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Hi.

I've decided to explore this forum again after an absence of a couple of years.

I am a grad student studying the biology of aging. I work primarily with long-lived mutant mice and caloric restriction.

I've been reading about Objectivism for a decade, since I read The Fountainhead at 15. In the last few years my understanding has dramatically increased, in part due to my greatly expanded library of lectures from the Ayn Rand Bookstore. I recommend particularly Leonard Peikoff's courses on the history of philosophy, the DIM Hypothesis, and Objectivism through induction. As to applying Objectivism in action, Tara Smith's lectures are invaluable, especially those on purpose and pride, as well as on self-interest and rationality. I've also found of great educational value generally Eric Daniels' courses on the history of America and on the inventors, and David Harriman's lecture on the philosophic corruption of physics, as well as his fantastic course on physics available through the VanDamme Academy, to name a few.

I found the discussion here to be valuable in the past and I look forward to participating.

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Hello, I was not around when you were using this forum last I suspect. I certaintly dont remember you, but in any case I hope you enjoy the forum this time around.

Indeed t is quite different to what you will remember, a lot of good changes have been made, I am sure that you will largely agree.

Oh and thanks for the suggestions on the lectures, I had forgotten to try track some of those down.

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Hi.

I've decided to explore this forum again after an absence of a couple of years.

I am a grad student studying the biology of aging. I work primarily with long-lived mutant mice and caloric restriction.

Hi, welcome back.

How's that going with regard to its feasibility for humans? Last I had heard(as a laymen, not in the field) it was not thought to be effective for humans for reasons I do not remember.

ps...mods, new thread is fine by me if necessary.

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The efficacy of caloric restriction in humans is of course a question of enormous interest in aging research. CR remains the gold standard for life-extension in a wide variety of animal models, and in my view it is currently the only intervention for which a strong empirical case can be made supporting a probable beneficial effect on human aging.

However, a number of theoretical arguments, usually based on evolutionary grounds, have been raised against the possible effectiveness of human CR. On the basis of these kinds of arguments, some take the view that CR is likely to affect human aging, but only modestly, so that rather than the 50% increase in maximum lifespan seen in rodents, lifelong CR initiated in early adulthood might give a person only a few extra years at best. Moreover, there appear to be cases where CR doesn't work in certain species, or even only in certain strains within species. We cannot therefore assume that the animal findings will translate to human life-extension.

Ultimately we will not know if CR works until we have some especially long-lived restricted people to prove it, given the current difficulty in finding reliable surrogate indicators predictive of future lifespan (i.e. biomarkers of aging). In other words, we cannot now simply examine the physiology of a person on CR and say whether their biological aging process is being affected or not.

Given these reservations, however, it remains true that a large body of evidence supports the view that CR is widely effective throughout the phylogenetic spectrum, from yeast cells to insects to mammals. There is an increasingly popular view that the CR effect is an ancient and conserved adaptive response to times of food scarcity--that is, the longer lifespan on CR is a consequence of a protective metabolic strategy that was positively selected for early on in evolutionary history and still retained by most animals. The existence of species that don't benefit from CR is not prima facie evidence against this view, because there are a number of reasons why exceptions might arise during evolution. It is still possible, however, that CR is simply a passive side-effect of the way metabolism works, and not an adaptive mechanism.

Importantly, there a number of tentatively promising, suggestive findings coming out of the human CR studies that have been conducted, as well as from the longevity studies in rhesus monkeys currently underway. I think the evidence quite clearly shows that human CR provides a strong protective effect against certain specific diseases associated with aging, including diabetes, atherosclerosis, and possibly cancer. In itself this does not establish that CR would affect maximum lifespan, but it would be expected to lead to a significant increase in average lifespan. The NIA's human CR program, the CALERIE study, has recently completed its preliminary stage of 6 month to 1 year trials and will soon be initiating the more comprehensive 2 year trial phase. In addition, intriguing research has been conducted on the remarkable community of people who have voluntarily undergone long-term CR for many years, the Calorie Restriction Society.

As an introduction to the debate over human CR, I would recommend reading the special issue of the journal Biogerontology on this question. The full text articles are freely available. (Note the article from Objectivist aging researcher Robin Mockett.)

My view is that research on caloric restriction, and on the relationship between diet and the diseases of aging more generally, provides ample reason to seriously undertake the adoption of a healty diet. You need not go on outright caloric restriction to make a significant improvement in your risk of disease later in life. And even if you do not intend to restrict the amount of food you eat, appropriately selecting the kind of food you eat so as to be low in calories will effectively result in some reduction of caloric intake.

