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Comparative genomics / ‘wildlife’ transcriptomics uncovers the mechanisms of halted ageing in mammals

Final Report Summary - AGELESS (Comparative genomics / ‘wildlife’ transcriptomics uncovers the mechanisms of halted ageing in mammals)

Ageing, the nearly ubiquitous deterioration of physical and mental function that occurs with time, has the greatest impact on global health: people everywhere are experiencing longer life spans, but not necessarily longer healthspans. Thus, understanding the processes that underlie healthy ageing, remains a critical challenge. While researchers have made substantial progress studying ageing in short-lived mammals such as mice, there is little evidence that these methods will translate to more ageing-resistant species such as humans. An alternative approach is to analyze species that are even more ageing-resistant than humans: bats.
By far, the most successful mammals in healthy ageing are the bats: some species live nearly 10 times longer than an average mammal of the same size (humans live less than 5 times longer), and show negligible signs of ageing. Logistically it is difficult to study bats in an ageing context, as most are only found in the wild and not easily maintained in captivity. New molecular methodology has made it possible to non-lethally sample individual bats across their lifetime, allowing us to explore their ageing process. However to date, the molecular mechanisms underlying bats’ extended healthspans are still little understood.
To address this problem we performed a unique eight year, longitudinal capture-mark-recapture study of a wild population of long-lived Myotis myotis bats. Our results suggest that the longest lived genera of bats (Myotis) maintain the length of their telomeres with age without developing cancer, potentially due to adaptations in their DNA repair and maintenance mechanisms. Similarly, despite having some of the highest recorded oxygen consumption rates in mammals, long lived bats (Myotis) shown no signs of increased mitochondrial DNA damage with age as predicted, suggesting that bats may have evolved novel mechanisms to repair or remove damaged mitochondria. Immune challenges show that bat macrophages are capable of mounting an aggressive and sustained anti-inflammatory response to counter their initial inflammatory reaction on exposure, quickly restoring homeostasis. This can limit the immunopathology and resulting damage of their high metabolic rates and ultimately can reduce inflammation driven ageing.
As the ageing process is highly complex and is driven by multiple interacting pathways, we also carried out the first systems-level comparative analysis to ascertain the age-related transcriptional changes and the miRNA-directed regulation that may underlie bats’ exceptional longevity. Bats showed unique ageing-transcriptomic shifts not observed in humans, mice and wolves, suggesting that the regulation and interactive network of genes associated with DNA repair, cell-cycle regulation, autophagy, immunity and tumor suppression underlies bats’ extraordinary longevity. Our results show that bats have naturally evolved transcriptomic signatures that are known to extend life-span in model organisms, and we also identify novel potential targets for future intervention studies. The regulatory network we uncovered suggests that bat’s longevity pathways are partially mediated by miRNA, providing a molecular mechanism that drives their longevity-associated transcriptomic signature.
Using cutting edge molecular techniques coupled with intense field studies and comparative evolutionary analyses, we utilized the diversity within nature to identify key targets and regions that regulate and control extraordinary ageing in mammals. These results will drive a better understanding of the ageing process and can provide molecular targets that in the future, could be modified to alleviate human ageing and stimulate novel treatments for disease.