Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Autophagy in aging and longevity


Our understanding of the process of autophagy and its role in health and diseases has grown remarkably in the last two decades. Early work established autophagy as a general bulk recycling process which involves the sequestration and transport of intracellular material to the lysosome for degradation. Currently, autophagy is viewed as a nexus of metabolic and proteostatic signalling that can determine key physiological decisions from cell fate to organismal lifespan. Here, we review the latest literature on the role of autophagy and lysosomes in stress response and longevity. We highlight the connections between autophagy and metabolic processes, the network associated with its regulation, and the links between autophagic dysfunction, neurodegenerative diseases, and aging.

This is a preview of subscription content, log in to check access.

Fig. 1


  1. Artal-Martinez de Narvajas A, Gomez TS, Zhang JS, Mann AO, Taoda Y, Gorman JA, Herreros-Villanueva M, Gress TM, Ellenrieder V, Bujanda L, Kim DH, Kozikowski AP, Koenig A, Billadeau DD (2013) Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol 33:3983–3993

  2. Ashkenazi A, Bento CF, Ricketts T, Vicinanza M, Siddiqi F, Pavel M, Squitieri F, Hardenberg MC, Imarisio S, Menzies FM, Rubinsztein DC (2017) Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545:108–111

  3. Bagherniya M, Butler AE, Barreto GE, Sahebkar A (2018) The effect of fasting or calorie restriction on autophagy induction: a review of the literature. Ageing Res Rev 47:183–197

  4. Bordone L, Guarente L (2005) Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6:298–305

  5. Bowman CJ, Ayer DE, Dynlacht BD (2014) Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat Cell Biol 16:1202–1214

  6. Bujak Adam L, Crane Justin D, Lally James S, Ford Rebecca J, Kang Sally J, Rebalka Irena A, Green Alex E, Kemp Bruce E, Hawke Thomas J, Schertzer Jonathan D, Steinberg Gregory R (2015) AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. Cell Metab 21:883–890

  7. Caballero B, Wang Y, Diaz A, Tasset I, Juste YR, Stiller B, Mandelkow EM, Mandelkow E, Cuervo AM (2018) Interplay of pathogenic forms of human tau with different autophagic pathways. Aging Cell 17:e12692

  8. Cadwell K, Debnath J (2018) Beyond self-eating: the control of nonautophagic functions and signaling pathways by autophagy-related proteins. J Cell Biol 217:813–822

  9. Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27:2276–2288

  10. Castellano BM, Thelen AM, Moldavski O, Feltes M, van der Welle RE, Mydock-McGrane L, Jiang X, van Eijkeren RJ, Davis OB, Louie SM, Perera RM, Covey DF, Nomura DK, Ory DS, Zoncu R (2017) Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science 355:1306–1311

  11. Chen H, Fan M, Pfeffer LM, Laribee RN (2012) The histone H3 lysine 56 acetylation pathway is regulated by target of rapamycin (TOR) signaling and functions directly in ribosomal RNA biogenesis. Nucleic Acids Res 40:6534–6546

  12. Chen BJ, Ueberham U, Mills JD, Kirazov L, Kirazov E, Knobloch M, Bochmann J, Jendrek R, Takenaka K, Bliim N, Arendt T, Janitz M (2017) RNA sequencing reveals pronounced changes in the noncoding transcriptome of aging synaptosomes. Neurobiol Aging 56:67–77

  13. Cherra SJ 3rd, Kulich SM, Uechi G, Balasubramani M, Mountzouris J, Day BW, Chu CT (2010) Regulation of the autophagy protein LC3 by phosphorylation. J Cell Biol 190:533–539

  14. Cortes CJ, La Spada AR (2019) TFEB dysregulation as a driver of autophagy dysfunction in neurodegenerative disease: molecular mechanisms, cellular processes, and emerging therapeutic opportunities. Neurobiol Dis 122:83–93

  15. Cotzomi-Ortega I, Aguilar-Alonso P, Reyes-Leyva J, Maycotte P (2018) Autophagy and its role in protein secretion: implications for cancer therapy. Mediators Inflamm 2018:4231591

  16. D’Angelo MA, Raices M, Panowski SH, Hetzer MW (2009) Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in post-mitotic cells. Cell 136:284–295

