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Autophagy in metabolic disease and ageing

Abstract

Autophagy is an evolutionarily conserved, lysosome-dependent catabolic process whereby cytoplasmic components, including damaged organelles, protein aggregates and lipid droplets, are degraded and their components recycled. Autophagy has an essential role in maintaining cellular homeostasis in response to intracellular stress; however, the efficiency of autophagy declines with age and overnutrition can interfere with the autophagic process. Therefore, conditions such as sarcopenic obesity, insulin resistance and type 2 diabetes mellitus (T2DM) that are characterized by metabolic derangement and intracellular stresses (including oxidative stress, inflammation and endoplasmic reticulum stress) also involve the accumulation of damaged cellular components. These conditions are prevalent in ageing populations. For example, sarcopenia is an age-related loss of skeletal muscle mass and strength that is involved in the pathogenesis of both insulin resistance and T2DM, particularly in elderly people. Impairment of autophagy results in further aggravation of diabetes-related metabolic derangements in insulin target tissues, including the liver, skeletal muscle and adipose tissue, as well as in pancreatic β-cells. This Review summarizes the role of autophagy in the pathogenesis of metabolic diseases associated with or occurring in the context of ageing, including insulin resistance, T2DM and sarcopenic obesity, and describes its potential as a therapeutic target.

Key points

  • Autophagic activity decreases with age in many species, and adequate autophagy is recognized as an important biological pathway that promotes health and longevity.

  • Basal autophagy and appropriate adaptive autophagy responses induced by intracellular stress and changes in nutrient status enable elimination of damaged cellular components and contribute to cellular homeostasis.

  • Nutrient-sensing pathways, including those involving mTORC1, AMPK and SIRT1, are involved in the regulation of autophagy at multiple steps during autophagic flux.

  • Impairment of autophagy results in further aggravation of diabetes-related metabolic derangements in insulin target tissues, including the liver, skeletal muscle and adipose tissue, as well as in pancreatic β-cells.

  • Calorie restriction, exercise and pharmacological interventions, including several antidiabetic medicines, induce autophagy and are, therefore, recognized as candidate therapies for age-related metabolic disease.

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Fig. 1: Autophagy.
Fig. 2: Selective autophagy.
Fig. 3: Effects of autophagy on cellular senescence and regulation of autophagy by nutrient-sensing pathways.
Fig. 4: Relationships between obesity, insulin resistance, T2DM and autophagy.

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M.K. researched data for the article and wrote the manuscript. M.K. and D.K. contributed to discussion of the article content and editing of the manuscript. Both authors critically appraised the manuscript for important intellectual content and approved the final version to be published. M.K. and D.K. are responsible for the integrity of the content.

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Kitada, M., Koya, D. Autophagy in metabolic disease and ageing. Nat Rev Endocrinol 17, 647–661 (2021). https://doi.org/10.1038/s41574-021-00551-9

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