How did aging evolve? Inasmuch as aging might be described as the loss of (Darwinian) fitness as a function of post-reproductive age, it seems counterintuitive that natural selection could have produced such a phenomenon.
While biogerontologists love to bicker about the evolutionary origins of aging, one idea that has gained traction is the theory of antagonistic pleiotropy: A gene that has a beneficial effect early in life, but a bad effect late, can be positively selected. Oft-quoted examples include the prostate and breast, where robust proliferation improves early-life fitness (via effects on reproduction and child-rearing, respectively) but can increase cancer risk (and thereby mortality rate) in old age.
One might, therefore, expect to find that gerontogenes (genes whose wildtype function promotes or accelerates aging) are enriched among what are sometimes referred to as “housekeeping genes”: genes with run-of-the-mill functions in metabolism, whose efficacy is intimately linked with the success of fundamental processes like cell division, protein production, etc. The idea is that the specific alleles of these genes that have become fixed in populations (and become the “wildtype” alleles) would be especially good at taking an organism from zygote to reproductive maturity, but at a cost (specifically, deleterious function in post-reproductive life when selection is weaker).
Unfortunately for this theory, it’s particularly hard to identify mutations in these genes, where loss of function means loss of life. In order to investigate the hypothesis outlined above, one would need to allow these essential genes to function throughout development, and then turn them off at maturity.
That’s just what Curran and Ruvkun have done. By exploiting a relatively easy technique for conditionally knocking down gene function in adult C. elegans, and focusing their attention on essential genes, they’ve found a treasure trove of novel gerontogenes:
Lifespan Regulation by Evolutionarily Conserved Genes Essential for Viability
Evolutionarily conserved mechanisms that control aging are predicted to have prereproductive functions in order to be subject to natural selection. Genes that are essential for growth and development are highly conserved in evolution, but their role in longevity has not previously been assessed. We screened 2,700 genes essential for Caenorhabditis elegans development and identified 64 genes that extend lifespan when inactivated postdevelopmentally. These candidate lifespan regulators are highly conserved from yeast to humans. Classification of the candidate lifespan regulators into functional groups identified the expected insulin and metabolic pathways but also revealed enrichment for translation, RNA, and chromatin factors. Many of these essential gene inactivations extend lifespan as much as the strongest known regulators of aging. Early gene inactivations of these essential genes caused growth arrest at larval stages, and some of these arrested animals live much longer than wild-type adults. daf-16 is required for the enhanced survival of arrested larvae, suggesting that the increased longevity is a physiological response to the essential gene inactivation. These results suggest that insulin-signaling pathways play a role in regulation of aging at any stage in life.
Several of the genes identified either operate in (or feed into) known genetic pathways of lifespan regulation, such as insulin/IGF-1 signaling, but others operate in essential metabolic pathways such as protein translation (which is starting to be recognized as a major contributor to the rate of aging). The approach in this paper thus demonstrates the power of conditional genetics (i.e., the manipulation of gene function in a manner that depends on time or some other variable) in the study of lifespan.
From the results, it seems likely that there are many essential genes optimized for function during development that are deleterious (to the extent of being completely dispensable for life) in late life. While this falls short of proving the evolutionary theory of antagonistic pleiotropy, these data are entirely consistent with that hypothesis — and they point us toward a rich source of information, as yet largely explored, about the genetic control of aging.