Abstract
The genetics of lifespan determination is poorly understood. Most research has been done on short-lived animals and it is unclear if these insights can be transferred to long-lived mammals like humans. Some African mole-rats (Bathyergidae) have life expectancies that are multiple times higher than similar sized and phylogenetically closely related rodents. To gain new insights into genetic mechanisms determining mammalian lifespans, we obtained genomic and transcriptomic data from 17 rodent species and scanned eleven evolutionary branches associated with the evolution of enhanced longevity for positively selected genes (PSGs). Indicating relevance for aging, the set of 250 identified PSGs showed in liver of long-lived naked mole-rats and short-lived rats an expression pattern that fits the antagonistic pleiotropy theory of aging. Moreover, we found the PSGs to be enriched for genes known to be related to aging. Among these enrichments were “cellular respiration” and “metal ion homeostasis”, as well as functional terms associated with processes regulated by the mTOR pathway: translation, autophagy and inflammation. Remarkably, among PSGs are RHEB, a regulator of mTOR, and IGF1, both central components of aging-relevant pathways, as well as genes yet unknown to be aging-associated but representing convincing functional candidates, e.g. RHEBL1, AMHR2, PSMG1 and AGER. Exemplary protein homology modeling suggests functional consequences for amino acid changes under positive selection. Therefore, we conclude that our results provide a meaningful resource for follow-up studies to mechanistically link identified genes and amino acids under positive selection to aging and lifespan determination.
Highlights
Most of the available information about the genetic mechanisms that govern lifespan and aging were obtained by studying single-gene mutations in invertebrates or short-lived, highly inbred vertebrate species
By searching for signs of positive selection on phylogenetic braches associated with the evolution of enhanced longevity, we aimed to provide a set of target genes/sites for future follow-up approaches to explore mechanistically their putative link to aging and lifespan determination
To ensure that the dataset represents a meaningful resource for aging research, we postulated four criteria for evaluation: (i) the positively selected genes (PSGs) show expression patterns during aging that are compatible with established theories of aging, (ii) the gene set is enriched for genes known to be agingrelated, (iii) the gene set contains functional candidates for being relevant for aging but have not yet been associated therewith, and (iv) protein homology modeling of known aging-related genes suggests functional consequences for amino acid changes under positive selection
Summary
Most of the available information about the genetic mechanisms that govern lifespan and aging were obtained by studying single-gene mutations in invertebrates or short-lived, highly inbred vertebrate species. It is not clear whether insights about aging relevant genes and pathways gained from these species can be applied to long-lived species like human [1]. Comparative evolutionary approaches that search for genetic differences between closely related species that are long- and short-lived with respect to their body mass may reveal novel candidate genes and pathways or open new perspectives on known ones, e.g. by identifying amino acid sites under positive selection that are of potential functional relevance. Genome and transcriptome sequences of longand short-lived species are available and can be used for comparative analysis
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