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Aging Cell. 2015 Aug;14(4):511-23. doi: 10.1111/acel.12342. Epub 2015 Apr 10.

Longevity and skeletal muscle mass: the role of IGF signalling, the sirtuins, dietary restriction and protein intake.

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Stem Cells, Ageing & Molecular Physiology Unit, Research Institute for Sport and Exercise Sciences (RISES), Exercise Metabolism and Adaptation Research Group (EMARG), Liverpool John Moores University, Tom Reilly Building, Liverpool, L3 3AF, UK.
Department of Neurobiology, Physiology and Behavior, University of California, Davis California, CA, 95616, USA.
MRC/ARUK Centre of Excellence for Musculoskeletal Ageing Research, School of Medicine, University of Nottingham, Royal Derby Hospital, Derby, DE22 3DT, UK.
School of Health and Social Care, Bournemouth University, Bournemouth, BH12 5BB, UK.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, 171 77, Sweden.
Glasgow Ageing Research Network (GARNER), Institute of Biodiversity, Animal Health and Comparative Medicine, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK.


Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio-economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin-like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS-1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging.


AKT; AMPK; FOXO; IGF-I; IRS-1; MAFBx; MURF; SIRT; SkM; TSC; cachexia; calorie restriction; high-protein diets; lifespan; longevity; mTOR; regeneration; sarcopenia; satellite cells

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