Fight Aging!

Bats are a popular choice in the study of the comparative biology of aging because there is considerable variation in life span between closely related species, a good place to start looking for specific genes that might be important in determining species differences in life span. Further, some bat species are particularly long-lived for their small size, which is again a place to start if seeking to understand how genetics determines life span. While some inroads have been made, these are still early days in the process of building a robust set of bridges between the islands represented by the present understanding of (a) genetics, (b) cell metabolism, and (c) aspects of aging. Much remains unknown.

As is the case for investigations of the biochemistry of naked mole-rats, elephants, and whales, some fraction of research into the genetics of long-lived bat species is motivated by their resistance to cancer. Cancer is a numbers game; either a greater number of cells or a given number of cells existing for a longer period of time implies an increased risk of cancerous mutation. Larger species and long-lived species can only be large or long-lived because they have evolved means of cancer suppression that do not exist in their smaller or short-lived relatives. Will study of the comparative biology of aging find mechanisms that can be used to produce therapies to treat and prevent cancer in humans in the near future? At this point it is too early to tell whether discoveries will be amenable to therapeutic development in this way, but this is the hope.

Extensive longevity and DNA virus-driven adaptation in nearctic Myotis bats

Bats are widely known for their long lifespan, cancer resistance, and viral tolerance. As highly complex and pleiotropic processes, the genes and mechanisms underlying these phenotypes can be challenging to identify. Here we outline an approach that enables functional comparative biology by generating cell lines from wing punches of wild caught bats for genome assembly, comparative genomics, and functional follow up. Cell lines are generated from minimally-invasive biopsies collected in the field thus avoiding disturbing natural populations. Given the high density of bat species concentrated at single locations world-wide, it is feasible to collect wing punches from a large number of individuals across a wide phylogenetic range; these wing punches can be used to generate cell lines and sequencing libraries for reference genomes in a matter of weeks.

By explicitly modeling the evolution of lifespan separately from body size, we recapitulate the extant relationship between body size and lifespan across mammals in evolutionary time. Contrary to prior work, we show that overall bats exhibit allometric lifespan scaling, comparable to other mammals. However, two bat clades - Myotis and Phyllostomidae - exhibit distinct trends with Myotis demonstrating an increased rate of change in lifespan given body size compared to other mammals. This altered scaling of longevity in Myotis has dramatic consequences for their intrinsic, per-cell cancer risk and for the evolution of tumor-suppressor genes and pathways.

We found a number of genes under selection across multiple longevity-associated pathways, consistent with the pleiotropic nature of the aging process. These include members of canonical longevity pathways such as mTOR-IGF signaling, DNA damage repair, oxidative stress, and the senescence-associated secretory phenotype. We additionally identified selection in various pathways that have likely emerged as a result of the unique biology of bats, including genes at the intersection of immunity and senescence, such as Serpin-family genes; genes in metabolic pathways including amino acid metabolism; and pervasive selection observed in the ferroptosis pathway, which sits at the intersection of bats' extreme oxidative challenges, metabolic demands, immune function, and cancer resistance.

By quantifying the relative contributions of genes under selection to cancer-related pathways at each node, we found significant enrichment of these processes across the phylogeny, especially at nodes undergoing the greatest changes in lifespan and cancer risk. While cancer risk scales linearly with body size, it scales over time as a power law of 6. Unlike other systems where the evolution of cancer resistance has been driven by rapid changes in body size, the body size of Myotis has not significantly changed since their common ancestor. Instead, the rapid and repeated changes in lifespan across an order of magnitude in Myotis lead to some of the most significant changes in intrinsic cancer risk seen across mammals.

While no reports or studies of neoplasia rates have been published in Myotis, the use of in vitro models of carcinogenesis provides a promising avenue for comparative studies of cancer resistance under controlled conditions. In agreement with our results, in vitro and xenograft transplant models have shown that cells of long-lived bats, including M. lucifugus, are more resistant to carcinogenesis than shorter-lived bats and other mammals.