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.