Fight Aging!

Investigation of the comparative biology of aging is one of many notable communities within the broader research community focused on aging and age-related disease. Scientists use comparisons between different species with very different life spans as a way to try to pin down the mechanisms that are most important in aging. Thus there is work on naked mole-rats versus mice, both similarly sized rodents. Whales capable of living for centuries are compared to smaller mammals that are not. Humans are compared to our nearest primate relatives, all of whom are less long-lived than we are. And so forth.

One of the more interesting comparisons to be made is between bats and other mammals. It is quite clear that flight requires considerable metabolic adaptation, and it seems plausible that these adaptations make individuals more resistant to some of the processes of aging. Both birds and bats tend to be long-lived for their size. Not all bats are long-lived, however, which means that perhaps there are things to be learned from a comparison of long-lived and short-lived bat species. That is the subject of today's open access paper.

It remains a question as to whether work on the comparative biology of aging will produce practical outcomes. It is one thing to identify a mechanism, or a different arrangement of cellular biochemistry, as likely important in aging. It is entirely another thing to try to build a therapy based on the way that bat, whale, or naked mole-rat cells function. There is no guarantee that any particular species difference is a practical basis for medical applications. Engineering a better human that ages more slowly by changing cellular metabolism into something that looks more like that of another species is more likely a product for later in the century, not now. Also, aging more slowly is of little use to people already old - we want rejuvenation and repair of damage, not ways to make damage accumulate more slowly.

Genetic variation between long-lived versus short-lived bats illuminates the molecular signatures of longevity

Natural selection has shaped a large variation of lifespan across mammals, with maximum lifespan ranging from a few months (e.g. short-lived shrews) to 211 years (e.g. bowhead whale). Although the bowhead whale is exceptionally long-lived, its lifespan is arguably not as extreme as that of a 30 years old naked mole-rat given their body sizes, as maximum lifespan (MLS) exhibits a positive correlation with body size within mammals. Thus, lifespan comparison across mammals requires body size correction. To resolve this, the longevity quotient (LQ) was introduced, which is defined as the ratio of observed lifespan to predicted lifespan for a non-flying mammal of the same body size. Using this approach bats are the longevity extremists, with some species living up to ten times longer than expected given their body size. The Brandt's bat (Myotis brandtii) holds the record for longevity, with a maximum lifespan of more than 40 years, living 8-10 times longer than expected given a body weight of ~7 grams. This renders bats as one of the most ideal taxa to explore the molecular basis of extraordinary longevity in mammals.

Although the majority of bat species are long-lived, especially within the Myotis genus, there are a few short-lived exceptions, such as the velvety free-tailed bat (Molossus molossus) and the evening bat (Nycticeius humeralis), living as long as would be expected given their body size. A recent study has suggested that the ancestral bat lived up to 2.6 times longer than expected given body size, indicating that the extreme longevity observed in the longest-lived bat genera may have evolved multiple times. This also suggests that short-lived bat species may have lost their longevity adaptations. Therefore, this wide range of lifespans observed in bats enables us to utilize comparative evolutionary approaches to search for genetic differences within closely-related long- and short-lived bat species.

In this study we performed a comparative genomic and transcriptomic analysis between long-lived Myotis myotis (MLS = 37.1 years; LQ = 5.71) and short-lived Molossus molossus (MLS = 5.6 years; LQ = 0.99) to ascertain the molecular signatures associated with longevity in bats. Based on the genome-wide alignments of single-copy orthologous genes between these two species, we detected and further investigated the genes that were fast-evolving and showed significant positive selection. We also deep sequenced blood transcriptomes from eight adult individuals for each species, and explored the genes and pathways that were differentially expressed. To ascertain if long-lived bats have evolved a transcriptomic signature of longevity, we further investigated the expression of 'pro'- and 'anti'-longevity genes in the blood transcriptomes of M. myotis and M. molossus. Although the majority of genes underwent purifying selection, we observed a significant transcriptional alteration between these two species.

Among 2,086 genes that exhibited large interspecific expression variation, the genes that showed higher expression in long-lived M. myotis were mainly enriched in DNA repair and autophagy. Further pathway analysis suggested that six biological processes, including autophagy, were differentially expressed between M. myotis and M. molossus. We also show that M. myotis had significantly lower expression levels of anti-longevity genes, suggestive of a transcriptomic signature of longevity naturally evolved in long-lived bats. Together with the previous findings in other long-lived mammals, our study implies that enhanced DNA repair and autophagy activity may represent a universal mechanism to achieve longevity in long-lived mammals.