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.
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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Saeedi, P. et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res. Clin. Pract. 157, 107843 (2019).
Kuk, J. L., Saunders, T. J., Davidson, L. E. & Ross, R. Age-related changes in total and regional fat distribution. Ageing Res. Rev. 8, 339–348 (2009).
Batsis, J. A. & Villareal, D. T. Sarcopenic obesity in older adults: aetiology, epidemiology and treatment strategies. Nat. Rev. Endocrinol. 14, 513–537 (2018).
Li, N. et al. Aging and stress induced β cell senescence and its implication in diabetes development. Aging 11, 9947–9959 (2019).
Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Choi, A. M., Ryter, S. W. & Levine, B. Autophagy in human health and disease. N. Engl. J. Med. 368, 651–662 (2013).
Hurley, J. H. & Young, L. N. Mechanisms of autophagy initiation. Annu. Rev. Biochem. 86, 225–244 (2017).
Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).
Nakatogawa, H., Ishii, J., Asai, E. & Ohsumi, Y. Atg4 recycles inappropriately lipidated Atg8 to promote autophagosome biogenesis. Autophagy 8, 177–186 (2012).
Melia, T. J., Lystad, A. H. & Simonsen, A. Autophagosome biogenesis: from membrane growth to closure. J. Cell Biol. 219, e202002085 (2020).
Lawrence, R. E. & Zoncu, R. The lysosome as a cellular centre for signalling, metabolism and quality control. Nat. Cell Biol. 21, 133–142 (2019).
Osawa, T. et al. Atg2 mediates direct lipid transfer between membranes for autophagosome formation. Nat. Struct. Mol. Biol. 26, 281–288 (2019).
Matoba, K. et al. Atg9 is a lipid scramblase that mediates autophagosomal membrane expansion. Nat. Struct. Mol. Biol. 27, 1185–1193 (2020).
Maeda, S. et al. Structure, lipid scrambling activity and role in autophagosome formation of ATG9A. Nat. Struct. Mol. Biol. 27, 1194–1201 (2020).
Mancias, J. D. & Kimmelman, A. C. Mechanisms of selective autophagy in normal physiology and cancer. J. Mol. Biol. 428, 1659–1680 (2016).
Gatica, D., Lahiri, V. & Klionsky, D. J. Cargo recognition and degradation by selective autophagy. Nat. Cell Biol. 20, 233–242 (2018).
Chu, C. T. et al. Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat. Cell Biol. 15, 1197–1205 (2013).
Dany, M. & Ogretmen, B. Ceramide induced mitophagy and tumor suppression. Biochim. Biophys. Acta 1853, 2834–2845 (2015).
Mizushima, N. & Murphy, L. O. Autophagy assays for biological discovery and therapeutic development. Trends Biochem. Sci. 45, 1080–1093 (2020).
Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 17, 1–382 (2021).
Moulis, M. & Vindis, C. Methods for measuring autophagy in mice. Cells 6, 14 (2017).
Puente, C., Hendrickson, R. C. & Jiang, X. Nutrient-regulated phosphorylation of ATG13 inhibits starvation-induced autophagy. J. Biol. Chem. 291, 6026–6035 (2016).
Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).
Shang, L. et al. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc. Natl Acad. Sci. USA 108, 4788–4793 (2011).
Yuan, H. X., Russell, R. C. & Guan, K. L. Regulation of PIK3C3/VPS34 complexes by MTOR in nutrient stress-induced autophagy. Autophagy 9, 1983–1995 (2013).
Nazio, F. et al. mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association and function through AMBRA1 and TRAF6. Nat. Cell Biol. 15, 406–416 (2013).
Ma, X. et al. MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy. Autophagy 13, 592–607 (2017).
Park, J. M. et al. The ULK1 complex mediates mTORC1 signaling to the autophagy initiation machinery via binding and phosphorylating ATG14. Autophagy 12, 547–564 (2016).
Wan, W. et al. mTORC1 phosphorylates acetyltransferase p300 to regulate autophagy and lipogenesis. Mol. Cell 68, 323–335.e6 (2017).
Wan, W. et al. mTORC1-regulated and HUWE1-mediated WIPI2 degradation controls autophagy flux. Mol. Cell 72, 303–315.e6 (2018).
