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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, 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.

SUBMITTER: Fuentealba M

PROVIDER: S-EPMC7895802 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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

Fuentealba Matias M Fabian Daniel K DK Dönertaş Handan Melike HM Thornton Janet M JM Partridge Linda L

Mechanisms of ageing and development 20210114

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 targ ...[more]

PMID: 33454277

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Project description:Age is an important factor in the development of osteoarthritis. Microarray studies provide insight into cartilage aging but do not reveal the full transcriptomic phenotype of chondrocytes such as small noncoding RNAs, pseudogenes, and microRNAs. RNA-Seq is a powerful technique for the interrogation of large numbers of transcripts including nonprotein coding RNAs. The aim of the study was to characterise molecular mechanisms associated with age-related changes in gene signatures.RNA for gene expression analysis using RNA-Seq and real-time PCR analysis was isolated from macroscopically normal cartilage of the metacarpophalangeal joints of eight horses; four young donors (4 years old) and four old donors (>15 years old). RNA sequence libraries were prepared following ribosomal RNA depletion and sequencing was undertaken using the Illumina HiSeq 2000 platform. Differentially expressed genes were defined using Benjamini-Hochberg false discovery rate correction with a generalised linear model likelihood ratio test (P < 0.05, expression ratios ± 1.4 log? fold-change). Ingenuity pathway analysis enabled networks, functional analyses and canonical pathways from differentially expressed genes to be determined.In total, the expression of 396 transcribed elements including mRNAs, small noncoding RNAs, pseudogenes, and a single microRNA was significantly different in old compared with young cartilage (± 1.4 log2 fold-change, P < 0.05). Of these, 93 were at higher levels in the older cartilage and 303 were at lower levels in the older cartilage. There was an over-representation of genes with reduced expression relating to extracellular matrix, degradative proteases, matrix synthetic enzymes, cytokines and growth factors in cartilage derived from older donors compared with young donors. In addition, there was a reduction in Wnt signalling in ageing cartilage.There was an age-related dysregulation of matrix, anabolic and catabolic cartilage factors. This study has increased our knowledge of transcriptional networks in cartilage ageing by providing a global view of the transcriptome.

Dataset Information

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

Publications

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

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