Telomeres do not shorten with age in longest-lived bats.

Bats are the longest-lived mammals, given their body size. However, the underlying molecular mechanisms of their extended healthspans are poorly understood. To address this question we carried out an eight-year longitudinal study of ageing in longlived bats (Myotis myotis). We deep-sequenced ~1.7 trillion base pairs of RNA from 150 blood samples collected from known aged bats to ascertain the age-related transcriptomic shifts and potential microRNA-directed regulation that occurred. We also compared ageing transcriptomic profiles between bats and other mammals by analysis of 298 longitudinal RNA sequencing datasets. Bats did not show the same transcriptomic changes with age as commonly observed in humans and other mammals, but rather exhibited a unique, age-related gene expression pattern associated with DNA repair, autophagy, immunity and tumour suppression that may drive their extended healthspans. We show that bats have naturally evolved transcriptomic signatures that are known to extend lifespan in model organisms, and identify novel genes not yet implicated in healthy ageing. We further show that bats' longevity profiles are partially regulated by microRNA, thus providing novel regulatory targets and pathways for future ageing intervention studies. These results further disentangle the ageing process by highlighting which ageing pathways contribute most to healthy ageing in mammals. Articles Nature ecology & evolutioN results and discussion Overview of M. myotis ageing transcriptomes. Using a non-lethal sampling process developed to maximize transcript representation from bat blood (>60% of all protein-coding genes represented) 23 , we deep-sequenced ~1.7 trillion base pairs of RNA from 100 bat blood samples (69.6 ± 9.0 s.d. million reads per sample) using Illumina RNA-sequencing (RNA-Seq). These blood samples (~50-200 μl) were collected from 70 individual bats ranging in age from 0 to >7 years (for example, first caught as an adult 6 years before subsequent recapture) at five colonies in Brittany, France (Supplementary Tables 1-3 and Supplementary Fig. 1). The majority of the raw reads (98.5%) showed high quality (>Q30). On average, 77% of clean reads were successfully mapped to the reference genome (Myotis lucifugus), 64.2% of which had unique mapping coordinates. Of all mapped reads, 88.1% were concordantly aligned. Only those reads that were uniquely and concordantly mapped were used for downstream analyses. To gain an overview of the bat blood tran

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Bats are the only mammals capable of true, powered flight, which drives an extremely high metabolic rate. The “Free Radical Theory of Ageing” (FTRA) posits that a high metabolic rate causes mitochondrial heteroplasmy and the progressive ageing phenotype. Contrary to this, bats are the longest-lived order of mammals given their small size and high metabolic rate. To investigate if bats exhibit increased mitochondrial heteroplasmy with age, we performed targeted, deep sequencing of mitogenomes and measured point heteroplasmy in wild, long lived Myotis myotis. Blood was sampled from 195 individuals, aged between <1 and at 6+ years old, and whole mitochondria deep-sequenced, with a subset sampled over multiple years. The majority of heteroplasmies were at a low frequency and were transitions. Oxidative mutations were present in only a small number of individuals, suggesting local oxidative stress events. Cohort data showed no significant increase in heteroplasmy with age, while longitudinal data from recaptured individuals showed heteroplasmy is dynamic, and does not increase uniformly over time. We show that bats do not suffer from the predicted, inevitable increase in heteroplasmy as posited by the FRTA, instead heteroplasmy was found to be dynamic, questioning its presumed role as a primary driver of ageing.