Differences in Autophagy-Related Genes Point to a Role in Species Life Span

Autophagy is the name given to a collection of processes responsible for recycling damaged and worn proteins and cell structures. Increased autophagy is a feature of the cellular response to various forms of stress. Many ways of adjusting metabolism to extend life span in short-lived species result in improved autophagy. Is improved autophagy also important in the much larger differences in life span observed between species, however? This is an interesting question. Therapeutic enhancement of autophagy, such as via mTOR inhibitors like rapamycin, or via various forms of calorie restriction mimetic drug, so far seems like an uninspiring path to only marginal gains in health and life span in longer-lived mammals. Might there be other, better ways to adjust the operation of autophagy that could be discovered by comparing mechanisms between mammalian species with widely divergent life spans?

Lifespan extension has independently evolved several times during mammalian evolution, leading to the emergence of a group of long-lived animals. Though the mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is shown as a central regulator of lifespan and aging, the underlying influence of mTOR pathway on the evolution of lifespan in mammals is not well understood. Here, we performed evolution analyses of 72 genes involved in the mTOR network across 48 mammals to explore the underlying mechanism of lifespan extension.

In our study, autophagy related genes were identified to be under positive selection (PRKCB, WDR24, NPRL3 and LAMTOR2) or convergent (ATP6V1H and SESN2) in long-lived species, or associated with maximum life span (LAMTOR4), suggesting that enhanced autophagy might be a potential mechanism for mammals to extend lifespan. Moreover, eight genes with evolutionary signals identified in long-lived species were cancer related genes, six of them were also associated with aging, suggesting that regulation of cancer and aging may be another important mechanism for extending lifespan. In conclusion, we identified 20 genes with significant evolutionary signals unique to long-lived species, which provided new insight into the lifespan extension of mammals and might bring new strategies to extend human lifespan.

Link: https://doi.org/10.1186/s12864-023-09554-4