  17. Danieli A, Martens S (2018) p62-mediated phase separation at the intersection of the ubiquitin-proteasome system and autophagy. J Cell Sci 131:jcs214304

  18. Decressac M, Mattsson B, Weikop P, Lundblad M, Jakobsson J, Bjorklund A (2013) TFEB-mediated autophagy rescues midbrain dopamine neurons from alpha-synuclein toxicity. Proc Natl Acad Sci USA 110:E1817–E1826

  19. Demoinet E, Li S, Roy R (2017) AMPK blocks starvation-inducible transgenerational defects in Caenorhabditis elegans. Proc Natl Acad Sci USA 114:E2689–E2698

  20. Deng Z, Purtell K, Lachance V, Wold MS, Chen S, Yue Z (2017) Autophagy receptors and neurodegenerative diseases. Trends Cell Biol 27:491–504

  21. Denzel MS, Lapierre LR, Mack HID (2019) Emerging topics in C. elegans aging research: transcriptional regulation, stress response and epigenetics. Mech Ageing Dev 177:4–21

  22. Diaz-Troya S, Perez-Perez ME, Florencio FJ, Crespo JL (2008) The role of TOR in autophagy regulation from yeast to plants and mammals. Autophagy 4:851–865

  23. Dong F, Li C, Wang P, Deng X, Luo Q, Tang X, Xu L (2018) The RNA binding protein tristetraprolin down-regulates autophagy in lung adenocarcinoma cells. Exp Cell Res 367:89–96

  24. Efeyan A, Comb WC, Sabatini DM (2015) Nutrient-sensing mechanisms and pathways. Nature 517:302–310

  25. Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS, Grima JC, Bennett RE, Tepper K, DeTure M, Vanderburg CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RYH, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT (2018) Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99:925–940

  26. Egan D, Kim J, Shaw RJ, Guan K-L (2011) The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7:643–644

  27. Escobar KA, Cole NH, Mermier CM, VanDusseldorp TA (2019) Autophagy and aging: maintaining the proteome through exercise and caloric restriction. Aging Cell 18:e12876

  28. Fahrenkrog B, Harel A (2018) Perturbations in traffic: aberrant nucleocytoplasmic transport at the heart of neurodegeneration. Cells 7:232

  29. Fang EF, Hou Y, Palikaras K, Adriaanse BA, Kerr JS, Yang B, Lautrup S, Hasan-Olive MM, Caponio D, Dan X, Rocktaschel P, Croteau DL, Akbari M, Greig NH, Fladby T, Nilsen H, Cader MZ, Mattson MP, Tavernarakis N, Bohr VA (2019) Mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease. Nat Neurosci 22:401–412

  30. Fecto F, Yan J, Vemula SP, Liu E, Yang Y, Chen W, Zheng JG, Shi Y, Siddique N, Arrat H, Donkervoort S, Ajroud-Driss S, Sufit RL, Heller SL, Deng HX, Siddique T (2011) SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch Neurol 68:1440–1446

  31. Folick A, Oakley HD, Yu Y, Armstrong EH, Kumari M, Sanor L, Moore DD, Ortlund EA, Zechner R, Wang MC (2015) Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science 347:83

  32. Fonseca Costa SS, Ripperger JA (2015) Impact of the circadian clock on the aging process. Front Neurol 6:43

  33. Frankel LB, Lubas M, Lund AH (2017) Emerging connections between RNA and autophagy. Autophagy 13:3–23

  34. Fritzen AM, Frøsig C, Jeppesen J, Jensen TE, Lundsgaard A-M, Serup AK, Schjerling P, Proud CG, Richter EA, Kiens B (2016) Role of AMPK in regulation of LC3 lipidation as a marker of autophagy in skeletal muscle. Cell Signal 28:663–674

  35. Fu H, Hardy J, Duff KE (2018) Selective vulnerability in neurodegenerative diseases. Nat Neurosci 21:1350–1358

  36. Fullgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, Hermanson O, Rosenfeld MG, Klionsky DJ, Joseph B (2013) The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature 500:468–471

  37. Fullgrabe J, Ghislat G, Cho DH, Rubinsztein DC (2016) Transcriptional regulation of mammalian autophagy at a glance. J Cell Sci 129:3059–3066

