Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Autophagy and the cell biology of age-related disease

Abstract

Macroautophagy (autophagy) is a conserved lysosomal degradation process essential for cellular homeostasis and adaption to stress. Accumulating evidence indicates that autophagy declines with age and that impaired autophagy predisposes individuals to age-related diseases, whereas interventions that stimulate autophagy often promote longevity. In this Review, we examine how the autophagy pathway restricts cellular damage and degeneration, and the impact of these functions towards tissue health and organismal lifespan.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Signalling pathways that regulate autophagy and lifespan.
Fig. 2: Geroprotective mechanisms of autophagy and age-related diseases manifest by autophagy dysfunction.

References

  1. 1.

    Kenyon, C. J. The genetics of ageing. Nature 464, 504–512 (2010).

    CAS  PubMed  Google Scholar 

  2. 2.

    Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Kaur, J. & Debnath, J. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461–472 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Gelino, S. & Hansen, M. Autophagy - an emerging anti-aging mechanism. J. Clin. Exp. Pathol. 4, 006 (2012).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rubinsztein, D. C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Lamb, C. A., Yoshimori, T. & Tooze, S. A. The autophagosome: origins unknown, biogenesis complex. Nat. Rev. Mol. Cell Biol. 14, 759–774 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Kim, Y. C. & Guan, K. L. mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest. 125, 25–32 (2015).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Cuervo, A. M. & Dice, J. F. How do intracellular proteolytic systems change with age? Front. Biosci. 3, 25–43 (1998).

    Google Scholar 

  10. 10.

    Sarkis, G. J., Ashcom, J. D., Hawdon, J. M. & Jacobson, L. A. Decline in protease activities with age in the nematode Caenorhabditis elegans. Mech. Ageing Dev. 45, 191–201 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Demontis, F. & Perrimon, N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell 143, 813–825 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Kaushik, S. et al. Loss of autophagy in hypothalamic POMC neurons impairs lipolysis. EMBO Rep. 13, 258–265 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Simonsen, A. et al. Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4, 176–184 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Lipinski, M. M. et al. Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc. Natl Acad. Sci. USA 107, 14164–14169 (2010).

    CAS  PubMed  Google Scholar 

  15. 15.

    Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412–420 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Menzies, F. M., Fleming, A. & Rubinsztein, D. C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16, 345–357 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Chang, J. T., Kumsta, C., Hellman, A. B., Adams, L. M. & Hansen, M. Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging. eLife 6, e18459 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Saftig, P., Beertsen, W. & Eskelinen, E. L. LAMP-2: a control step for phagosome and autophagosome maturation. Autophagy 4, 510–512 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Fernandez, A. F. et al. Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558, 136–140 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Hars, E. S. et al. Autophagy regulates ageing in C. elegans. Autophagy 3, 93–95 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hansen, M. et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet. 4, e24 (2008).

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Juhasz, G., Erdi, B., Sass, M. & Neufeld, T. P. Atg7-dependent autophagy promotes neuronal health, stress tolerance, and longevity but is dispensable for metamorphosis in Drosophila. Genes Dev. 21, 3061–3066 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Mammucari, C. et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Zhao, J. et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 6, 472–483 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004).

    CAS  PubMed  Google Scholar 

  28. 28.

    Kapahi, P., Kaeberlein, M. & Hansen, M. Dietary restriction and lifespan: lessons from invertebrate models. Ageing Res. Rev. 39, 3–14 (2017).

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Mattison, J. A. et al. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 8, 14063 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Weindruch, R. & Walford, R. L. Dietary restriction in mice beginning at 1 year of age: effect on life-span and spontaneous cancer incidence. Science 215, 1415–1418 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Gelino, S. et al. Intestinal autophagy improves healthspan and longevity in C. elegans during dietary restriction. PLoS Genet. 12, e1006135 (2016).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Jia, K. & Levine, B. Autophagy is required for dietary restriction-mediated life span extension in C. elegans. Autophagy 3, 597–599 (2007).

