Exploring the cellular mechanisms of enhanced lifespan in bats

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PROJECT SUMMARY/ABSTRACT Human aging is characterized by dynamic changes in biological and physiological processes that negatively impact health and quality of life. Given the rapidly aging human population, characterizing and mitigating these negative impacts is an increasingly urgent goal of biology. Progress toward this goal has been hampered by the fact that commonly used, shorter-lived lab animals (e.g., mouse) make less than ideal tools with which to identify the processes that drive longevity in longer-lived mammals, including humans. Bats, in contrast, provide an excellent study system for mammalian longevity. Bats are the longest-lived mammals relative to their body size and extreme longevity evolved at least four times in the clade. Many bats also maintain their health during their long lifespan; for example, bats display extended fertility and rarely if ever get cancer. Despite the numerous advantages of the group, the cellular processes by which most bats achieve their striking longevity remain largely unknown. This oversight has been driven, in part, by the inability of researchers to accurately estimate the chronological age of wild bats, given many bats’ lack of obvious signs of biological aging. As a result, studies of bat aging have been mostly limited to the few species for which captive or “mark and recapture” colonies have been maintained for decades, and in which tissue collection is necessarily minimal. This project takes advantage of a newly developed, methylation-based method that reliably estimates chronological age across mammals, including wild bats, to overcome this obstacle. This new method will be coupled with field- and lab- work on several clades of wild bats to establish wild bats as a powerful model for cellular-level aging in long-lived mammals, such as humans, and use this model to begin to identify cellular processes that drive longevity and mitigate aging-related morbidity. Preliminary data suggest that bats minimize DNA damage and cellular-level aging through several cellular processes, and that the specific processes involved likely vary from bat to bat. Each additional bat sampled therefore has the potential to yield novel and informative results. This project will achieve its goals through completion of two specific aims. Aim 1 is to characterize and compare the relationship between aging-related, cellular processes and chronological age in the tissues of wild bats from twelve diverse species from the Family Phyllostomidae, including longer and shorter -lived representatives. Aim 2 is to functionally manipulate and characterize aging-relevant cellular processes such as oxidative stress, DNA damage, and senescence (among others) using standard mammalian cell culture methods on primary and iPSC cells from diverse bat species, including those characterized for Aim 1. Through completion of these aims, the project is expected to identify cellular processes that are associated with longevity in wild bats and can mitigate aging-related morbidity (e.g., DNA damage, senescence) when manipulated in cells grown in culture. With this critical foundation, this project is expected to establish wild bats as a model system for future studies of cellular aging in long-lived mammals.