Aging as the Failure of Youth-Maintenance Systems

A group of scientists who are primarily involved in calorie restriction research here make the case aging to be caused in part by the declining activity of youth-maintenance programs, such as high levels of stem cell activity, high levels of the cellular repair processes of autophagy, and so forth. This is a novel viewpoint insofar as they wish to highlight this decline as something distinct from the matter of damage, and cordon it off as an area for particular study. This makes some sense from the perspective of calorie restriction and related interventions that slow aging via increased stress response activities, meaning more repair and more regeneration.

Why does maintenance of tissues fail with age? Those of us in the camp that sees aging as the result of accumulated molecular damage consider this decline to be the result of rising levels of molecular damage in cells and tissues. The programmed aging camp would no doubt suggest it to be part of an evolved program that actively limits life span. I think that the existence of metabolic waste products that are both damaging and resistant to clearance by our biochemistry tends to swing the argument in favor of aging as damage. One cannot just instruct cells to act in a more youthful fashion in order to reverse the accumulation of these waste products, which is the preferred approach for many in the programmed aging community.

Many theories have been proposed to explain the aging process ranging from the free radical theory of aging, to the disposability theory, and antagonistic pleiotropy theories. These were formulated to explain why organisms age and are consistent with the acceleration of damage and dysfunction as the force of natural selection declines. However, we can also consider aging to be the result of the end or at least of a partial inactivation of a "longevity program" whose scope is to maintain the organism in a youthful state. This is distinct from the more controversial "programmed aging" theory, in which the aging process has been selected to provide both genetic variability and the nutritional resources to promote fitness.

Although the existence a longevity program is very much consistent with the natural selection theory and may appear to be just another way to explain aging, it is not because it relates less to senescence and much more to a series of protection, repair, and replacement events aimed at keeping the organism young. I propose that this field can be termed "juventology" (the study of youth) from the Latin iuventus or "the age of youth."

For example, we know that S. cerevisiae grown in glucose medium can survive for ~6 days in a relatively low protection mode. However, when it is switched to water, stress resistance can increase several folds as does lifespan but also the period in which cells are able to reproduce and form colonies. Thus, there are clearly at least 2 longevity programs that can be selected by yeast cells and which are entered based on the type and level of nutrients in the medium.

This is a fundamental distinction from the "aging-centered" view for two reasons: (a) a longevity program based on the understanding of juventology, such as the alternative lifespan programs entered in response to fasting, may be independent or partially independent of aging. For example, the use of drugs and periodic fasting, both of which target the mTor-S6K and PKA pathways, can promote regeneration and rejuvenation. Thus, an organism could be aging at a higher rate and yet have a longer healthspan and lifespan by periodically activating regenerative and rejuvenating processes and (b) by shifting the focus from "old or older age" in which dysfunction generates high morbidity and mortality, to the period during which both morbidity and mortality are very low and difficult to detect.

For example, human diseases are rare before age 40, but very common after age 65, yet no specific field of science is focusing on how evolution resulted in a program that is so effective for the first 40 years of life and how that program may be extended by dietary, pharmacological, or other interventions.



I wouldn't call it (as the author of the paper does) a "longevity program." It is a "development & reproduction program." It's obvious that there must be a evolutionary program to take an organism from conception to young adulthood and reproductive years. It seems clear to me that once reproductive age is reached, the evolutionary pressure to maintain homeostasis is weak or nonexistent, thus allowing damage accumulation to commence, without a countervailing imperative to repair damage and regenerate. As damage accumulates, the inflammmaging burden does also, accelerated by the SASP, driving the aging phenotype leading to the onset of the many diseases of old age. So I reject the notion of an "aging program"…but there definitely is (in my view) a development program which become dis-regulated with the passage of time.

Posted by: Gary at October 24th, 2018 11:55 AM

Gary you are absolutely right about "development & reproduction program."!
The paradox of Petty - Large organisms live longer than small ones, their cells are less susceptible to cancer. The reason is that they develop longer, the health maintenance program is longer.

Posted by: Dmitry Dzhagarov at October 25th, 2018 6:09 AM

The existence of a program to take an organism to reproductive years is undeniable. But why does the duration of that program vary so much even between mammals? Takes a human about 12-14 years to reach sexual maturity, but a horse - less than a year! Chimps or gorillas sexually mature around 7-8 years old, and gorillas are bigger than humans. So it's obviously not a matter of size: even whales mature at 5-7 years of age. Clearly, evolution isn't always trying to speed up reproduction. Or maximize it for that matter - humans are capable of giving birth to large litters (think septuplets), but most of the time there's only one fetus per pregnancy.

Also, why should selective pressure decrease once an organism reaches sexual maturity? The longer an individual can stay reproductively active, the more progeny it can create. The cost of keeping a breeding adult organism alive sure seems lower than creating one from scratch and then growing it for an X number of years to reach the very same result of a reproducing adult. So again, it doesn't look like evolution is trying to maximize an individual's reproductive period. On the contrary, it actively restricts it: post-reproductive lifespans are a common trait from nematodes to drosophila to mammals.

Finally, why doesn't "damage" accumulate faster in whales than in humans? They are many orders of magnitude bigger than us but live longer.

Posted by: Curious George at October 25th, 2018 10:55 PM

@ Curious George: All excellent questions. I don't claim to be an evolutionary biologist, so I can't answer them. My purpose in writing down my random thoughts above was largely to get people thinking about a hybrid solution to the programmed vs. damage accumulation theories of aging.

I think some answers might be found by looking at so-called negligibly senescing animals, such as certain pelagic seabirds which produce offspring throughout their lives (Tuck Finch has the story of a long-lived Stormy Petrel in his "Natural History of Aging" book), the Blanding's tortoise (which grows more fecund with age, females actually increase clutch sizes) and similar critters.

Posted by: Gary at October 26th, 2018 12:22 AM

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