A Programmed Aging View on the Mitochondrial Free Radical Theory of Aging

The data that will eventually make up a complete understanding of how aging progresses in an entire organism - with full descriptions of the relevant processes running all the way down to cells, sub-cellular components such as mitochondria, and interactions between proteins - is still very early in the game of assembly. It's a vast jigsaw puzzle in which researchers have assembled some of the more interesting areas, and have a good idea of the overall shape of things, but lots of pieces have yet to be fitted and large gaps remain. One of the consequences of this state of affairs is that researchers with quite different and even mutually exclusive theories on how aging progresses can all marshal a decent argument and use the known assembled areas to support their view.

The most important difference between different theories of aging is, I think, that between programmed aging and aging as stochastic damage. Programmed aging suggests that aging is an evolved genetic program that enacts epigenetic changes that in turn cause harm, perhaps because evolution optimizes for early life success, and the resulting programs run awry in older age, after the point at which there is little to no selection pressure to correct the crumbling of old flesh. The view of aging as stochastic damage is the exact opposite: damage to cells and protein machinery accumulates as a side-effect of ordinary metabolic operation, and the characteristic epigenetic changes observed with age are evolved compensatory mechanisms that try - and ultimately fail - to adapt to growing levels of damage. Evolutionary pressures that lead to good damage resistance, compensatory, and repair mechanisms are strongest for young individuals and weakest for old individuals. Hence the result is aging, which is just wear and tear in an evolved self-repairing system, wherein evolution (to a first approximation) only cares about the young.

So we have programmed aging, in which epigenetic change causes damage, and then aging as stochastic damage, in which damage causes epigenetic change. This is an important division because theory drives research strategy: in the programmed aging world there can be no rejuvenation without rebuilding or resetting human metabolism, and periodic repair of damage is doomed to ultimate futility. In the aging as stochastic damage world, periodic repair of damage will produce rejuvenation of the old and is the best of all therapies, while attempts to rebuild human metabolism are futile, expensive, and doomed to produce little benefit. Based on my years of reading around the field, I think that the balance of evidence strongly points to our living in stochastic damage world, which is why I support SENS research - but people who think otherwise are going to advocate for research strategies such as manipulation of mTOR levels in adult tissues that I see as largely useless in terms of practical results on human life span.

Mitochondria are the power plants of the cell, and their role in aging currently spans a handful of semi-assembled sections of the jigsaw puzzle. There is enough empty space left in this area of the puzzle for various groups to field their own quite different interpretations on how exactly it is that mitochondria contribute to aging. The view I'm in favor of is essentially the mitochondrial free radical theory of aging - the DNA inside mitochondria becomes damaged, some damaged forms take over some cells because they are not destroyed as readily by quality control mechanisms, and then the cells malfunction to export lots of damaging oxidative compounds. This is very much a viewpoint of the aging as stochastic damage camp, but another good reason to favor it is that it is only a few years of decent funding away from being testable in mice, through one of the nascent methods of repairing or replacing mitochondria.

Here is a different take on the mitochondrial free radical theory of aging, however, one from the programmed aging camp, set out as an explanation for the layperson:

New Take on Free Radicals

In Barja's version [of the mitochondrial free radical theory], the leakage of free radicals [from mitochondria] is not unavoidable; rather toxic by-products are borrowed (co-opted) for a purposeful self-destruction. Thus he turns the weakness of MFRTA into a strength, noting that the rate of leakage is dramatically variable from one animal species to another, and in different tissues at different times. This must be purposeful, and the purpose (aging→ death) is modulated according to environmental cues.

Part of the problem with the MFRTA theory is that the damage is centered on the mitochondria, which are dynamic, "disposable" organelles within the cell. Barja wondered how might it come about that mitochondria inflict permanent damage on the cell? Three years ago he found a clue. Mitochondria retain a bit of their own DNA, a relic from their historic origins as independent bacteria. Mitochondrial DNA (abbreviated mtDNA) is exposed to the [free radical] products of oxidative chemistry at close range, and is easily damaged. Sometimes the mtDNA is broken by the [free radicals that the mitochondria produce].

What Barja found (in collaboration with labs of Juan Sastre and Maria Jesus Pertas) is that mtDNA fragments are released into the cell and even into the bloodstream. Some of these fragments find their way into the cell nucleus, and they can insert themselves into the nuclear DNA, where they might do great damage. There are many redundant copies of mtDNA, but only two copies of the nuclear DNA. Barja was able to detect sequences associated with mtDNA in samples of the nuclear DNA taken from tissues of young and old rats. There was consistently more mtDNA in the old rats than the young, and up to four times as much in some samples. This suggests that [damage] occurring at the site of the mitochondria can transfer itself to the cell nucleus, and there it can persist and accumulate with age.

Though you should really read the open access paper for a better outline of this researcher's objections to the mitochondrial free radical theory of aging. It's much more of a casual read than the abstract might suggest:

Updating the Mitochondrial Free Radical Theory of Aging: An Integrated View, Key Aspects, and Confounding Concepts

An updated version of the mitochondrial free radical theory of aging (MFRTA) and longevity is reviewed. Key aspects of the theory are emphasized. Another main focus concerns common misconceptions that can mislead investigators from other specialties, even to wrongly discard the theory. Those different issues include (i) the main reactive oxygen species (ROS)-generating site in the respiratory chain in relation to aging and longevity: complex I; (ii) the close vicinity or even contact between that site and the mitochondrial DNA, in relation to the lack of local efficacy of antioxidants and to sub-cellular compartmentation; (iii) the relationship between mitochondrial ROS production and oxygen consumption; (iv) recent criticisms on the MFRTA; (v) the widespread assumption that ROS are simple "by-products" of the mitochondrial respiratory chain; (vi) the unnecessary postulation of "vicious cycle" hypotheses of mitochondrial ROS generation which are not central to the free radical theory of aging; and (vii) the role of DNA repair concerning endogenous versus exogenous damage. After considering the large body of data already available, two general characteristics responsible for the high maintenance degree of long-lived animals emerge: (i) a low generation rate of endogenous damage: and (ii) the possession of tissue macromolecules that are highly resistant to oxidative modification.

It is an interesting assembly of data, and as usual with publications one might disagree with at the high level there's plenty in there to agree with on other levels. I'm somewhat skeptical of the relevance of some of the points, however. For example, that antioxidant supplementation doesn't really do much to the pace of aging. That is a valid and good objection to the early and general free radical or oxidative theories of aging, but it is absolutely the case that suitably designed antioxidant compounds targeted to mitochondria improve health and extend life. What the general failure of all other antioxidant strategies tells us is that the biology here is complex: it matters exactly where those antioxidants go, and what chemical form they have. Near all forms of antioxidant won't find their way to the mitochondria where they might do some good, and will in fact tend to interfere in the role of oxidative compounds in hormetic processes, such as those involved in producing the health benefits of exercise.

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