Fight Aging!

In aging research, just as in any field of science where much is left to discover and catalog, and where the pace of discovery is slow in comparison to the size of the territory left to map, you will find a promiscuous proliferation of theories and hypotheses. A well constructed theory of aging can last for decades waiting to be disproved, all the while spawning variants and competitors. Hypotheses come and go almost like fashions when the time taken to gather sufficient evidence to swing the pendulum one way or another can extend for a sizable fraction of a researcher's career. This is something to bear in mind when reading any discussion of theories of aging: you are looking at a snapshot of science in development, the final answer still unsettled, all too many details yet to be filled in robustly and defensibly.

The present consensus position on aging is that it is caused by an accumulation of damage. There are probably a score of good theories discussing exactly what damage is involved, and how important various different types of damage might be. There are another score of outdated, or dubious, or too narrowly focused, or myopic theories on aging as damage beyond that circle. On the small scale there are a hundred debates over cellular and tissue damage with relation to aging, all of which are waiting on better data for one side to declare a definitive victory. That will happen for some of these issues over the next decade, with the damage caused by cellular senescence being one of the next in line, I'd imagine.

At the large scale, the big debate is between the majority position of aging as damage accumulation versus the minority position of aging as an evolved program that causes damage. This division emerges from work on evolutionary theories of aging, which are as much focused on trying to explain the origin and history of aging as on the precise mechanisms involved. Nonetheless this seems to me more important to the near future of efforts to treat aging as a medical condition than divisions within the aging-as-damage community. This is because the recommended strategy for treating aging that emerges from the programmed aging view is very different, and probably ineffective if aging is indeed damage accumulation.

In the programmed aging framework the best approach to rejuvenation is to identify changes in metabolism characteristic of old age and try to revert them to youthful configurations, such as through pharmacological interventions to change the levels of circulating proteins. In that view, changing the operation of metabolism to a more youthful track should cause damage accumulation to cease and existing damage to be repaired to at least some degree. From the perspective of aging as damage accumulation, altered levels of circulating proteins are a reaction to damage, however, and thus aiming to alter them is putting the cart before the horse - it is targeting consequences rather than causes, and should thus be largely ineffective in comparison to direct efforts to repair the damage.

Ironically much of the research community adheres to the view of aging as damage, but for historical and regulatory reasons these scientists follow research strategies that are more suited to the programmed aging playbook. If you survey the laboratories involved in aging research you are far more likely to find researchers developing drugs to alter protein levels than you are to find researchers trying to repair the recognized forms of cellular and tissue damage. This must change, I believe, if we are to see meaningful progress in our lifetimes.

Theories of Aging: An Ever-Evolving Field

Senescence has been the focus of research for many centuries. Despite significant progress in extending average human life expectancy, the process of aging remains largely elusive and, unfortunately, inevitable. In this review, we attempted to summarize the current theories of aging and the approaches to understanding it. A number of theories, which fall into two main categories, have been proposed in an attempt to explain the process of aging. The first category is comprised of concepts holding that aging is programmed and those positing that aging is caused by the accumulation of damage. Conversely, the latter category of theories suggests various sources and targets of the damage. They are not necessarily mutually exclusive. Rather, aging could vary across different species, and programmed senescence can accelerate the buildup of damage or decrease the capacity for repair.

Most obviously, the average lifespan within a given species is genetically programmed in one way or the other. Nevertheless, the current theories of aging differ in viewing aging as a consequence or a side effect of genetic pathways. According to the well-known disposable soma theory, aging is a trade-off in the allocation of limited energy resources between maintenance and restoration of tissue homeostasis and other traits needed for survival. This trade-off is demonstrated when comparing the mean lifespan of related animal species with different predation risks. When the risk is high, delayed senescence has no added benefit relative to, for example, rapid reproduction.

Nearly all current theories of aging have in common the fact that the fundamental cause of aging is the accumulation of molecular damage brought about mainly by reactive oxygen species, but the role of amyloid protein, glycation end-products, and lipofuscin is acknowledged as well. The current theories differ in the extent to which the buildup of waste is encoded in the genome and whether it is programmed death or this accumulation that is deemed to bear the costs of evolutionary benefits. In addition to damage itself, the rate of accumulation is also of concern, which results from overall metabolic activity. The most significant changes in the longevity of model organisms prove to be mutations in metabolic pathways.