Kim, Y. M. et al. mTORC1 phosphorylates UVRAG to negatively regulate autophagosome and endosome maturation. Mol. Cell 57, 207–218 (2015).
Munson, M. J. et al. mTOR activates the VPS34–UVRAG complex to regulate autolysosomal tubulation and cell survival. EMBO J. 34, 2272–2290 (2015).
Cheng, X. et al. Pacer is a mediator of mTORC1 and GSK3–TIP60 signaling in regulation of autophagosome maturation and lipid metabolism. Mol. Cell 73, 788–802.e7 (2019).
Roczniak-Ferguson, A. et al. The transcription factor TFEB links mTORC1 signaling to transcriptional control of lysosome homeostasis. Sci. Signal. 5, ra42 (2012).
Martina, J. A., Chen, Y., Gucek, M. & Puertollano, R. mTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB. Autophagy 8, 903–914 (2012).
Martina, J. A. et al. The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris. Sci. Signal. 7, ra9 (2014).
Vega-Rubin-de-Celis, S., Peña-Llopis, S., Konda, M. & Brugarolas, J. Multistep regulation of TFEB by mTORC1. Autophagy 13, 464–472 (2017).
Napolitano, G. & Ballabio, A. TFEB at a glance. J. Cell Sci. 129, 2475–2481 (2016).
Napolitano, G. et al. mTOR-dependent phosphorylation controls TFEB nuclear export. Nat. Commun. 9, 3312 (2018).
Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).
Lee, J. W., Park, S., Takahashi, Y. & Wang, H. G. The association of AMPK with ULK1 regulates autophagy. PLoS ONE 5, e15394 (2010).
Gwinn, D. M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).
Bach, M., Larance, M., James, D. E. & Ramm, G. The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. Biochem. J. 440, 283–291 (2011).
Tian, W. et al. Phosphorylation of ULK1 by AMPK regulates translocation of ULK1 to mitochondria and mitophagy. FEBS Lett. 589, 1847–1854 (2015).
Mack, H. I., Zheng, B., Asara, J. M. & Thomas, S. M. AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization. Autophagy 8, 1197–1214 (2012).
Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).
Tamargo-Gómez, I. & Mariño, G. AMPK: regulation of metabolic dynamics in the context of autophagy. Int. J. Mol. Sci. 19, 3812 (2018).
Shiloh, R. et al. Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy. Nat. Commun. 9, 1759 (2018).
Xu, D. Q. et al. PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L-associated PI3K activity. EMBO J. 35, 496–514 (2016).
Zhao, Y. et al. RACK1 promotes autophagy by enhancing the Atg14L-Beclin 1-Vps34-Vps15 complex formation upon phosphorylation by AMPK. Cell Rep. 13, 1407–1417 (2015).
Aas, S. N. et al. The impact of age and frailty on skeletal muscle autophagy markers and specific strength: a cross-sectional comparison. Exp. Gerontol. 125, 110687 (2019).
Kim, J. et al. Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152, 290–303 (2013).
Weerasekara, V. K. et al. Metabolic-stress-induced rearrangement of the 14-3-3ζ interactome promotes autophagy via a ULK1- and AMPK-regulated 14-3-3ζ interaction with phosphorylated Atg9. Mol. Cell Biol. 34, 4379–4388 (2014).
Huang, R. et al. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol. Cell 57, 456–466 (2015).
Lee, I. H. et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl Acad. Sci. USA 105, 3374–3379 (2008).
Gu, X. et al. SIRT1-mediated FoxOs pathways protect against apoptosis by promoting autophagy in osteoblast-like MC3T3-E1 cells exposed to sodium fluoride. Oncotarget 7, 65218–65230 (2016).
Kume, S. et al. Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney. J. Clin. Invest. 120, 1043–1055 (2010).
Price, N. L. et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 15, 675–690 (2012).
Ghosh, H. S., McBurney, M. & Robbins, P. D. SIRT1 negatively regulates the mammalian target of rapamycin. PLoS ONE 5, e9199 (2010).
Cantó, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).
Takeda-Watanabe, A., Kitada, M., Kanasaki, K. & Koya, D. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells. Biochem. Biophys. Res. Commun. 427, 191–196 (2012).
Kume, S., Thomas, M. C. & Koya, D. Nutrient sensing, autophagy, and diabetic nephropathy. Diabetes 61, 23–29 (2012).
