Abstract
Naked mole-rats (NMRs) have amongst the longest lifespans relative to body size of any known, non-volant mammalian species. They also display an enhanced stress resistance phenotype, negligible senescence and very rarely are they burdened with chronic age-related diseases. Alternative splicing (AS) dysregulation is emerging as a potential driver of senescence and ageing. We hypothesised that the expression of splicing factors, important regulators of patterns of AS, may differ in NMRs when compared to other species with relatively shorter lifespans. We designed assays specific to NMR splicing regulatory factors and also to a panel of pre-selected brain-expressed genes known to demonstrate senescence-related alterations in AS in other species, and measured age-related changes in the transcript expression levels of these using embryonic and neonatal developmental stages through to extreme old age in NMR brain samples. We also compared splicing factor expression in both young mouse and NMR spleen and brain samples. Both NMR tissues showed approximately double the expression levels observed in tissues from similarly sized mice. Furthermore, contrary to observations in other species, following a brief period of labile expression in early life stages, adult NMR splicing factors and patterns of AS for functionally relevant brain genes remained remarkably stable for at least two decades. These findings are consistent with a model whereby the conservation of splicing regulation and stable patterns of AS may contribute to better molecular stress responses and the avoidance of senescence in NMRs, contributing to their exceptional lifespan and prolonged healthspan.
Highlights
Naked mole-rats (NMRs; Heterocephalus glaber) are eusocial animals which live in subterranean colonies of up to 300 individuals with a single breeding female, in a manner analogous to bees or other social insects (Jarvis 1981; Brett 1991)
Slightly fewer splicing factors demonstrated altered expression compared to mice, major differences in expression were apparent, for the Hnrnpa0, Hnrnph3, Hnrnpk, Hnrnpul2, Srsf1, Srsf2, Srsf3 and Srsf6 genes (p = < 0.001 for each)
To demonstrate the functional consequences of splicing factor changes during NMR development and ageing, we assessed changes in the isoform repertoire of a panel of genes that we have previously demonstrated to be differentially expressed in human astrocyte senescence; some of which are associated with cognitive decline in human populations (Lye et al 2019)
Summary
Naked mole-rats (NMRs; Heterocephalus glaber) are eusocial animals which live in subterranean colonies of up to 300 individuals with a single breeding female, in a manner analogous to bees or other social insects (Jarvis 1981; Brett 1991) Sized rodents such as mice have a lifespan limited to 3–4 years, whereas NMRs typically survive to over 20 years of age, with a maximum recorded lifespan of 37 years in a still extant male. NMRs can survive 18 min in pure nitrogen atmospheres and under these anoxic conditions switch from glucose-based anaerobic metabolism to that of fructose and appear to have several neuroprotective mechanisms to prevent neuronal death under hypoxia (Park et al 2017; Munro et al 2019) These long living, resilient animals present an interesting paradox in ageing biology and an opportunity to examine fundamental mechanisms of ageing
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