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Does skeletal muscle stop ageing physiologically?
* 1, 2 , 1, 3 , 4, 5 , 1 , 1 , 6 , 7 , 7 , 4, 5 , 1, 3 , 8, 9 , 6 , 5, 10 , 7, 11 , 1
1  Australian Regenerative Medicine Institute, Monash University, Wellington Road, Clayton, VIC 3800, Australia
2  Department of Anatomy & Physiology, The University of Melbourne, Parkville, VIC, Australia
3  Systems Biology Institute Australia, Monash University, Clayton, VIC 3800, Australia
4  Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
5  Monash Proteomics and Metabolomics Facility, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
6  Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
7  Leibniz Institute on Aging – Fritz Lipmann Institute (FLI), 07745 Jena, Germany
8  Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
9  Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC, Australia
10  Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
11  Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, 07745 Jena, Germany
Academic Editor: Alexander E. Kalyuzhny


Ageing is associated with an exponential increase in mortality, but paradoxically, in many organisms mortality rates decline late in life, a phenomenon known as late-life mortality deceleration. How late-life differs to ageing physiologically, and if mortality deceleration implies that ageing stops or reverses at a specific point of an organism’s life remains unknown. Therefore, to examine the cellular and metabolic basis for mortality deceleration, we used a novel model of ageing – that of the African killifish, an extremely short-lived vertebrate that displays mortality deceleration. Using skeletal muscle, where the stereotypic hallmarks of ageing are well characterized, we highlight that ageing and late-life phases are physiologically distinct. Using a systems metabolomics approach, we demonstrate that during ageing there is a striking depletion of triglycerides, mimicking a state of calorie restriction, which triggers mitohormesis, a reactive oxygen species mediated stress resistance mechanism. This improves lipid and mitochondrial metabolism, subsequently maintaining nutrient homeostasis during late-life and driving mortality deceleration. Our results not only provide evidence of mitohormesis in regulating lifespan in vertebrates that naturally live-longer, but they also collectively show that the metabolic hallmarks of ageing are reversible.

Keywords: sarcopenia, skeletal muscle, killifish. mitohormesis, longevity