Filomeni, G., De Zio, D. & Cecconi, F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 22, 377–388 (2015).
Rashid, H. O., Yadav, R. K., Kim, H. R. & Chae, H. J. ER stress: autophagy induction, inhibition and selection. Autophagy 11, 1956–1977 (2015).
Sardiello, M. et al. A gene network regulating lysosomal biogenesis and function. Science 325, 473–477 (2009).
Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).
Hars, E. S. et al. Autophagy regulates ageing in C. elegans. Autophagy 3, 93–95 (2007).
Meléndez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).
Dwivedi, M., Song, H. O. & Ahnn, J. Autophagy genes mediate the effect of calcineurin on life span in C. elegans. Autophagy 5, 604–607 (2009).
Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).
Sou, Y. S. et al. The Atg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol. Biol. Cell 19, 4762–4775 (2008).
Komatsu, M. et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425–434 (2005).
Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013).
Fernández, Á. F. et al. Disruption of the beclin 1–BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558, 136–140 (2018).
Nakamura, S. et al. Suppression of autophagic activity by Rubicon is a signature of aging. Nat. Commun. 10, 847 (2019).
Zhou, B. et al. Mitochondrial permeability uncouples elevated autophagy and lifespan extension. Cell 177, 299–314.e16 (2019).
Wilhelm, T. et al. Neuronal inhibition of the autophagy nucleation complex extends life span in post-reproductive C. elegans. Genes Dev. 31, 1561–1572 (2017).
Bjedov, I. et al. Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila. PLoS Genet. 16, e1009083 (2020).
Lim, Y. M. et al. Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes. Nat. Commun. 5, 4934 (2014).
Fernández, Á. F. et al. Autophagy couteracts weight gain, lipotoxicity and pancreatic β-cell death upon hypercaloric pro-diabetic regimens. Cell Death Dis. 8, e2970 (2017).
Ebato, C. et al. Autophagy is important in islet homeostasis and compensatory increase of β cell mass in response to high-fat diet. Cell Metab. 8, 325–332 (2008).
Jung, H. S. et al. Loss of autophagy diminishes pancreatic β cell mass and function with resultant hyperglycemia. Cell Metab. 8, 318–324 (2008).
Goginashvili, A. et al. Insulin granules. Insulin secretory granules control autophagy in pancreatic β cells. Science 347, 878–882 (2015).
Yamamoto, S. et al. Autophagy differentially regulates insulin production and insulin sensitivity. Cell Rep. 23, 3286–3299 (2018).
Masini, M. et al. Autophagy in human type 2 diabetes pancreatic β cells. Diabetologia 52, 1083–1086 (2009).
Cnop, M. et al. RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate. Diabetes 63, 1978–1993 (2014).
Las, G., Serada, S. B., Wikstrom, J. D., Twig, G. & Shirihai, O. S. Fatty acids suppress autophagic turnover in β-cells. J. Biol. Chem. 286, 42534–42544 (2011).
Mir, S. U. et al. Inhibition of autophagic turnover in β-cells by fatty acids and glucose leads to apoptotic cell death. J. Biol. Chem. 290, 6071–6085 (2015).
Zummo, F. P. et al. Glucagon-like peptide 1 protects pancreatic β-cells from death by increasing autophagic flux and restoring lysosomal function. Diabetes 66, 1272–1285 (2017).
Trudeau, K. M. et al. Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity. J. Cell Biol. 214, 25–34 (2016).
Bugliani, M. et al. Modulation of autophagy influences the function and survival of human pancreatic β cells under endoplasmic reticulum stress conditions and in type 2 diabetes. Front. Endocrinol. 10, 52 (2019).
Abedini, A. & Schmidt, A. M. Mechanisms of islet amyloidosis toxicity in type 2 diabetes. FEBS Lett. 587, 1119–1127 (2013).
Kim, J. et al. Amyloidogenic peptide oligomer accumulation in autophagy-deficient β cells induces diabetes. J. Clin. Invest. 124, 3311–3324 (2014).
Shigihara, N. et al. Human IAPP-induced pancreatic β cell toxicity and its regulation by autophagy. J. Clin. Invest. 124, 3634–3644 (2014).
