Does skeletal muscle stop ageing physiologically?

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

Published: 07 February 2023 by MDPI in Cells, Cells and Nothing but Cells: Discoveries, Challenges and Directions session Molecular and Cellular Mechanisms of Aging and Regeneration

Abstract:

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

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