  38. Furuta M, Kose S, Koike M, Shimi T, Hiraoka Y, Yoneda Y, Haraguchi T, Imamoto N (2004) Heat-shock induced nuclear retention and recycling inhibition of importin alpha. Genes Cells 9:429–441

  39. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, Choi AM, Chu CT, Codogno P, Colombo MI, Cuervo AM, Debnath J, Deretic V, Dikic I, Eskelinen EL, Fimia GM, Fulda S, Gewirtz DA, Green DR, Hansen M, Harper JW, Jaattela M, Johansen T, Juhasz G, Kimmelman AC, Kraft C, Ktistakis NT, Kumar S, Levine B, Lopez-Otin C, Madeo F, Martens S, Martinez J, Melendez A, Mizushima N, Munz C, Murphy LO, Penninger JM, Piacentini M, Reggiori F, Rubinsztein DC, Ryan KM, Santambrogio L, Scorrano L, Simon AK, Simon HU, Simonsen A, Tavernarakis N, Tooze SA, Yoshimori T, Yuan J, Yue Z, Zhong Q, Kroemer G (2017a) Molecular definitions of autophagy and related processes. EMBO J 36:1811–1836

  40. Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G (2017b) Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov 16:487–511

  41. Gao F, Yang J, Wang D, Li C, Fu Y, Wang H, He W, Zhang J (2017) Mitophagy in Parkinson’s disease: pathogenic and therapeutic implications. Front Neurol 8:527

  42. Garg G, Singh S, Singh AK, Rizvi SI (2016) Antiaging Effect of metformin on brain in naturally aged and accelerated senescence model of rat. Rejuvenation Res 20:173–182

  43. Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S, Banko MR, Gozani O, Brunet A (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466:383–387

  44. Gu J, Wang Y, Wang X, Zhou D, Wang X, Zhou M, He Z (2018a) Effect of the LncRNA GAS5-MiR-23a-ATG3 axis in regulating autophagy in patients with breast cancer. Cell Physiol Biochem 48:194–207

  45. Gu Z, Hou Z, Zheng L, Wang X, Wu L, Zhang C (2018b) LncRNA DICER1-AS1 promotes the proliferation, invasion and autophagy of osteosarcoma cells via miR-30b/ATG5. Biomed Pharmacother 104:110–118

  46. Guo L, Kim HJ, Wang H, Monaghan J, Freyermuth F, Sung JC, O’Donovan K, Fare CM, Diaz Z, Singh N, Zhang ZC, Coughlin M, Sweeny EA, DeSantis ME, Jackrel ME, Rodell CB, Burdick JA, King OD, Gitler AD, Lagier-Tourenne C, Pandey UB, Chook YM, Taylor JP, Shorter J (2018) Nuclear-import receptors reverse aberrant phase transitions of RNA-binding proteins with prion-like domains. Cell 173:677–692

  47. Hansen M, Rubinsztein DC, Walker DW (2018) Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 19:579

  48. Hargarten JC, Williamson PR (2018) Epigenetic regulation of autophagy: a path to the control of autoimmunity. Front Immunol 9:1864

  49. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392

  50. He C, Klionsky DJ (2009) Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 43:67–93

  51. He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, An Z, Loh J, Fisher J, Sun Q, Korsmeyer S, Packer M, May HI, Hill JA, Virgin HW, Gilpin C, Xiao G, Bassel-Duby R, Scherer PE, Levine B (2012a) Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481:511–515

  52. He C, Sumpter R Jr, Levine B (2012b) Exercise induces autophagy in peripheral tissues and in the brain. Autophagy 8:1548–1551

  53. Hood S, Amir S (2017) The aging clock: circadian rhythms and later life. J Clin Investig 127:437–446

  54. Huang R, Xu Y, Wan W, Shou X, Qian J, You Z, Liu B, Chang C, Zhou T, Lippincott-Schwartz J, Liu W (2015) Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol Cell 57:456–466

  55. Ingram DK, Anson RM, De Cabo R, Mamczarz J, Zhu MIN, Mattison J, Lane MA, Roth GS (2004) Development of calorie restriction mimetics as a prolongevity strategy. Ann N Y Acad Sci 1019:412–423

