Thoughts on Aging as Damage versus Aging as a Program of Altered Gene Expression
The article I'll point out today manages to capture much of the gist of the present state of interactions between two opposing viewpoints on aging: firstly that aging is the consequence of an accumulation of cell and tissue damage, a byproduct of evolutionary focus on early life success, and secondly that aging is an evolved program in its entirety. In essence, the trend is now towards some form of synthesis of these two viewpoints, that the panoply of mechanisms making up degenerative aging contain something of both stochastic damage and programmed functions. One might look at the present state of the hyperfunction theory of aging as an at times confusing and contradictory effort to produce such a synthesis.
At the time that these views emerged in opposition, it mattered as to which viewpoint governed the direction of research and development aimed at intervening in the aging process. If aging is damage, then identifying and repairing damage is the only viable approach likely to produce sizable gains in health. If aging is a program (that produces damage), then adjusting gene expression and the operation of metabolism is the only viable approach likely to produce sizable gains in health.
One could point to the Strategies for Engineered Negligible Senescence for a clear paradigm of damage repair (and still can, as its component parts have been demonstrated to be useful by the results of animal studies). One could point to efforts to alter epigenetic control over gene expression, and thus the operation of metabolism, as clearly falling into a paradigm of attempts to control an aging program. That division has been muddied by the discovery that DNA double strand break repair produces epigenetic aging, coupled with the development of epigenetic reprogramming as an approach to restoring youthful epigenetic patterns to aged cells. Epigenetic reprogramming would have been called an effort to alter metabolism to adjust the aging program, but thanks to new discoveries can now be thought of as a form of damage repair. The world turns, and matters change.
Why Aging Is Not Fundamentally Programmed - and Why Programming Still Matters
Theories of aging can be broadly categorized into two groups. On one hand are those that think aging is caused by accumulation of damage due to entropy and that solving aging requires repairing these damages. On the other hand are those that think aging is driven by an evolved genetic program whose function is to cause aging. They think the solution to aging is to instruct the body to fix itself by reprogramming its cells.
The latter view has become more popular lately since it was discovered that cells can be reprogrammed to become younger in most aspects, by changing their gene expression. That shift was also amplified because several early "damage theories" were framed as overly narrow single-cause explanations that failed to explain aging (the free radical theory of aging is a classic example). Reprogramming therefore started feeling like a more complete theory. Some scientists think that if we could simply rejuvenate all the cells in the body through reprogramming their gene expression, we could then rejuvenate the whole body and effectively solve aging.
A critical error in modern aging debates is thinking that aging must be caused by either damage accumulation or programming, while in fact, both factors play a strong role in aging. More accurately, aging is fundamentally caused by accumulation of damages, but it is also influenced very strongly by programming. Reprogramming is a highly promising strategy to slow down and reverse aging. The point is, we will never get close to fully reversing aging in humans without addressing damage accumulation also. Reprogramming may partially restore many cells to more youthful states, but it cannot automatically remove a great portion of structural damages such as many of those found in the extracellular matrix.
Olafur is close to hitting the target, but I count this essay as a miss for two reasons. (1) He ignores the fact that humans, like ants, bees, and termites, are a social species, which means the the evoluntioary unit is the group, and that evolutionary forces continue to act long after the age of reproduction, leading to our long lifespans as primates. (2) The word "mitochondrion" appears in the article only in one of the reference titles. In discussing the general concept of damage, he ignores the strong evidence that the unrepaired damage to mitochondrial DNA grows at least 20 times faster than that of nuclear DNA, and that past about age 65, mtDNA deletion damage grows exponentially, with a short doubling time, leading to a devastating loss of ATP cell energy and triggering all the other aging "hallmarks." Ignoring or misunderstanding these key aspects makes the essay rather beside the point in understanding human aging,
"The practical implications of the above are that aging will not be stopped or reversed fully by picking sides and tackling only damage accumulation or programming."
I don't agree with the author on this. He clearly demonstrated that reprogramming is not enough for treating aging, but I don't see any proof in the article that damage repair is not enough.
Dr John Cramer (90) is a physicist, so he knows something about entropy. He is also the first volunteering to get bioreactor grown mitochondria transplant, so he has done his homework on that. He is also on biological age self assessment since long. So overall I trust what he says.
If aging isn't programmed then explain why we can't make a mouse live as long as a human?
Explain why people living a 'hard life' can still live well into 70 (or later if you're Keith Richards).
If this was about random damage, then lifestyle should have a much more drastic effect on longevity. As is, outside of starvation or morbid obesity, a lifetime of shitty diets, drugs, sun over exposure, etc, doesn't shift the curve all that meaningfully. It leads to more cancer and heart disease, sure, but the aging process isn't affected much.
And if we were to eliminate all cancer and heart disease, overall longevity would barely budge for the general population.