Biochemistry (Moscow)'s Issue on Programmed Aging
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Leonid Gavrilov was kind enough to point the Gerontology Research Group list in the direction of a recent open access issue of Biochemistry (Moscow). It's in English and the focus is on what the editors call "phenoptosis," a term that means programmed aging.

Some debate continues within the scientific community over the degree to which aging is programmed, which aspects of aging are programmed, and whether it is fair to call the body's characteristic responses to accumulated stochastic damage a form of programmed aging. Patterns of gene expression clearly change in fairly defined ways with aging, for example, and it is well known that stem cell populations decline and become less active - but is that just a reaction to levels of damage, or something else? This feeds into discussion over strategy when it comes to how to approach development of therapies for aging. Is it sufficient to repair all cellular and molecular damage caused by the operation of metabolism, because all forms of programmed aging are just reaction to that damage? Or even after researchers realize the SENS vision of rejuvenation biotechnology, would they then have to build further genetic therapies to block forms of decline that proceed independently of damage? From my view of what is known, I think the evidence leans more towards the former than the latter situation - and either way, we should still be working to realize rejuvenation biotechnology.

In any case here is an excerpt from the open access papers in Biochemistry (Moscow) Volume 77(7):

What Is "Phenoptosis" and How to Fight It?

Aging of an organism can be defined as a balanced decay of many physiological functions with age, leading to gradually increasing risk of death. The key question is: what is the cause of such a decay of body functions? Two main views on this problem have been competing in biology for a long time - an optimistic and a pessimistic one. The first approach believes aging to be the final stage of our ontogenetic program; this assumption implies the possibility of canceling aging by switching off this stage. The second approach considers aging to be an inevitable result of the functioning of a complex living system: the accumulation of errors and damage in its biomolecules, depletion of "life force", operation of certain genes that used to be originally useful but became harmful with age, etc.

It is obvious that if the pessimistic hypothesis is true, then any attempts to fight the process of aging are doomed to failure: all of us are destined to get broken like an old car. One of the leading gerontologists of the XX century, Alex Comfort, stated though that it is difficult to believe a horse and a carriage age in the same way. Nevertheless, the majority of gerontologists still oppose the theory of programmed aging. It is only very recently that certain data have been obtained providing direct support for the optimistic concept. These data allow us to understand how these age-activated biochemical mechanisms of the decay of body functions might have appeared in the course of evolution.

Interestingly, this is the exact opposite of the way I see the situation. We are actually in a far better situation as the damaged car than as an entity that undergoes programmed aging. If the SENS view and the reliability theory view of damage as the source of aging are correct, then we already well understand how to fix things: we have a detailed list of the damage modes, and a detailed list of plans to deal with them. When it comes to programmed aging, however, there is nothing in the field that even begins to amount to that level of clarity. It's exactly the same problem as for attempts to slow aging through genetic and metabolic manipulation: it requires understanding and safely producing new long-term working states in human metabolism - an undertaking of massive proportions. In contrast the just-repair-the-damage approach requires that researchers revert known age-related changes in human metabolism to restore it to the state it held when young. No new working state, but rather keep the metabolism that is already known to work and repair it every so often.

But you should peruse the whole issue: many interesting arguments are put forward.

Comments

We come to this question with a set of preconceptions: that Darwinian selection has maximized our individual fitness, and that it's not possible for Evolution to have created a genetic program that is bad for us as individuals.

I'd like to point out, first that there are many good reasons to suppose that Evolution favors the group as much as the individual, and will sacrifice the individual in a heartbeat when necessary to preserve the group; and second, that if we look at the evidence dispassionately, without preconception, there is overwhelming reason to think that aging is programmed.

1. Reasons to suppose evolution is oriented toward groups and not just individuals:
a) The existence of 2 sexes costs us all a factor 2 in fitness, compared to hermaphrodites like worms and most flowers. Separate sexes has evolved in a great majority of higher species, at a cost of a factor of 2.
b) Ecosystem stability does not come free. If every species is in a free-for-all, then every population is either growing exponentially or crashing catastrophically. You can't build a stable ecosystem out of individuals that are all trying to maximize their individual reproduction.
c) Think about the evolution of hox genes. The whole system of inheritance has been highly optimized to promote not fitness but the RATE OF EVOLUTION. This is more evidence that evolution is capable of doing more than just maximizing individual fitness.

2. Once we drop this idea that individual fitness has been maximized, there are abundant reasons to see aging as programmed:
a) The genetic mechanisms that control aging are very old and highly conserved. AGE-1 and DAF-16=FOXO and IGF-1 are families of genes that go way back to worms and yeast, and are still active in mammalian aging. Genes that are highly conserved suggest adaptive value.
b) We do better under hardship than under cushy conditions. Hormesis. The mice that live longest are starved near to death and running (human-scale) miles every day. If the body were trying its hardest to live as long as possible, then why would it do better when struggling than when the pressure is off? Exactly what is the body capable of doing only when stressed and starving that it is NOT capable of doing when fully-fed and relaxed?
c) Many of the pro-aging genes that have been identified have no known pleiotropic benefits.
d) The two ancient mechanisms of programmed death of single-cell protozoans - apoptosis and cellular senescence - are deeply implicated in human aging.

Much more on all these points here: http://mathforum.org/~josh/TheCase4AdaptiveAging.pdf

Posted by: Josh Mitteldorf at July 26, 2012 5:40 AM
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