Perry, R. J., Samuel, V. T., Petersen, K. F. & Shulman, G. I. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 510, 84–91 (2014).
Yang, L., Li, P., Fu, S., Calay, E. S. & Hotamisligil, G. S. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab. 11, 467–478 (2010).
González-Rodríguez, A. et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis. 5, e1179 (2014).
Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).
Jaber, N. et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc. Natl Acad. Sci. USA 109, 2003–2008 (2012).
Settembre, C. et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat. Cell Biol. 15, 647–658 (2013).
Tanaka, S. et al. Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology 64, 1994–2014 (2016).
Zhang, Y. et al. Adipose-specific deletion of autophagy-related gene 7 (Atg7) in mice reveals a role in adipogenesis. Proc. Natl Acad. Sci. USA 106, 19860–19865 (2009).
Tchkonia, T. et al. Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684 (2010).
Kovsan, J. et al. Altered autophagy in human adipose tissues in obesity. J. Clin. Endocrinol. Metab. 96, E268–E277 (2011).
Jansen, H. J. et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 153, 5866–5874 (2012).
Kosacka, J. et al. Autophagy in adipose tissue of patients with obesity and type 2 diabetes. Mol. Cell Endocrinol. 409, 21–32 (2015).
Abad-Jiménez, Z. et al. Systemic oxidative stress and visceral adipose tissue mediators of NLRP3 inflammasome and autophagy are reduced in obese type 2 diabetic patients treated with metformin. Antioxidants 9, 892 (2020).
Yamamuro, T. et al. Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy. Nat. Commun. 11, 4150 (2020).
Anagnostis, P. et al. Type 2 diabetes mellitus is associated with increased risk of sarcopenia: a systematic review and meta-analysis. Calcif. Tissue Int. 107, 453–463 (2020).
Wang, T. et al. Type 2 diabetes mellitus is associated with increased risks of sarcopenia and pre-sarcopenia in Chinese elderly. Sci. Rep. 6, 38937 (2016).
Srikanthan, P. & Karlamangla, A. S. Relative muscle mass is inversely associated with insulin resistance and prediabetes. Findings from the third National Health and Nutrition Examination Survey. J. Clin. Endocrinol. Metab. 96, 2898–2903 (2011).
O’Neill, B. T. et al. Differential role of insulin/IGF-1 receptor signaling in muscle growth and glucose homeostasis. Cell Rep. 11, 1220–1235 (2015).
O’Neill, B. T. et al. Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. J. Clin. Invest. 126, 3433–3446 (2016).
Masiero, E. et al. Autophagy is required to maintain muscle mass. Cell Metab. 10, 507–515 (2009).
Carnio, S. et al. Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep. 8, 1509–1521 (2014).
Potes, Y. et al. Overweight in elderly people induces impaired autophagy in skeletal muscle. Free Radic. Biol. Med. 110, 31–41 (2017).
Møller, A. B. et al. Altered gene expression and repressed markers of autophagy in skeletal muscle of insulin resistant patients with type 2 diabetes. Sci. Rep. 7, 43775 (2017).
Chang, Y. C. et al. Resveratrol protects muscle cells against palmitate-induced cellular senescence and insulin resistance through ameliorating autophagic flux. J. Food Drug Anal. 26, 1066–1074 (2018).
Drake, J. C. & Yan, Z. Mitophagy in maintaining skeletal muscle mitochondrial proteostasis and metabolic health with ageing. J. Physiol. 595, 6391–6399 (2017).
Lam, T. et al. Reversal of intramyocellular lipid accumulation by lipophagy and a p62-mediated pathway. Cell Death Discov. 2, 16061 (2016).
Tang, A. H. & Rando, T. A. Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation. EMBO J. 33, 2782–2797 (2014).
García-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016).
Fontana, L. & Partridge, L. Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106–118 (2015).
Jia, K. & Levine, B. Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3, 597–599 (2007).
Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 4, e24 (2008).
Mercken, E. M. et al. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell 12, 645–651 (2013).
Yang, L. et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 14, 422–428 (2016).
Kim, K. E. et al. Caloric restriction of db/db mice reverts hepatic steatosis and body weight with divergent hepatic metabolism. Sci. Rep. 6, 30111 (2016).
