Longevity-Related Genes are Under Greater Evolutionary Constraint in Large and Long-Lived Mammals

Both the evolution of aging and the comparative biology of aging between species with widely divergent lifespans are fascinating topics, though likely of limited relevance to the near future of rejuvenation therapies. Those treatments will be based on repairing cell and tissue damage as it occurs, using the understanding of the human metabolism that exists now, rather than on attempts to rebuild that human metabolism to age more slowly, a goal that will require a great deal more knowledge. The more distant future will certainly include human populations engineered from birth to exhibit enhanced longevity, however, and a greater understanding of the intersection between metabolism, genetics, and species longevity will be an essential part of that endeavor.

Although lifespan in mammals varies over 100-fold, the precise evolutionary mechanisms underlying variation in longevity remain unknown. Species-specific genetic changes have been observed in long-lived species including the naked mole-rat, bats, and the bowhead whale, but these adaptations do not generalize to other mammals. We present a novel method to identify associations between rates of protein evolution and continuous phenotypes across the entire mammalian phylogeny. Unlike previous analyses that focused on individual species, we treat absolute and relative longevity as quantitative traits and demonstrate that these lifespan traits affect the evolutionary constraint on hundreds of genes.

Specifically, we find that genes related to cell cycle, DNA repair, cell death, the IGF1 pathway, and immunity are under increased evolutionary constraint in large and long-lived mammals. For mammals exceptionally long-lived for their body size, we find increased constraint in inflammation, DNA repair, and NFKB-related pathways. Strikingly, these pathways have considerable overlap with those that have been previously reported to have potentially adaptive changes in single-species studies, and thus would be expected to show decreased constraint in our analysis. This unexpected finding of increased constraint in many longevity-associated pathways underscores the power of our quantitative approach to detect patterns that generalize across the mammalian phylogeny.

Link: https://doi.org/10.7554/eLife.51089

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