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Lapierre, L. R. et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267 (2013).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Hansen, M. et al. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95–110 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Grandison, R. C., Piper, M. D. & Partridge, L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462, 1061–1064 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Johnson, S. C., Rabinovitch, P. S. & Kaeberlein, M. mTOR is a key modulator of ageing and age-related disease. Nature 493, 338–345 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Matecic, M. et al. A microarray-based genetic screen for yeast chronological aging factors. PLoS Genet. 6, e1000921 (2010).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lelegren, M., Liu, Y., Ross, C., Tardif, S. & Salmon, A. B. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol. Aging Age Relat. Dis. 6, 31793 (2016).

    PubMed  Google Scholar 

  40. 40.

    Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980–989 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Li, J., Kim, S. G. & Blenis, J. Rapamycin: one drug, many effects. Cell Metab. 19, 373–379 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Steffen, K. K. & Dillin, A. A ribosomal perspective on proteostasis and aging. Cell Metab. 23, 1004–1012 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Ulgherait, M., Rana, A., Rera, M., Graniel, J. & Walker, D. W. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 8, 1767–1780 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Kumsta, C., Chang, J. T., Schmalz, J. & Hansen, M. Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans. Nat. Commun. 8, 14337 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Toth, M. L. et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4, 330–338 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Morselli, E. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1, e10 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kaushik, S. & Cuervo, A. M. Proteostasis and aging. Nat. Med. 21, 1406–1415 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Liang, C. C., Wang, C., Peng, X., Gan, B. & Guan, J. L. Neural-specific deletion of FIP200 leads to cerebellar degeneration caused by increased neuronal death and axon degeneration. J. Biol. Chem. 285, 3499–3509 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Komatsu, M. et al. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131, 1149–1163 (2007).

    CAS  PubMed  Google Scholar 

  52. 52.

    Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Joo, J. H. et al. The noncanonical role of ULK/ATG1 in ER-to-Golgi trafficking is essential for cellular homeostasis. Mol. Cell 62, 491–506 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).

    CAS  PubMed  Google Scholar 

  55. 55.

    Komatsu, M. et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc. Natl Acad. Sci. USA 104, 14489–14494 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Nishiyama, J., Miura, E., Mizushima, N., Watanabe, M. & Yuzaki, M. Aberrant membranes and double-membrane structures accumulate in the axons of Atg5-null Purkinje cells before neuronal death. Autophagy 3, 591–596 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Lee, M. J., Lee, J. H. & Rubinsztein, D. C. Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog. Neurobiol. 105, 49–59 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Nixon, R. A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol Exp. Neurol. 64, 113–122 (2005).

    PubMed  PubMed Central  Google Scholar 

  59. 59.

    Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Bordi, M. et al. Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy. Autophagy 12, 2467–2483 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Corneveaux, J. J. et al. Association of CR1, CLU and PICALM with Alzheimer’s disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum. Mol. Genet. 19, 3295–3301 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Miller, S. E. et al. The molecular basis for the endocytosis of small R-SNAREs by the clathrin adaptor CALM. Cell 147, 1118–1131 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Moreau, K. et al. PICALM modulates autophagy activity and tau accumulation. Nat. Commun. 5, 4998 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Gowrishankar, S., Wu, Y. & Ferguson, S. M. Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology. J. Cell Biol. 216, 3291–3305 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Pickford, F. et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J. Clin. Invest. 118, 2190–2199 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Rocchi, A. et al. A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid oligomers and improved cognition in Alzheimer’s disease. PLoS Genet. 13, e1006962 (2017).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    Yu, W. H. et al. Macroautophagy--a novel Bβ-amyloid peptide-generating pathway activated in Alzheimer’s disease. J. Cell Biol. 171, 87–98 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Nilsson, P. et al. Aβ secretion and plaque formation depend on autophagy. Cell Rep 5, 61–69 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Michel, P. P., Hirsch, E. C. & Hunot, S. Understanding dopaminergic cell death pathways in Parkinson disease. Neuron 90, 675–691 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Ross, O. A. et al. Genomic investigation of α-synuclein multiplication and parkinsonism. Ann. Neurol. 63, 743–750 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Giasson, B. I. et al. Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34, 521–533 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N. & Rubinsztein, D. C. α-Synuclein is degraded by both autophagy and the proteasome. J. Biol. Chem. 278, 25009–25013 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Vogiatzi, T., Xilouri, M., Vekrellis, K. & Stefanis, L. Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells. J. Biol. Chem. 283, 23542–23556 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Cuervo, A. M., Stefanis, L., Fredenburg, R., Lansbury, P. T. & Sulzer, D. Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Volpicelli-Daley, L. A. et al. Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes. Mol. Biol. Cell 25, 4010–4023 (2014).

