Mark D. Schwartz and Julia Hyland Bruno
Jeanne Calment rode her bicycle until age 100, quit smoking at 117, and died in 1977 at 122 years of age in Arles, France. This news-worthy story raises some questions: Why do we age at all? Why don’t we live forever? And many of us are asked by our patients, is old age a disease we can cure?
First, some useful distinctions: Aging is getting chronologically older, while senescence is physiologic degeneration that diminishes our function and vitality and makes us more vulnerable to disease and death. Lifespan is the average age at death for a population and varies widely by species, while longevity is that for an individual and depends on its unique interactions of genes, environment, and chance. Extrinsic mortality is the stochastic death rate due to environmental factors like earthquakes, starvation, and predation. Most species in the wild do not live long enough to grow old. Intrinsic mortality is the death rate absent environmental factors, resulting from how the species allocates limited resources over its biological functions like growth, tissue repair, and reproduction.
As discussed in the previous column in this series , biological questions of causality like these are of two types. In medicine we typically ask proximate “how” questions about mechanisms (pathophysiology) or development (ontogeny) over an individual’s lifetime. We less commonly ask evolutionary “why” questions about function (adaptation) or development of a trait in species over millennia (phylogeny).
In human history, average life expectancy has increased (Figure) but our maximal longevity has not. Our lifespan expanded thanks to changes we made in our environment that reduced our extrinsic mortality. Most important of these were the agricultural and industrial revolutions, and more recent advances in public health and the development of antibiotics. However, while we now have more centenarians, it remains exceedingly rare for anyone to live beyond 115 years, suggesting we have a biological limit due to intrinsic mortality.
So why do we senesce and die? Proximate answers about mechanisms are emerging but remain controversial. Damage-based theories propose that injury to DNA, telomeres, and tissues due to normal toxic by-products of metabolism (e.g. free radicals) or inefficient repair or defense accumulates throughout the lifespan and causes senescence. Circulating levels of superoxide dismutase, uric acid, and other antioxidants are linked to lifespan across species. An alternative theory is that senescence is driven by a genetically regulated, programmed process with hormonal mechanisms as its pacemaker. Recent work has focused on neuroendocrine signaling that may account for increased longevity associated with caloric restriction.
From an evolutionary perspective, individuals that do not senesce would have a tremendous reproductive advantage. So why hasn’t natural selection eliminated senescence? Why don’t we live and reproduce indefinitely?
Evolutionary answers to the problem of aging reflect the range of thinking about evolutionary processes. Weissman and others proposed death as an adaptation for the good of the species-an idea that has been discounted on the grounds that natural selection is far stronger at the individual than at the group level. Three more contemporary theories of why we senesce offer complementary explanations that account for natural selection and may also illuminate proximate explanations of aging.
In 1952 Peter Medawar proposed that we senesce because the force of natural selection decreases as we age (mutation accumulation theory). Since most organisms die of extrinsic causes, genes beneficial early in life are favored by natural selection over genes beneficial late in life. By an age when few organisms survive, the force of selection is too weak to oppose the genetic drift and mutation accumulation that can lead to the loss of late acting beneficial genes or to the expression of late acting harmful genes.
George Williams (1957) expanded this idea and posed the theory of antagonistic pleiotropy, in which genes that increase reproductive fitness in younger organisms will be favored by selection, even if they have adverse effects post reproductive age. An example of such a tradeoff is testosterone in males, promoting reproductive fitness in youth, but increasing risk of prostate cancer and heart disease later in life.
Tom Kirkwood (1977) further specified that senescence results from the inevitable tradeoffs in the allocation of resources between reproduction and somatic maintenance (disposable soma theory). Maintenance requires resources (DNA repair, immune system surveillance) at the expense of fecundity. Genes will be favored that shift the balance toward investing scarce resources in mechanisms that promote reproductive fitness and maintenance of the germ line versus the soma.
The strongest driver of the evolution of longevity is the force of extrinsic mortality. When high, life expectancy is short, harmful gene effects accrue earlier, and selection for somatic maintenance is weaker. When extrinsic mortality is lower as in humans, selection against senescence attenuates more slowly, and selection for investing in somatic maintenance is stronger.
Therefore, senescence is the price we pay for vigor and reproductive fitness in our youth. The humbling takeaway is that natural selection optimizes our reproductive fitness, not our health or lifespan. As physicians we cannot cure our aging patients of senescence but we can endeavor to postpone its effects. Biologically, we are here to transmit our genes, so living well beyond 100 years is likely to remain news.
Please also see the Proceedings of the National Academy of Sciences Supplement on Evolution in Health and Medicine published this week.
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