Age-Related Upregulation of Autophagy as a Possible Contribution to Bat Longevity

Bat species include many that are long-lived for their size. Flying species in general are long lived; one can find many similarities in metabolism between bats and birds. It may be the case that the much higher metabolic rate of flying species requires improved mechanisms of cell resilience and cell maintenance that have the side-effect of better resisting the damage of aging. On the cell resilience side, the membrane pacemaker hypothesis considers that longer-lived species have cell membranes more resistant to oxidation by the byproducts of metabolic activity. On the cell maintenance side, we have studies such as this one, in which researchers show that bats appear to upregulate the cellular recycling mechanism of autophagy with age, and thereby presumably better clear out damaged structures and proteins.

The hallmarks of aging are remarkably similar across mammals, but the rate vastly differs and the molecular basis for this natural variation in longevity is not well understood. This suggests that studying the aging process in exceptionally long-lived species, such as bats, will enable us to elucidate the mechanisms underlying naturally evolved longer healthspans and ultimately contribute to a greater understanding of aging biology. Relative to body mass, bats show the longest lifespans of all mammals and exhibit little signs of senescence. For this reason, bats are now being recognised as novel, relevant models to study the mechanisms of healthy aging.

Comparative studies focused on bats have furthered our understanding of variation in aging across the mammal tree of life and suggested factors that may underlie their extended healthspans: telomeres, mitochondria, microbiome, and metabolome. A recently published longitudinal study highlighted that bats exhibit a unique, age-related gene expression pattern associated with DNA repair, immunity, and autophagy. Indeed, autophagy and proteostasis were previously suggested to be the common mechanisms that maintain health in long-lived species, including bats. Enhanced autophagy has also been suggested as an anti-viral mechanism in bats which may also contribute to longer healthspans. However until now, studying the age-dependent changes of autophagy in wild bat populations has been hindered by the logistical challenges

Autophagy is a convergent mechanism of multiple longevity pathways, playing a role in lifespan extension promoted by reduced insulin/IGF-1, mTOR inhibition, and dietary restriction in mammals. Functional studies in model species demonstrate that reduced autophagy shortens lifespan, while increased autophagy extends it. Accordingly, many studies have demonstrated that autophagy decreases with age, and it has been inferred that this gradual decrease could play a major role in the functional deterioration of aging organisms.

Here, drawing on more than eight years of mark-recapture field studies, we report the first longitudinal analysis of autophagy regulation in bats. Mining of published population level aging blood transcriptomes (M. myotis, mouse and human) highlighted a unique increase of autophagy related transcripts with age in bats, but not in other mammals. This bat-specific increase in autophagy transcripts was recapitulated by the western blot determination of the autophagy marker, LC3II/I ratio, in skin primary fibroblasts (M. myotis, Pipistrellus kuhlii, mouse), that also showed an increase with age in both bat species. Further phylogenomic selection pressure analyses across eutherian mammals (n=70 taxa; 274 genes) uncovered 10 autophagy-associated genes under selective pressure in bat lineages. These molecular adaptations potentially mediate the exceptional age-related increase of autophagy signalling in bats, which may contribute to their longer healthspans.



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