assuming a cyclic underlying pattern. I liked their last paper (http://readingrejuvenationresearch.blogspot.com/2010/06/circadian-hyper-amplitude-tension-chat.html), it was a bit out there, used quite unusual-to-me analysis and graphs, and had a bit of data. This one is waaaayyyyy too out there. They basically want to pump the study of all time cycles, and though I can see good reasons for circadian and yearly and all sorts of in-between rhythms being important, they suggested links between the sunspots on the sun and the levels of some type of steroids in urine based on the collections of one person for 1.5 cycles. I'm not buying this second type of cycle. I was surprised this paper was not rejected based on its literary style alone.
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For dealing with everyday physiology, that is, with respect to physiological variation in the normal range, the prevailing position corresponds to that in preatomic physics. The "a-tom" was then the smallest known particle that could not be further split. Breaking the atom opened the door to a new universe of particles governed by new forces and physical laws. Nuclear physics evolved and brought new knowledge, a new energy source and a wealth of practical applications. The analogy applies to the splitting of the normal range into the time structures of everyday physiology. From picking different times of day and seasons for study, a trans-disciplinary science, chronobiology, emerged. Chronobiology objectively maps chronomes (portmanteau'd from chronos = time and nomos = rule), time structures quantifying the relations among cycles and other events. The chronomes of variables in and around us intermodulate with each other; thus, we start exploring organisms as dynamic systems open to their environments near and far, and dependent upon them, beyond air and food. Entering the realm of everyday physiology allowed us to quantify, with refined indices, associations of life with remote drummers. The intermodulating feedsideward mechanisms involved in cosmophysical associations of life on earth may be in part endocrine responses to factors far beyond visible light and temperature. Pertinent knowledge may serve to optimize the quality and duration of life.

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

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

Interestingness: 2

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

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

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

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

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

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

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

Interestingness: 3

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

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

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

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

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Abstract follows:

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

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

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

Interestingness: 6

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

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

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

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

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

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

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

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

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

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

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

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

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

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Abstract follows:

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