    PubMed  PubMed Central  Google Scholar 

  76. 76.

    Winslow, A. R. et al. α-Synuclein impairs macroautophagy: implications for Parkinson’s disease. J. Cell Biol. 190, 1023–1037 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Zavodszky, E. et al. Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat. Commun. 5, 3828 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Ristow, M. & Schmeisser, S. Extending life span by increasing oxidative stress. Free Radical Bio. Med. 51, 327–336 (2011).

    CAS  Google Scholar 

  80. 80.

    Zhong, Z. et al. NF-κB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Wiley, C. D. et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 23, 303–314 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Valente, E. M. et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304, 1158–1160 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Kitada, T. et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605–608 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Narendra, D., Tanaka, A., Suen, D. F. & Youle, R. J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183, 795–803 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Matsuda, N. et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189, 211–221 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Lee, J. Y. et al. HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy. EMBO J. 29, 969–980 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Palacino, J. J. et al. Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. 279, 18614–18622 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Gautier, C. A., Kitada, T. & Shen, J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proc. Natl Acad. Sci. USA 105, 11364–11369 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    McWilliams, T. G. et al. Basal mitophagy occurs independently of PINK1 in mouse tissues of high metabolic demand. Cell Metab. 27, 439–449 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Lee, J. J. et al. Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin. J. Cell Biol. 217, 1613–1622 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Wei, Y., Chiang, W. C., Sumpter, R. Jr., Mishra, P. & Levine, B. Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell 168, 224–238 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Sliter, D. A. et al. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561, 258–262 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Park, J. et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157–1161 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Romanello, V. et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 29, 1774–1785 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Masiero, E. et al. Autophagy is required to maintain muscle mass. Cell Metab. 10, 507–515 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Billia, F. et al. PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc. Natl Acad. Sci. USA 108, 9572–9577 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Sciarretta, S., Maejima, Y., Zablocki, D. & Sadoshima, J. The role of autophagy in the heart. Annu. Rev. Physiol. 80, 1–26 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Taneike, M. et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6, 600–606 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Romanello, V. & Sandri, M. Mitochondrial quality control and muscle mass maintenance. Front. Physiol 6, 422 (2015).

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Joseph, A. M. et al. Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging. PLoS ONE 8, e69327 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Gouspillou, G. et al. Increased sensitivity to mitochondrial permeability transition and myonuclear translocation of endonuclease G in atrophied muscle of physically active older humans. FASEB J. 28, 1621–1633 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Carnio, S. et al. Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep. 8, 1509–1521 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Castets, P. et al. Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy. Cell Metab. 17, 731–744 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Bujak, A. L. et al. AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. Cell Metab. 21, 883–890 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Reznick, R. M. et al. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metab. 5, 151–156 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111.

    Colman, R. J., Beasley, T. M., Allison, D. B. & Weindruch, R. Attenuation of sarcopenia by dietary restriction in rhesus monkeys. J. Gerontol. A Biol. 63, 556–559 (2008).

    Google Scholar 

  112. 112.

    Yang, L. et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep. 14, 422–428 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Tchkonia, T. et al. Fat tissue, aging, and cellular senescence. Aging Cell 9, 667–684 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Korolchuk, V. I., Miwa, S., Carroll, B. & von Zglinicki, T. Mitochondria in cell senescence: is mitophagy the weakest link? EBioMedicine 21, 7–13 (2017).

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 4, e12997 (2015).

    PubMed  PubMed Central  Google Scholar 

  117. 117.