Gao, X., Yan, D., Zhao, Y., Tao, H. & Zhou, Y. Moderate calorie restriction to achieve normal weight reverses β-cell dysfunction in diet-induced obese mice: involvement of autophagy. Nutr. Metab. 12, 34 (2015).
Cui, M., Yu, H., Wang, J., Gao, J. & Li, J. Chronic caloric restriction and exercise improve metabolic conditions of dietary-induced obese mice in autophagy correlated manner without involving AMPK. J. Diabetes Res. 2013, 852754 (2013).
Liu, H. et al. Intermittent fasting preserves β-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway. Autophagy 13, 1952–1968 (2017).
Martinez-Lopez, N. et al. System-wide benefits of intermeal fasting by autophagy. Cell Metab. 26, 856–871.e5 (2017).
He, B., Liu, L., Yu, C., Wang, Y. & Han, P. Roux-en-Y gastric bypass reduces lipid overaccumulation in liver by upregulating hepatic autophagy in obese diabetic rats. Obes. Surg. 25, 109–118 (2015).
Ma, N., Ma, R., Tang, K., Li, X. & He, B. Roux-en-Y gastric bypass in obese diabetic rats promotes autophagy to improve lipid metabolism through mTOR/p70S6K signaling pathway. J. Diabetes Res. 2020, 4326549 (2020).
He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).
Grumati, P. et al. Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles. Autophagy 7, 1415–1423 (2011).
Lira, V. A. et al. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J. 27, 4184–4193 (2013).
Luo, L. et al. Chronic resistance training activates autophagy and reduces apoptosis of muscle cells by modulating IGF-1 and its receptors, Akt/mTOR and Akt/FOXO3a signaling in aged rats. Exp. Gerontol. 48, 427–436 (2013).
Pi, H. et al. Long-term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy-lysosomal machinery. FASEB J. 33, 11870–11883 (2019).
Tang, H. et al. Swimming prevents nonalcoholic fatty liver disease by reducing migration inhibitory factor through Akt suppression and autophagy activation. Am. J. Transl. Res. 11, 4315–4325 (2019).
Ghareghani, P. et al. Aerobic endurance training improves nonalcoholic fatty liver disease (NAFLD) features via miR-33 dependent autophagy induction in high fat diet fed mice. Obes. Res. Clin. Pract. 12, 80–89 (2018).
Vainshtein, A., Tryon, L. D., Pauly, M. & Hood, D. A. Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle. Am. J. Physiol. Cell Physiol. 308, C710–C719 (2015).
Wohlgemuth, S. E., Seo, A. Y., Marzetti, E., Lees, H. A. & Leeuwenburgh, C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp. Gerontol. 45, 138–148 (2010).
Kulkarni, A. S., Gubbi, S. & Barzilai, N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 32, 15–30 (2020).
Martin-Montalvo, A. et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 4, 2192 (2013).
Song, Y. M. et al. Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway. Autophagy 11, 46–59 (2015).
Li, M., Sharma, A., Yin, C., Tan, X. & Xiao, Y. Metformin ameliorates hepatic steatosis and improves the induction of autophagy in HFD‑induced obese mice. Mol. Med. Rep. 16, 680–686 (2017).
Jiang, Y. et al. Metformin plays a dual role in MIN6 pancreatic β cell function through AMPK-dependent autophagy. Int. J. Biol. Sci. 10, 268–277 (2014).
Jing Yin, J., Bo Li, Y., Ming Cao, M. & Wang, Y. Liraglutide improves the survival of INS-1 cells by promoting macroautophagy. Int. J. Endocrinol. Metab. 11, 184–190 (2013).
Fan, M. et al. Liraglutide enhances autophagy and promotes pancreatic β cell proliferation to ameliorate type 2 diabetes in high-fat-fed and streptozotocin-treated mice. Med. Sci. Monit. 24, 2310–2316 (2018).
Miao, X. et al. The glucagon-like peptide-1 analogue liraglutide promotes autophagy through the modulation of 5′-AMP-activated protein kinase in INS-1 β-cells under high glucose conditions. Peptides 100, 127–139 (2018).
Lim, S. W., Jin, L., Jin, J. & Yang, C. W. Effect of exendin-4 on autophagy clearance in β cells of rats with tacrolimus-induced diabetes mellitus. Sci. Rep. 6, 29921 (2016).
