Bats are the most extraordinary of all mammals, they fly, can use sound to orient in complete darkness, can tolerate a multitude of deadly viruses such as SARS, Ebola and rabies without dying. They are key to the functioning of our ecosystems, regulating arthropod diversity, pollinating and dispersing seeds in the tropics and one in five of all living mammals today are bats [Bat1K]. However, one of the most unique adaptations of bats is that they live way longer than expected given their body size, showing little signs of ageing, experiencing little to no cancer. Any field bat biologist knows that once embarking on a mark-recapture project with bats, you will be in it for the long haul!
The longest lived bat species known, Myotis brandtii, was caught as an adult and re-caught 41 years later with little signs of ageing, but most remarkable, is that this species weighs 1/3 that of a lab mouse, yet can live so long despite its small body size, challenging our understanding of the ageing process. Typically, little things live fast and die young, think of shrew or a mouse, big things live longer, think of a whale or elephant. Bats are exceptional as they are small, live fast but also live long, apparently resistant to ageing, having naturally evolved longer healthspans.
As a bat biologist and phylogeneticist, I have been fascinated by understanding how bats achieve longer healthspans and apparently defy the ageing process. But, how do you study bats in an ageing context? Is it difficult! The longest-lived bat species do not readily survive in captivity so you must study these bats in the wild. The only way to accurately age bats is to catch them as babies, when their finger bones are not yet fused, mark- release- recapture and age that recaptured individual given the date of first capture associated with the tag/transponder. Therefore, you need a longitudinal mark-recapture study of long-lived bat species and the funding, determination and madness (bat field biology is not for the faint hearted given its nocturnal nature and difficulty in catching these clever, elusive mammals) required to continue that study for decades. Also, the species of choice must be large enough to non-lethally sample and measure year after year to understand how bats age.
Luckily enough, Bretagne Vivante, a grass roots conservation society in Brittany, France has been studying such a colony of long lived Myotis myotis bats for over 20 years, marked with transponders since 2010, which is the basis of our Nature Ecology and Evolution paper, Huang et al 2019, uncovering the molecular basis of longer healthspan in bats. Working with Bretagne Vivante and an international team of French and Irish scientists, funded by the European Research Council and the Irish Research Council, we have captured-marked-released the entire population of Myotis bats for over eight years, sampling key individuals, year after year taking non-lethal samples (3mm wing punch, <140ul of whole blood) and studying their ecology and biology.
It was not easy. We needed to overcome language barriers, constantly re-invent new capture and sampling methods, ensure that our samples were appropriately preserved and maintained while on transit and every year some new ‘drama’ would happen, with up to 20-30 biologists and volunteers working/eating/living together in Brittany, France for most of July.
Necessity is the-mother-of-all-invention, and where there is a will there is a way! We made it work, have become great friends and allies and my one piece of advice to any one embarking on a project like this is that good food and wine break down any barrier!
In University College Dublin, Ireland we developed the molecular techniques and tools to estimate telomere length Foley et al 2018 , whole mitochondrial dynamics Jebb et al 2018, gut-microbiome diversity Hughes et al 2018, immune function and how this changed with age in bats. However, as ageing is inherently complex and needs to be studied from more than a single biomarker perspective, we wanted to investigate how different biological pathways interact and are regulated with age in these long lived bats.
To do these we firstly developed the molecular pipelines and laboratory methods to deep sequence the entire blood transcriptome from <140ul (few drops), showing that 60-80% of all protein transcripts can be found in whole blood. We used these methods and deep sequenced about 1.7 trillion base pairs of RNA from 150 blood samples collected from known aged bats to uncover the age-related gene expression changes in bats that may underlie their extended healthspan which is the basis of our Nature Ecology and Evolution paper, Huang et al 2019. Bats showed unique age related gene-expression shifts not observed in humans or other mammals, suggesting that the regulation and interaction of genes associated with DNA repair, autophagy, immunity and tumor suppression underlies bats’ extraordinary longevity and low cancer incidence.
To uncover how this ‘anti-ageing’ gene expression pattern is controlled in bats, we also sequenced small regulatory genes, the microRNAs, and uncovered key genes that may control the longevity pathway in bats. For example, we showed that microRNAs acting as tumour suppressors are upregulated in bats with age, while microRNAs promoting carcinogenesis are downregulated. These results show the prominent roles of microRNA in the regulation of multiple anti-ageing pathways that may underpin bats’ extended healthspan, providing novel molecular targets for future ageing intervention studies.
Most excitingly we show that bats have naturally evolved transcriptomic signatures that are known to extend lifespan in model organisms, validating our unconventional methods. However, even more thrilling is that we have also identified novel genes not yet implicated in healthy ageing providing new avenues of research into extended healthspan. Therefore, studying wild long-lived bats in an ageing context could provide new solutions to slow down the ageing process.