Abstract
Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, and provide a powerful context in which to unravel the molecular mechanisms at work. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes, and also the whole transcriptome, the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes.
Highlights
IntroductionIn humans, it causes a gradual decline in physiological function, and it is the major risk factor for many serious diseases (MacNee et al, 2014; Niccoli and Partridge, 2012; Partridge et al, 2020)
We first asked if genetic interventions that lengthen or shorten life span show characteristic transcriptomic changes, by comparing publicly available microarray and RNA-seq data from 10 long-lived and 8 shortlived mouse models of ageing (Fig. 1)
We further compared the genes leading the regulation of energy and lipid metabolism in long- and short-lived mice (Fig. 3B–C) and we identified 5 genes in common: cytochrome c oxidase subunit 5A (Cox5a), cytochrome c-1 (Cyc1), NADH:ubiquinone oxidoreductase subunit B10 (Ndufb10), NADH:ubiquinone oxidoreductase core subunit V2 (Ndufv2) and ubiquinol-cytochrome c reductase (Uqcrfs1)
Summary
In humans, it causes a gradual decline in physiological function, and it is the major risk factor for many serious diseases (MacNee et al, 2014; Niccoli and Partridge, 2012; Partridge et al, 2020). The rate of ageing is influenced by hundreds of genes, but it can be modulated in mice and other model organisms by single gene mutations (Bartke, 2011; Folgueras et al, 2018; Kenyon, 2005; Piper and Partridge, 2018; Uno and Nishida, 2016). Mutant mouse models of increased genomic instability have been suggested to be characterised by accel erated ageing, with shortened lifespan and early onset of age-associated pathologies (Dolle et al, 2011; Osorio et al, 2011; Van Der Pluijm et al, 2007; Weeda et al, 1997)
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