    Singh, R. et al. Autophagy regulates adipose mass and differentiation in mice. J. Clin. Invest. 119, 3329–3339 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    van Deursen, J. M. The role of senescent cells in ageing. Nature 509, 439–446 (2014).

    PubMed  PubMed Central  Google Scholar 

  119. 119.

    Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Young, A. R. et al. Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Yang, H., Wang, H., Ren, J., Chen, Q. & Chen, Z. J. cGAS is essential for cellular senescence. Proc. Natl Acad. Sci. USA 114, 4612–4620 (2017).

    Google Scholar 

  124. 124.

    Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125.

    Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Kang, C. et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612 (2015).

    PubMed  PubMed Central  Google Scholar 

  127. 127.

    Carames, B., Taniguchi, N., Otsuki, S., Blanco, F. J. & Lotz, M. Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 62, 791–801 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128.

    Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129.

    Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432–1440 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Bouderlique, T. et al. Targeted deletion of Atg5 in chondrocytes promotes age-related osteoarthritis. Ann. Rheum. Dis. 75, 627–631 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131.

    Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J. & van Deursen, J. M. Cellular senescence in renal ageing and disease. Nat. Rev. Nephrol. 13, 77–89 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Baisantry, A. et al. Autophagy induces prosenescent changes in proximal tubular S3 segments. J. Am. Soc. Nephrol. 27, 1609–1616 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Liu, S. et al. Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury. Autophagy 8, 826–837 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Oh, J., Lee, Y. D. & Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20, 870–880 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Garcia-Prat, L. et al. Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Warr, M. R. et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494, 323–327 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Ho, T. T. et al. Autophagy maintains the metabolism and function of young and old stem cells. Nature 543, 205–210 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Levine, B., Packer, M. & Codogno, P. Development of autophagy inducers in clinical medicine. J. Clin. Invest. 125, 14–24 (2015).

    PubMed  PubMed Central  Google Scholar 

  139. 139.

    Madeo, F., Pietrocola, F., Eisenberg, T. & Kroemer, G. Caloric restriction mimetics: towards a molecular definition. Nat. Rev. Drug Discov. 13, 727–740 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Barzilai, N., Crandall, J. P., Kritchevsky, S. B. & Espeland, M. A. Metformin as a tool to target aging. Cell Metab. 23, 1060–1065 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141.

    Morselli, E. et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615–629 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Lee, I. H. & Finkel, T. Regulation of autophagy by the p300 acetyltransferase. J. Biol. Chem. 284, 6322–6328 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Pietrocola, F. et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Deruy, E. et al. Level of macroautophagy drives senescent keratinocytes into cell death or neoplastic evasion. Cell Death Dis. 5, e1577 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Liu, Y. et al. Autosis is a Na+, K+-ATPase-regulated form of cell death triggered by autophagy-inducing peptides, starvation, and hypoxia-ischemia. Proc. Natl Acad. Sci. USA 110, 20364–20371 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017).

    PubMed  PubMed Central  Google Scholar 

  149. 149.

    Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to those researchers whose work we were unable to cite due to space limitations. Grant support includes the NIH (AG057462, CA213775, CA126792, CA201849 and CA188404 to JD; CA109618 and AI199725 to B.L.), QB3/Calico Longevity Fellowship (to J.D.), Samuel Waxman Cancer Research Foundation (to J.D.), and DOD BCRP (W81XWH-11-1-0130 to J.D.), and CPRIT (RP120718) and a Leducq Foundation grant (15CBD04) to B.L. A.M.L. is the recipient of a Banting Postdoctoral Fellowship (201409BPF-335868) from the Government of Canada and a Cancer Research Society Scholarship for the Next Generation Scientists (22805).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Jayanta Debnath.

Ethics declarations

Competing interests

J.D. serves on the Scientific Advisory Board for Vescor Therapeutics, LLC. B.L. is a Scientific Founder of Casma Therapeutics, Inc.

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

Leidal, A.M., Levine, B. & Debnath, J. Autophagy and the cell biology of age-related disease. Nat Cell Biol 20, 1338–1348 (2018). https://doi.org/10.1038/s41556-018-0235-8

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing