WITHSTANDING FEAST AND FAMINE:
Courtesy of Leonard P. Guarente
Yeast form dormant spores during times of starvation in order to survive for future times of plenty. The cycle between diploid a/α cells and haploid spores is regulated by
Since the dawn of consciousness, humans have been in a unique position to contemplate their own mortality. While this exercise has been a boon to philosophical musings, it has not led to any real scientific progress in understanding aging. Yet studies over the past several years provide evidence that the aging process is regulated under certain environmental conditions, such as caloric restriction (CR). Therapies based on this knowledge may not be far behind.
In contradiction to the classical views about aging in evolution, simple organisms such as yeast or worms have mechanisms regulating aging that are easily altered through external stimuli, such as CR, or...
Current findings have led to a reevaluation of aging in the context of evolutionary theory. Classically, evolution places aging as a default mechanism; cellular and organismal processes across the board decline in an unpredictable way. This generates deterioration. Haphazard decline occurs in the postreproductive phase of life, and Darwinian selection does not effectively prevent such regression if an individual's genes have already been passed on to the next generation.
Thus, our genes have a limited shelf life, sufficient to get us through reproductive age, but in functional decline thereafter. By this reckoning, aging would have many causes, which could vary from organism to organism. Moreover, the postreproductive shortcomings of many genes would have to be remedied to slow aging.
Recent genetic studies in the budding yeast,
The critical function of Sir2 proteins is an enzymatic one. Sir2 is an NAD-dependent protein deacetylase. Such activity is revealing, because it couples gene silencing, via local histone deacetylation, to the cell's metabolic state. Sir2 proteins cannot bind DNA themselves, but must be directed to genes by partner proteins. The genes upon which Sir2 proteins act determine the pathways affected. In different organisms, Sir2 proteins have evolved to bind different partner proteins and thereby target different genes. In yeast, these include the ribosomal DNA, which is known to determine the life span for the organism. In
The Sir2-NAD link may allow organisms to sense food availability and stall the aging process in times of deprivation. CR prolongs life span for a wide variety of organisms, including mammals, but it was previously supposed that it altered metabolism and slowed damage independently of any specific regulator. But in yeast, the ability of CR to extend the life span requires
Evolutionarily adaptive responses to CR come in many flavors. In times of starvation, both yeast and worms form specialized body types. Yeast spores and worm dauers can survive for extraordinarily long periods during famine. When conditions improve, these dormant life forms become rejuvenated and give rise to progeny. Once again,
These considerations lead to a new view of how a single gene can determine the life span of an organism.
So the classical evolutionary theory of aging must be modified. In times of plenty, aging plays out in accord with evolutionary theory, with reproduction followed by wholesale decline. The failure of many genes evidently leads to this decline. But in times of scarcity, the survival program kicks in to decelerate aging. And a single gene can promote this survival mechanism across a wide swath of nature's creatures.
Courtesy of Leonard P. Guarente
Sir2p's dependence on the metabolic coenzyme nicotinamide adenine dinucleotide (NAD) to deacetylate and silence genes suggests a provocative connection to observed life extension by caloric restriction.
This means the question "What causes aging?" may be a futile one with many answers (oxidative damage, short telomeres, unfolded or glycated proteins, etc.). Rather, the important question may be "What regulates aging?" because a regulator would have to slow any and all causes, under the right conditions. The answer to this latter question may well be
Of course, for the purposes of human health,
This is a "good news/bad news" finding. The good news is that we may have identified a contributor to mammalian aging: the gradual death of cells by apoptosis and the accompanying failure of organs, which can be mitigated by
I think it likely that any procancer effect from
SEEKING THE ELIXIR OF LIFE
The practical benefit of these new findings may be enormous. If single genes can determine the life span of mammals, it should be possible to develop drugs that bind to the protein products of these genes to alter their activities. In this regard, I, along with Cindy Bayley and Cynthia Kenyon, founded Elixir Pharmaceuticals (Cambridge, Mass.). The goal of Elixir is to take the recent advances in aging research and identify new drug targets in aging. Thus, drugs that slow the aging process may be on the horizon. But simply extending life may not be enough. Whether such drugs prolong youth and vitality or simply increase our stay in nursing homes is an important matter.
We can consider the effects of CR on animal health. Calorie-restricted rodents not only live longer, but are vigorous and healthy for the duration of their long lives. Moreover, diseases of aging, such as tumors in mice and kidney disease in rats, are forestalled or prevented altogether. We believe that targets like
The vagaries of drug development defy an accurate prediction as to when we might see such advances, but I believe that I will be taking an anti-disease-of-aging pill in my lifetime. Any life extension is likely to be modest. Based on the effects of CR in mice, and the likelihood that such a pill would be taken later in life, I would expect a benefit on the order of a decade. This is nothing to sneeze at, but far less than we have already achieved with medical intervention in the past century. More important than longevity may be the health benefits. Maintaining vigor at advanced ages would hold considerable benefits not just in quality of life but in societal costs. The future is approaching and it looks longer and better than ever before.
Leonard P. Guarente is the Novartis Professor of Biology at The Massachusetts Institute of Technology and a director at Elixir Pharmaceuticals. His recent book,
He can be contacted at