  56. Jang SY, Kang HT, Hwang ES (2012) Nicotinamide-induced mitophagy: event mediated by high NAD+/NADH ratio and SIRT1 protein activation. J Biol Chem 287:19304–19314

  57. Kang YA, Sanalkumar R, O’Geen H, Linnemann AK, Chang CJ, Bouhassira EE, Farnham PJ, Keles S, Bresnick EH (2012) Autophagy driven by a master regulator of hematopoiesis. Mol Cell Biol 32:226–239

  58. Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW-L, Thomas EL, Kockel L (2010) With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 11:453–465

  59. Kaur J, Debnath J (2015) Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol 16:461

  60. Kaushik S, Cuervo AM (2018) The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol 19:365–381

  61. Kenyon C (2010) The genetics of aging. Nature 464:504–512

  62. Khalil H, Tazi M, Caution K, Ahmed A, Kanneganti A, Assani K, Kopp B, Marsh C, Dakhlallah D, Amer AO (2016) Aging is associated with hypermethylation of autophagy genes in macrophages. Epigenetics 11:381–388

  63. Kim C, Kim W, Lee H, Ji E, Choe YJ, Martindale JL, Akamatsu W, Okano H, Kim HS, Nam SW, Gorospe M, Lee EK (2014) The RNA-binding protein HuD regulates autophagosome formation in pancreatic beta cells by promoting autophagy-related gene 5 expression. J Biol Chem 289:112–121

  64. Kirli K, Karaca S, Dehne HJ, Samwer M, Pan KT, Lenz C, Urlaub H, Gorlich D (2015) A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. Elife 4:e11466

  65. Kishimoto S, Uno M, Okabe E, Nono M, Nishida E (2017) Environmental stresses induce transgenerationally inheritable survival advantages via germline-to-soma communication in Caenorhabditis elegans. Nat Commun 8:14031

  66. Kourmouli N, Jeppesen P, Mahadevhaiah S, Burgoyne P, Wu R, Gilbert DM, Bongiorni S, Prantera G, Fanti L, Pimpinelli S, Shi W, Fundele R, Singh PB (2004) Heterochromatin and tri-methylated lysine 20 of histone H4 in animals. J Cell Sci 117:2491–2501

  67. Kulkarni VV, Maday S (2018) Compartment-specific dynamics and functions of autophagy in neurons. Dev Neurobiol 78:298–310

  68. Lahiri V, Hawkins WD, Klionsky DJ (2019) Watch what you (self-) eat: autophagic mechanisms that modulate metabolism. Cell Metab 29:803–826

  69. Lapierre LR, Gelino S, Melendez A, Hansen M (2011) Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr Biol 21:1507–1514

  70. Lapierre LR, De Magalhaes Filho CD, McQuary PR, Chu CC, Visvikis O, Chang JT, Gelino S, Ong B, Davis AE, Irazoqui JE, Dillin A, Hansen M (2013) The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat Commun 4:2267

  71. Lapierre LR, Kumsta C, Sandri M, Ballabio A, Hansen M (2015) Transcriptional and epigenetic regulation of autophagy in aging. Autophagy 11:867–880

  72. Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293

  73. Lawrence RE, Zoncu R (2019) The lysosome as a cellular centre for signalling, metabolism and quality control. Nat Cell Biol 21:133–142

  74. Lee JH, McBrayer MK, Wolfe DM, Haslett LJ, Kumar A, Sato Y, Lie PP, Mohan P, Coffey EE, Kompella U, Mitchell CH, Lloyd-Evans E, Nixon RA (2015) Presenilin 1 maintains lysosomal Ca2+ homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification. Cell Rep 12:1430–1444

  75. Lee DC, Brellenthin AG, Thompson PD, Sui X, Lee IM, Lavie CJ (2017) Running as a key lifestyle medicine for longevity. Prog Cardiovasc Dis 60:45–55

  76. Li L, Friedrichsen HJ, Andrews S, Picaud S, Volpon L, Ngeow K, Berridge G, Fischer R, Borden KLB, Filippakopoulos P, Goding CR (2018) A TFEB nuclear export signal integrates amino acid supply and glucose availability. Nat Commun 9:2685

