Fight Aging!

The puzzle of aging is less how it happens, given that the scientific community has a good catalog of the forms of cell and tissue damage that cause aging, and can work to prove relevance by repairing that damage, but rather why it happens. Serious attempts to intervene in the aging process have long been a minority concern when compared to the funding and careers devoted to explaining the existence of aging. Understanding why evolution has led to a world dominated by species that age, alongside a tiny number of species that do not, is a thorny problem.

This is in part the case because arguments over the evolution of aging proceed by thought experiment and modeling rather than by examination of data. There is the world as it exists today, a few slim hints about the past, and researchers must deduce how this fantastically complex array of systems came into being over hundreds of millions of years from the minuscule sliver of information provided. There is a great deal of room in which to be wrong. Indeed, everyone involved in any given debate on the evolution of aging may be dramatically incorrect in the details of their models, and there is little that can be done in the short term to prove or disprove their positions.

Insofar as there is any consensus in the field on why we age, it might be found somewhere in the vicinity of the antagonistic pleiotropy hypothesis. Evolution selects for reproductive success in an environment in which mortality from disease and predation is an ugly reality - so the sooner that reproductive success occurs, the better. Selection pressure is much stronger in early life than in later life, and thus mechanisms that achieve early life resilience and success at the cost of later decay are selected for, while the additional expense of long-term resilience and success is selected against, outcompeted. The result is age-related decline. This, needless to say, is an overly simplistic and very high-level description of an area of theory within which are found many variants and dissenting opinions.

The adaptive immune system is a good example of antagonistic pleiotropy. It remembers past threats, making it highly effective in earlier life. But that act of memory consumes resources, requiring cells to be devoted to memory rather than action against new threats. Eventually there is no room left; the system runs out of space and its function declines. We can envisage an adaptive immune system that could work more effectively over longer spans of time, given just a few comparatively simple alterations to the way in which it manages its resources. That didn't evolve, as there is insufficient selection pressure in later life for mechanisms that would make old adaptive immune systems more functional, and no gain in having those mechanisms in younger life where selection pressure is strong.

Is antagonistic pleiotropy ubiquitous in aging biology?

The logic of evolution by natural selection is straightforward. Within any population, the alleles of individuals that produce the most breeding descendants will increase in frequency in successive generations at the expense of the alleles of individuals less successful at reproduction. To be successful at leaving descendants requires that organisms also be successful at surviving - so that they live long enough to reach reproductive age and afterward continue reproducing. By this logic and process, natural selection ultimately produces individuals superbly designed to survive and reproduce in their environment.

From this perspective, aging presents an evolutionary puzzle. If continued survival and reproduction should always be favored by natural selection, why is aging - which in evolutionary terms can be defined as the age-related decline in survival rate and reproduction - nearly ubiquitous in the natural world? Or as George Williams put it, "it is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed." Why doesn't evolution, in other words, mold the biology of organisms such that aging never occurs?

One possible solution to this conundrum is that evolution does in fact mold the biology of organisms such that they never age in their natural environment, that is, the environment in which they evolved. Aging might seldom occur in nature and only become evident when animals live much longer than they ever would in the wild, such as when we protect them from natural hazards by making them pets or livestock, keeping them in zoos or, as in the case of ourselves, organizing them into climate controlled, predator-free civilizations. Some biomedical gerontologists believe this hypothesis to be the case. But it is not and, in fact, dozens of field studies to date have identified that aging in wild animals is rampant if not close to ubiquitous.

Thus, there is a real puzzle to be solved as to how aging develops in natural populations. Fortunately, evolutionary biologists have cracked this mystery. An evolutionary mechanism of aging was hypothesized 60 years ago to be the genetic trade-off between early life fitness and late life mortality. Genetic evidence supporting this hypothesis was unavailable then, but has accumulated recently. These tradeoffs, known as antagonistic pleiotropy, are common, perhaps ubiquitous. George Williams' 1957 paper developed the antagonistic pleiotropy hypothesis of aging, which had previously been hinted at by Peter Medawar. Antagonistic pleiotropy, as it applies to aging, hypothesizes that animals possess genes that enhance fitness early in life but diminish it in later life and that such genes can be favored by natural selection because selection is stronger early in life even as they cause the aging phenotype to emerge.

No genes of the sort hypothesized by Williams were known 60 years ago, but modern molecular biology has now discovered hundreds of genes that, when their activity is enhanced, suppressed, or turned off, lengthen life and enhance health under laboratory conditions. Does this provide strong support for Williams' hypothesis? What are the implications of Williams' hypothesis for the modern goal of medically intervening to enhance and prolong human health? Overall, whenever antagonistic pleiotropy effects have been seriously investigated, they have been found. However, not all trade-offs are directly between reproduction and longevity as is often assumed. The discovery that antagonistic pleiotropy is common if not ubiquitous implies that a number of molecular mechanisms of aging may be widely shared among organisms and that these mechanisms of aging can be potentially alleviated by targeted interventions.