Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

Abstract

Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, yet the molecular mechanisms behind these opposite phenotypes remain largely unknown. 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, we observed that 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.

Evolution of Natural Lifespan Variation and Molecular Strategies of Extended Lifespan

“…While many previous large-scale omics studies on aging have focused on genome-wide association [53,[61][62][63], recent comparative studies on transcriptomics [64,65], proteomics [66][67][68], metabolomics [69][70][71] and ionomics [72] have begun to shed light on molecular patterns and mechanisms associated with the aging process. For example, it has been suggested that natural variation is associated with extensive changes in gene expression, translation and metabolic regulation, which in turn may affect fitness under different stress conditions [73,74].…”