  77. Lim H, Lim YM, Kim KH, Jeon YE, Park K, Kim J, Hwang HY, Lee DJ, Pagire H, Kwon HJ, Ahn JH, Lee MS (2018) A novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes. Nat Commun 9:1438

  78. Lin XX, Sen I, Janssens GE, Zhou X, Fonslow BR, Edgar D, Stroustrup N, Swoboda P, Yates JR 3rd, Ruvkun G, Riedel CG (2018) DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity. Nat Commun 9:4400

  79. Liu CY, Zhang YH, Li RB, Zhou LY, An T, Zhang RC, Zhai M, Huang Y, Yan KW, Dong YH, Ponnusamy M, Shan C, Xu S, Wang Q, Zhang YH, Zhang J, Wang K (2018) LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nat Commun 9:29

  80. Lloyd-Evans E, Haslett LJ (2016) The lysosomal storage disease continuum with ageing-related neurodegenerative disease. Ageing Res Rev 32:104–121

  81. Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiacovo MP, Yankner BA (2014) REST and stress resistance in ageing and Alzheimer’s disease. Nature 507:448–454

  82. Ma C, Niu R, Huang T, Shao LW, Peng Y, Ding W, Wang Y, Jia G, He C, Li CY, He A, Liu Y (2018) N6-methyldeoxyadenine is a transgenerational epigenetic signal for mitochondrial stress adaptation. Nat Cell Biol 21:319–327

  83. Madrigal-Matute J, Cuervo AM (2016) Regulation of liver metabolism by autophagy. Gastroenterology 150:328–339

  84. Martinez-Lopez N, Singh R (2016) Telemetric control of peripheral lipophagy by hypothalamic autophagy. Autophagy 12:1404–1405

  85. Martinez-Lopez N, Garcia-Macia M, Sahu S, Athonvarangkul D, Liebling E, Merlo P, Cecconi F, Schwartz Gary J, Singh R (2016) Autophagy in the CNS and periphery coordinate lipophagy and lipolysis in the brown adipose tissue and liver. Cell Metab 23:113–127

  86. Martinez-Lopez N, Tarabra E, Toledo M, Garcia-Macia M, Sahu S, Coletto L, Batista-Gonzalez A, Barzilai N, Pessin JE, Schwartz GJ, Kersten S, Singh R (2017) System-wide benefits of intermeal fasting by autophagy. Cell Metab 26:856–871

  87. Martini-Stoica H, Xu Y, Ballabio A, Zheng H (2016) The autophagy-lysosomal pathway in neurodegeneration: a TFEB perspective. Trends Neurosci 39:221–234

  88. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM (2017) Caloric restriction improves health and survival of rhesus monkeys. Nat Commun 8:14063

  89. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Fullgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C, Licitra F, Lopez Ramirez A, Pavel M, Puri C, Renna M, Ricketts T, Schlotawa L, Vicinanza M, Won H, Zhu Y, Skidmore J, Rubinsztein DC (2017) Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93:1015–1034

  90. Miyamoto Y, Saiwaki T, Yamashita J, Yasuda Y, Kotera I, Shibata S, Shigeta M, Hiraoka Y, Haraguchi T, Yoneda Y (2004) Cellular stresses induce the nuclear accumulation of importin alpha and cause a conventional nuclear import block. J Cell Biol 165:617–623

  91. Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 15:1101–1111

  92. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10:458

  93. Napolitano G, Esposito A, Choi H, Matarese M, Benedetti V, Di Malta C, Monfregola J, Medina DL, Lippincott-Schwartz J, Ballabio A (2018) mTOR-dependent phosphorylation controls TFEB nuclear export. Nat Commun 9:3312

  94. Nativio R, Donahue G, Berson A, Lan Y, Amlie-Wolf A, Tuzer F, Toledo JB, Gosai SJ, Gregory BD, Torres C, Trojanowski JQ, Wang LS, Johnson FB, Bonini NM, Berger SL (2018) Dysregulation of the epigenetic landscape of normal aging in Alzheimer’s disease. Nat Neurosci 21:497–505

  95. Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng C-P, Huang Y, Haldar S, Verdin E (2017) Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab 26:547–557

  96. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ (2010) Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 467:963–966