Fu, J. et al. Liraglutide protects pancreatic β cells from endoplasmic reticulum stress by upregulating MANF to promote autophagy turnover. Life Sci. 252, 117648 (2020).
Li, X. D., He, S. S., Wan, T. T. & Li, Y. B. Liraglutide protects palmitate-induced INS-1 cell injury by enhancing autophagy mediated via FoxO1. Mol. Med. Rep. 23, 147 (2021).
Wang, J. et al. Liraglutide protects pancreatic β-cells against free fatty acids in vitro and affects glucolipid metabolism in apolipoprotein E–/– mice by activating autophagy. Mol. Med. Rep. 12, 4210–4218 (2015).
He, Q., Sha, S., Sun, L., Zhang, J. & Dong, M. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway. Biochem. Biophys. Res. Commun. 476, 196–203 (2016).
He, Y. et al. The preventive effect of liraglutide on the lipotoxic liver injury via increasing autophagy. Ann. Hepatol. 19, 44–52 (2020).
Sharma, S., Mells, J. E., Fu, P. P., Saxena, N. K. & Anania, F. A. GLP-1 analogs reduce hepatocyte steatosis and improve survival by enhancing the unfolded protein response and promoting macroautophagy. PLoS ONE 6, e25269 (2011).
Fang, Y. et al. Liraglutide alleviates hepatic steatosis by activating the TFEB-regulated autophagy-lysosomal pathway. Front. Cell Dev. Biol. 8, 602574 (2020).
Liu, L., Liu, J. & Yu, X. Dipeptidyl peptidase-4 inhibitor MK-626 restores insulin secretion through enhancing autophagy in high fat diet-induced mice. Biochem. Biophys. Res. Commun. 470, 516–520 (2016).
Zhu, B. et al. Alogliptin improves survival and health of mice on a high-fat diet. Aging Cell 18, e12883 (2019).
Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).
Linnemann, A. K. et al. Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy. FASEB J. 31, 4140–4152 (2017).
DeFronzo, R. A., Reeves, W. B. & Awad, A. S. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat. Rev. Nephrol. 17, 319–334 (2021).
Xu, J., Kitada, M., Ogura, Y., Liu, H. & Koya, D. Dapagliflozin restores impaired autophagy and suppresses inflammation in high glucose-treated HK-2 cells. Cells 10, 1457 (2021).
Fukushima, K., Kitamura, S., Tsuji, K., Sang, Y. & Wada, J. Sodium glucose co-transporter 2 inhibitor ameliorates autophagic flux impairment on renal proximal tubular cells in obesity mice. Int. J. Mol. Sci. 21, 4054 (2020).
Aragón-Herrera, A. et al. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochem. Pharmacol. 170, 113677 (2019).
Xu, C. et al. Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy in immune cells. Biochem. Pharmacol. 152, 45–59 (2018).
Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).
Zhang, Y. et al. Rapamycin extends life and health in C57BL/6 mice. J. Gerontol. A Biol. Sci. Med. Sci. 69, 119–130 (2014).
Chiao, Y. A. et al. Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. Aging 8, 314–327 (2016).
Chang, G. R. et al. Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice. J. Pharmacol. Sci. 109, 496–503 (2009).
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).
Sataranatarajan, K. et al. Rapamycin increases mortality in db/db mice, a mouse model of type 2 diabetes. J. Gerontol. A Biol. Sci. Med. Sci. 71, 850–857 (2016).
Arriola Apelo, S. I. et al. Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system. Aging Cell 15, 28–38 (2016).
Zhou, W. & Ye, S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol. Int. 42, 1282–1291 (2018).
Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).
Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).
Morselli, E. et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615–629 (2011).
Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).
Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).
Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).
Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).
Chen, G. et al. 3,4-Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB. EMBO Mol. Med. 11, e10469 (2019).
Carmona-Gutierrez, D. et al. The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species. Nat. Commun. 10, 651 (2019).
Bravo-San Pedro, J. M. et al. Acyl-CoA-binding protein is a lipogenic factor that triggers food intake and obesity. Cell Metab. 30, 754–767.e9 (2019).
Bravo-San Pedro, J. M. et al. Cell-autonomous, paracrine and neuroendocrine feedback regulation of autophagy by DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein): the obesity factor. Autophagy 15, 2036–2038 (2019).
The authors declare no competing interests.
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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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