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NPJ Aging Mech Dis. 2017 May 5;3:8. doi: 10.1038/s41514-017-0009-8. eCollection 2017.

Conserved and species-specific molecular denominators in mammalian skeletal muscle aging.

Author information

1
Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224 USA.
2
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy.
3
Interdepartmental Centre "L. Galvani" (CIG), University of Bologna, 40126 Bologna, Italy.
4
Functional Proteomics, SFB815 Core Unit, Cluster of Excellence Frankfurt "Macromolecular Complexes," Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.
5
Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Campus de Excelencia Internacional Agroalimentario ceiA3, Campus Rabanales Edificio Severo Ochoa, 3ª planta, 14014 Córdoba, Spain.
6
Bioanalytical and Drug Development Unit, National institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224 USA.
7
Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224 USA.
8
Translational Gerontology Branch, National Institute on Aging, Intramural Research Program, Poolesville, MD 20837 USA.
9
German Center of Cardiovascular Research (DZHK), Partner site RheinMain, Frankfurt, Germany.
10
IRCCS, Institute of Neurological Sciences of Bologna, 40139 Bologna, Italy.

Abstract

Aging is a complex phenomenon involving functional decline in multiple physiological systems. We undertook a comparative analysis of skeletal muscle from four different species, i.e. mice, rats, rhesus monkeys, and humans, at three different representative stages during their lifespan (young, middle, and old) to identify pathways that modulate function and healthspan. Gene expression profiling and computational analysis revealed that pathway complexity increases from mice to humans, and as mammals age, there is predominantly an upregulation of pathways in all species. Two downregulated pathways, the electron transport chain and oxidative phosphorylation, were common among all four species in response to aging. Quantitative PCR, biochemical analysis, mitochondrial DNA measurements, and electron microscopy revealed a conserved age-dependent decrease in mitochondrial content, and a reduction in oxidative phosphorylation complexes in monkeys and humans. Western blot analysis of key proteins in mitochondrial biogenesis discovered that (i) an imbalance toward mitochondrial fusion occurs in aged skeletal muscle and (ii) mitophagy is not overtly affected, presumably leading to the observed accumulation of abnormally large, damaged mitochondria with age. Select transcript expression analysis uncovered that the skeletal inflammatory profile differentially increases with age, but is most pronounced in humans, while increased oxidative stress (as assessed by protein carbonyl adducts and 4-hydroxynonenal) is common among all species. Expression studies also found that there is unique dysregulation of the nutrient sensing pathways among the different species with age. The identification of conserved pathways indicates common molecular mechanisms intrinsic to health and lifespan, whereas the recognition of species-specific pathways emphasizes the importance of human studies for devising optimal therapeutic modalities to slow the aging process.

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