  97. Niccoli T, Partridge L (2012) Ageing as a risk factor for disease. Curr Biol 22:R741–R752

  98. Nixon RA, Wegiel J, Kumar A, Yu WH, Peterhoff C, Cataldo A, Cuervo AM (2005) Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J Neuropathol Exp Neurol 64:113–122

  99. Omata Y, Lim Y-M, Akao Y, Tsuda L (2014) Age-induced reduction of autophagy-related gene expression is associated with onset of Alzheimer’s disease. Am J Neurodegener Dis 3:134–142

  100. Palikaras K, Lionaki E, Tavernarakis N (2015) Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521:525

  101. Paonessa F, Evans LD, Solanki R, Larrieu D, Wray S, Hardy J, Jackson SP, Livesey FJ (2019) Microtubules deform the nuclear membrane and disrupt nucleocytoplasmic transport in tau-mediated frontotemporal dementia. Cell Rep 26:582–593

  102. Peeters JGC, Picavet LW, Coenen S, Mauthe M, Vervoort SJ, Mocholi E, de Heus C, Klumperman J, Vastert SJ, Reggiori F, Coffer PJ, Mokry M, van Loosdregt J (2019) Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy. Autophagy 15:98–112

  103. Perera RM, Zoncu R (2016) The lysosome as a regulatory hub. Annu Rev Cell Dev Biol 32:223–253

  104. Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N (2015) Transcriptional control of autophagy-lysosome function drives pancreatic cancer metabolism. Nature 524:361–365

  105. Pickrell AM, Youle RJ (2015) The roles of PINK1, Parkin and mitochondrial fidelity in Parkinson’s disease. Neuron 85:257–273

  106. Pircs K, Petri R, Madsen S, Brattas PL, Vuono R, Ottosson DR, St-Amour I, Hersbach BA, Matusiak-Bruckner M, Lundh SH, Petersen A, Deglon N, Hebert SS, Parmar M, Barker RA, Jakobsson J (2018) Huntingtin aggregation impairs autophagy, leading to argonaute-2 accumulation and global MicroRNA dysregulation. Cell Rep 24:1397–1406

  107. Platt FM, Boland B, van der Spoel AC (2012) Lysosomal storage disorders: the cellular impact of lysosomal dysfunction. J Cell Biol 199:723

  108. Plaza-Zabala A, Sierra-Torre V, Sierra A (2017) Autophagy and microglia: novel partners in neurodegeneration and aging. Int J Mol Sci 18:598

  109. Polymenidou M (2018) The RNA face of phase separation. Science 360:859–860

  110. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92:829–839

  111. Raben N, Puertollano R (2016) TFEB and TFE3: linking lysosomes to cellular adaptation to stress. Annu Rev Cell Dev Biol 32:255–278

  112. Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330:1344–1348

  113. Ramachandran PV, Savini M, Folick AK, Hu K, Masand R, Graham BH, Wang MC (2019) Lysosomal signaling promotes longevity by adjusting mitochondrial activity. Dev Cell 48:685–696

  114. Rechavi O, Lev I (2017) Principles of transgenerational small RNA inheritance in Caenorhabditis elegans. Curr Biol 27:R720–R730

  115. Rechavi O, Houri-Ze’evi L, Anava S, Goh WSS, Kerk SY, Hannon GJ, Hobert O (2014) Starvation-induced transgenerational inheritance of small RNAs in C. elegans. Cell 158:277–287

  116. Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, McMackin MZ, Haj FG, Baar K, Cortopassi GA, Ramsey JJ, Lopez-Dominguez JA (2017) A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab 26:539–546

  117. Roth GS, Lane MA, Ingram DK (2005) Caloric restriction mimetics: the next phase. Ann N Y Acad Sci 1057:365–371

  118. Rubino E, Rainero I, Chiò A, Rogaeva E, Galimberti D, Fenoglio P, Grinberg Y, Isaia G, Calvo A, Gentile S, Bruni AC, St. George-Hyslop PH, Scarpini E, Gallone S, Pinessi L (2012) SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79:1556–1562

  119. Ryan BJ, Hoek S, Fon EA, Wade-Martins R (2015) Mitochondrial dysfunction and mitophagy in Parkinson’s: from familial to sporadic disease. Trends Biochem Sci 40:200–210

