The Growth of Programmed Aging Theories in the Research Community

There are two important battles in the matter of aging research. The first is to convince people that aging should be treated as a medical condition at all. This has, finally, largely been won within the scientific community, or at least those parts of it that matter, but is still very much an ongoing concern when it comes to the public and potential sources of large-scale funding. The second battle is between the classes of theory of aging that determine what types of therapy should be developed. On the one hand there is the prevailing majority view of aging as the result of accumulated molecular damage to cells and tissues, that in turn produces all sorts of further harm and reactions in cellular behavior. That means therapies should aim to repair that damage, though, sadly, most researchers who hold to the damage theories of aging are in fact more focused on therapies that only slow down the rate at which damage accumulates. On the other hand, there is the growing minority view of aging as an evolved program in which epigenetic changes cause changes in cellular behavior that in turn lead to the accumulation of damage. There is a lot of debate within the programmed aging community as to the nature of this program and its relationship with evolutionary theories on aging, but regardless of that, the basic concept implies that repair of damage is marginal and therapies should try to revert epigenetic changes that occur with age, such as via the use of drugs or gene therapies to alter cell behavior.

So we have two views of aging that stand in opposition to one another because the strategy for development of therapies that emerges from each is opposed. The yet-to-be-developed therapies thought to be effective in one paradigm are expected to be marginal in the other - and that matters greatly for those of us likely to age to death if the wrong lines of development come to dominate the field for too long. If you think that damage is the first cause of aging, then tinkering with epigenetics is evidently going to do little good. If you think that epigenetic changes are the first cause of aging, then repairing the damage without changing cellular operations is not the way to go. Interestingly, I think that the past decade of growth in publications and discussion of programmed aging has its roots in changes outside the scientific community; that it has a lot to do with the widespread adoption of automated translation technologies, as these have enabled closer ties between the Russian and English language aging research communities and their supporting network of advocates and funding sources. The Russian aging research community is much more in favor of programmed aging, and provides the necessary critical mass of thought and work to bring programmed aging to a larger audience in the English-language community.

For my part, I think that the best argument against programmed aging is that there are forms of metabolic waste that the body cannot effectively break down. Components of lipofuscin and glucosepane cross-links for example. You can change all the epigenetics you want, assuming a way can be found to force cells into a replica of their youthful state, but that won't enable them to clear out that harmful waste. Further, there is plentiful evidence for higher levels of these metabolic waste compounds to contribute directly to age-related pathologies, and it would be hard to postulate a way for that to happen with it also producing epigenetic changes in cells. These two points interact to strongly suggest that programmed aging is incorrect. I'm also of the mind that this debate will be settled fairly conclusively within the next decade, as the first therapies resulting from both sides are deployed. My expectation is that efforts to repair damage will produce robust rejuvenation and that efforts to restore youthful epigenetic patterns and signaling in cell environments will, where successful, produce results that look a lot like those achieved via stem cell therapies to date - putting damaged cells back to work, but not repairing underlying causes of aging. Regeneration, to some degree, but not rejuvenation. These are quite different outcomes, and should be clearly distinct from one another once biomarkers of aging are used in their assessment. At the moment, however, I suspect there is a quite of lot of confusing regeneration for rejuvenation taking place.

Twenty years ago, I first started writing that aging is something the body does to itself, a body function, rather than deterioration or loss of function. Journals would not even send my submission out for peer review. The conflict with prevailling evolutionary theory was just too deep. But in the interim, the evidence has continued to pile up, and many medical researchers have taken the message to heart in a practical way, setting aside the evolutionary question and just pursuing approaches that seem to work. The most promising developments in anti-aging medicine involve changing the signaling environment rather than trying to "fix what goes wrong" with the body.

My popular book exploring the evolutionary origins of aging (and implications for medical science) came out in June, and an academic version of the same content came out in October. Gandhi taught me, "First they ignore you, then they laugh at you, then they fight you, then you win." The paradigm of programmed aging passed this year from stage 2 to stage 3, with prominent articles arguing against the possibility of programmed aging. Current Aging Sciences devoted a full issue to the question. I welcome the discussion. This is a debate that colleagues and I have sought to initiate for many years. There are powerful theoretical arguments on one side, and diverse empirical observations on the other. The scientific community will eventually opt for empiricism, but not until theory digs in its heels and fights to the death. A basic principle of evolution is at stake, and many theorists will rise to defend the basis of their life work; but a re-evaluation of basic evolutionary theory is long overdue. The idea that fitness consists in reproducing as fast as possible is no longer tenable. For plants, this may be approximately true. But animal populations cannot afford to reproduce at a pace faster than the base of their food chain can support. Animals that exploit their food supply unsustainably will starve their own children, and there is no evolutionary future in that. This is a principle that links together entire ecologies, and the foundation of evolutionary theory will have to be rewritten to take it into account.

For many years, I put forward the argument that programmed aging means there are genes that serve no other purpose than to hasten our death, and that medical research should be targeting the products of those genes. But in recent years, epigenetics has eclipsed genetics as the major theme in molecular biology. Everything that happens in the body is determined by which genes are expressed where and when. The vast majority of our DNA is devoted not to coding of proteins but to promoter and repressor regions that control gene expression with exquisite subtlety. There has been a growing recognition of aging as an epigenetic program. As we get older, genes that protect us are dialed down, and genes for inflammation and apoptosis are dialed up so high that healthy tissue is being destroyed. Many epigenetic scientists have discovered this, and they find it natural to see aging as a programmed phenomenon.

A few years ago, I wrote about transcription factors as the key to aging. At first blush, it seems that an epigenetic program is just as amenable to pharmaceutical intervention as a genetic program. Transcription factors bind to DNA and turn whole suites of genes on and off in a coordinated way. This summer, I had a chance to work in a worm genetics lab and consult closely with people who know the experimental details. I learned that there is no clear line between functional proteins and transcription factors, that many proteins have multiple functions, and that metabolites feed back to control gene expression. I still believe that there are one or more aging clocks that inform the body of an age-appropriate metabolic state, and synchronize the aging of different systems. Telomere length is one such clock. If we can reset an aging clock, the body will repair and clean itself up. If we can reset several clocks, the body may be able to restore itself to a younger state. But I recognize the possibility that the clock is diffused through the detailed epigenetic status of a trillion cells, and may be beyond the reach of foreseeable technology. Short of resetting the aging clock, there are several technologies just over the horizon that should offer substantial life extension benefit. I believe the best prospects are senolytics (ridding the body of senescent cells), telomerase activators (rejuvenating old stem cells), and adjusting blood levels of key hormones and cytokines that increase or decrease with age.