Undergoing caloric restriction should not be attempted without serious research into the appropriate methodolgy and careful weighing of the potential benefits and especially the risks.

Simply eating less will not work. It is necessary to carefully select those foods that are both low in calories and high in nutrients--otherwise you are only malnourished. And CR should be imposed gradually, over months or years--adult rodents put on CR suddenly do not get a benefit, and might actually live shorter.

Those inclined to continue gorging as a show of support for capitalist abundance may yet be able to have their cake and live longer too, as the search for a "caloric restriction mimetic" is an area of great interest, especially for the entrepreneurially-minded biogerontogist. Basically, a drug that would affect the same mechanisms as CR could turn out to be CR-in-a-pill, without the need to become an ascetic. (In actual fact though, the diet need not be unpleasant, and many CR practitioners report enjoying it greatly.)

Ultimately, CR is not the holy grail of aging research.

My primary interest in CR is as a tool for understanding the mechanisms of aging, because such an understanding will eventually allow us to intervene and extend the human lifespan far more radically than CR ever could, even if it works fully as effectively in humans as in rodents. It is possible that aging research will result in life-extending technology in our lifetimes, but that outcome is still very much in question. The scientific obstacles are vast, and the cultural opposition is pervasive. If life is a value to you, then my advice is to advocate for or support aging research vigorously, in whatever avenue you have available.

Edited by Spong
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My professor mentioned that one of the proteins that is responsible for silencing genes is NADH (I believe, could also be NADPH) dependant. I'd need to look up the specifics to be sure, but the general idea was that this enzyme is imperative for cells to function properly, and its activity is lowered when the pool of its redox factor is low. When metabolism is high (i.e. when someone is eating a lot and their cells are constantly burning lots of calories) the pool of the redox factor is reduced (or rather, the balance shifts so that a larger percentage of the redox factor is in the form that the enzyme cannot use). This causes the enzyme to function less effectively, and in that way it is thought to influence aging and the general deterioration of cells.

**I'm sorry for not remembering the exact details, but I know I remember the general idea correctly. It could be that I mentioned the wrong redox factor (that it's NAD+ dependant instead of NADH, or perhaps NADP+/NADPH dependant).

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You're thinking of the sirtuin genes. The name comes from SIR2, a yeast gene that stands for "silent information regulator 2." These genes have been of interest in relation to aging and CR since the early 90's, when SIR2 was discovered by Leonard Guarente's lab to regulate replicative lifespan in yeast. Since then they have been found to increase lifespan when overexpressed in yeast, roundworms, and fruit flies, and they appear to be involved in the caloric restriction response in these same organisms, although certain aspects of this research are highly controversial. There are seven homologs of the SIR2 gene in mammals, and my understanding is that studies are currently underway to determine the effect of increasing or decreasing the levels of the various sirtuin proteins in mice.

Sirtuins are in fact NAD-dependent deacetylases (NAD and NADP are not proteins by the way, they are nucleotide-containing cofactors), and this does potentially link metabolism and nutrient availability to the regulation of the rate of aging. As far as the silencing of genes that you mentioned, SIR2 was originally found to be involved in the "silencing" of chromatin, in DNA repair, and in the maintenance of chromosome fidelity in yeast. This activity is involved in the peculiar mechanism of senescence in yeast, which involves the accumulation of stray bits of circular DNA called rDNA, for ribosomal DNA. However, it has subsequently been discovered that sirtuins deacetylate many proteins besides chromosomal proteins, and some of their important functions probably do not involve gene silencing. Moreover, the phenomenon of rDNA accumulation causing cellular aging is to my knowledge something specific to yeast, and apparently even only to certain strains of yeast. The involvement of sirtuins in aging probably involves distinct mechanisms in higher organisms.

An interesting thing about the sirtuins is that the popular chemical resveratrol, widely touted as a potential life-extending drug and perhaps a caloric restriction mimetic, has been found to be a potent activator of the SIR2 gene. Resveratrol has been proposed as one of the main chemicals responsible for the apparently beneficial affects of red wine consumption.

For the record, the evidence for the benefits of red wine is persuasive but hardly conclusive--nevertheless that doesn't stop me from a drinking a glass each night. Certain prominent aging researchers, at least one affiliated with a company that produces resveratrol supplements, in fact consume high-dose resveratrol pills themselves. I wouldn't recommend that just yet, if only because of concerns about the efficacy and availablility of the compound in pill form.

Edited by Spong
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