  120. Sakamaki JI, Wilkinson S, Hahn M, Tasdemir N, O’Prey J, Clark W, Hedley A, Nixon C, Long JS, New M, Van Acker T, Tooze SA, Lowe SW, Dikic I, Ryan KM (2017) Bromodomain protein BRD4 is a transcriptional repressor of autophagy and lysosomal function. Mol Cell 66(517–32):e9

  121. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 169:361–371

  122. Seah NE, de Magalhaes Filho CD, Petrashen AP, Henderson HR, Laguer J, Gonzalez J, Dillin A, Hansen M, Lapierre LR (2016) Autophagy-mediated longevity is modulated by lipoprotein biogenesis. Autophagy 12:261–272

  123. Settembre C, Di Malta C, Polito VA, Arencibia MG, Vetrini F, Erdin S, Erdin SU, Huynh T, Medina D, Colella P, Sardiello M, Rubinsztein DC, Ballabio A (2011) TFEB links autophagy to lysosomal biogenesis. Science 332:1429–1433

  124. Shin HJ, Kim H, Oh S, Lee JG, Kee M, Ko HJ, Kweon MN, Won KJ, Baek SH (2016) AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature 534:553–557

  125. Silvestrini MJ, Johnson JR, Kumar AV, Thakurta TG, Blais K, Neill ZA, Marion SW, St Amand V, Reenan RA, Lapierre LR (2018) Nuclear export inhibition enhances HLH-30/TFEB activity, autophagy, and lifespan. Cell Rep 23:1915–1921

  126. Simonsen A, Cumming RC, Brech A, Isakson P, Schubert DR, Finley KD (2008) Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4:176–184

  127. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ (2009) Autophagy regulates lipid metabolism. Nature 458:1131

  128. Singh S, Singh AK, Garg G, Rizvi SI (2018) Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration. Life Sci 193:171–179

  129. Taormina G, Mirisola MG (2014) Calorie restriction in mammals and simple model organisms. Biomed Res Int 2014:308690

  130. Tasset I, Cuervo AM (2016) Role of chaperone-mediated autophagy in metabolism. FEBS J 283:2403–2413

  131. Taylor RC, Dillin A (2013) XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153:1435–1447

  132. Tekirdag K, Cuervo AM (2018) Chaperone-mediated autophagy and endosomal microautophagy: joint by a chaperone. J Biol Chem 293:5414–5424

  133. Thomas HE, Zhang Y, Stefely JA, Veiga SR, Thomas G, Kozma SC, Mercer CA (2018) Mitochondrial complex I activity is required for maximal autophagy. Cell Rep 24(2404–17):e8

  134. Tzivion G, Dobson M, Ramakrishnan G (2011) FoxO transcription factors; regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta 1813:1938–1945

  135. Valvezan AJ, Manning BD (2019) Molecular logic of mTORC1 signalling as a metabolic rheostat. Nat Metab 1:321–333

  136. van Oosten-Hawle P, Porter RS, Morimoto RI (2013) Regulation of organismal proteostasis by trans-cellular chaperone signaling. Cell 153:1366–1378

  137. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Müller F (2003) Influence of TOR kinase on lifespan in C. elegans. Nature 426:620

  138. Wang F, Jia J, Rodrigues B (2017a) Autophagy, metabolic disease, and pathogenesis of heart dysfunction. Can J Cardiol 33:850–859

  139. Wang J, Cao B, Han D, Sun M, Feng J (2017b) Long non-coding RNA H19 induces cerebral ischemia reperfusion injury via activation of autophagy. Aging Dis 8:71–84

  140. Wani WY, Boyer-Guittaut M, Dodson M, Chatham J, Darley-Usmar V, Zhang J (2015) Regulation of autophagy by protein post-translational modification. Lab Invest 95:14–25

  141. Ward C, Martinez-Lopez N, Otten EG, Carroll B, Maetzel D, Singh R, Sarkar S, Korolchuk VI (2016) Autophagy, lipophagy and lysosomal lipid storage disorders. Biochim et Biophys Acta (BBA) 1861:269–284

  142. Weir HJ, Yao P, Huynh FK, Escoubas CC, Goncalves RL, Burkewitz K, Laboy R, Hirschey MD, Mair WB (2017) Dietary restriction and AMPK increase lifespan via mitochondrial network and peroxisome remodeling. Cell Metab 26:884–896

  143. Wilkinson Deepti S, Jariwala Jinel S, Anderson E, Mitra K, Meisenhelder J, Chang Jessica T, Ideker T, Hunter T, Nizet V, Dillin A, Hansen M (2015) Phosphorylation of LC3 by the hippo kinases STK3/STK4 is essential for autophagy. Mol Cell 57:55–68

  144. Wolfson RL, Chantranupong L, Wyant GA, Gu X, Orozco JM, Shen K, Condon KJ, Petri S, Kedir J, Scaria SM, Abu-Remaileh M, Frankel WN, Sabatini DM (2017) KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1. Nature 543:438

  145. Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G (2016) TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J 35:121–142

  146. Xu P, Das M, Reilly J, Davis RJ (2011) JNK regulates FoxO-dependent autophagy in neurons. Genes Dev 25:310–322

  147. Yan W, Chen ZY, Chen JQ, Chen HM (2018) LncRNA NEAT1 promotes autophagy in MPTP-induced Parkinson’s disease through stabilizing PINK1 protein. Biochem Biophys Res Commun 496:1019–1024

  148. Yang L, Wang H, Shen Q, Feng L, Jin H (2017) Long non-coding RNAs involved in autophagy regulation. Cell Death Dis 8:e3073

  149. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA (2005) Macroautophagy—a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 171:87–98

  150. Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, Gonzalez FJ, Semenza GL (2008) Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 283:10892–10903

  151. Zhang G, Wang Z, Du Z, Zhang H (2018a) mTOR regulates phase separation of PGL granules to modulate their autophagic degradation. Cell 174(1492–506):e22

  152. Zhang J, Wang J, Zhou Z, Park JE, Wang L, Wu S, Sun X, Lu L, Wang T, Lin Q, Sze SK, Huang D, Shen HM (2018b) Importance of TFEB acetylation in control of its transcriptional activity and lysosomal function in response to histone deacetylase inhibitors. Autophagy 14:1043–1059

  153. Zhang K, Daigle JG, Cunningham KM, Coyne AN, Ruan K, Grima JC, Bowen KE, Wadhwa H, Yang P, Rigo F, Taylor JP, Gitler AD, Rothstein JD, Lloyd TE (2018c) Stress granule assembly disrupts nucleocytoplasmic transport. Cell 173:95871.e17

  154. Zhang Q, Wu X, Chen P, Liu L, Xin N, Tian Y, Dillin A (2018d) The mitochondrial unfolded protein response is mediated cell-non-autonomously by retromer-dependent Wnt signaling. Cell 174:870–883

  155. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL (2007) FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6:472–483

  156. Zhao Y, Li X, Cai M-Y, Ma K, Yang J, Zhou J, Fu W, Wei F-Z, Wang L, Xie D, Zhu W-G (2013) XBP-1u suppresses autophagy by promoting the degradation of FoxO1 in cancer cells. Cell Res 23:491

  157. Zheng G, Zhan Y, Li X, Pan Z, Zheng F, Zhang Z, Zhou Y, Wu Y, Wang X, Gao W, Xu H, Tian N, Zhang X (2018) TFEB, a potential therapeutic target for osteoarthritis via autophagy regulation. Cell Death Dis 9:858

  158. Zhou J, Chong SY, Lim A, Singh BK, Sinha RA, Salmon AB, Yen PM (2017) Changes in macroautophagy, chaperone-mediated autophagy, and mitochondrial metabolism in murine skeletal and cardiac muscle during aging. Aging 9:583–599

  159. Zhuo C, Jiang R, Lin X, Shao M (2016) LncRNA H19 inhibits autophagy by epigenetically silencing of DIRAS3 in diabetic cardiomyopathy. Oncotarget 8:1429–1437

Download references


L.R.L is funded by a grant from the NIH/NIA (R01 AG051810) and a Glenn Award for Research in Biological Mechanisms of Aging from the Glenn Foundation for Medical Research.

Author information

Correspondence to Louis R. Lapierre.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wong, S.Q., Kumar, A.V., Mills, J. et al. Autophagy in aging and longevity. Hum Genet 139, 277–290 (2020).

Download citation