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Autophagy as a promoter of longevity: insights from model organisms

A Publisher Correction to this article was published on 25 July 2018

This article has been updated

Abstract

Autophagy is a conserved process that catabolizes intracellular components to maintain energy homeostasis and to protect cells against stress. Autophagy has crucial roles during development and disease, and evidence accumulated over the past decade indicates that autophagy also has a direct role in modulating ageing. In particular, elegant studies using yeasts, worms, flies and mice have demonstrated a broad requirement for autophagy-related genes in the lifespan extension observed in a number of conserved longevity paradigms. Moreover, several new and interesting concepts relevant to autophagy and its role in modulating longevity have emerged. First, select tissues may require or benefit from autophagy activation in longevity paradigms, as tissue-specific overexpression of single autophagy genes is sufficient to extend lifespan. Second, selective types of autophagy may be crucial for longevity by specifically targeting dysfunctional cellular components and preventing their accumulation. And third, autophagy can influence organismal health and ageing even non-cell autonomously, and thus, autophagy stimulation in select tissues can have beneficial, systemic effects on lifespan. Understanding these mechanisms will be important for the development of approaches to improve human healthspan that are based on the modulation of autophagy.

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Fig. 1: The macroautophagy process.
Fig. 2: Selective types of autophagy linked to organismal ageing.

Change history

  • 25 July 2018

    In the original article a Note added in proof was not included. This has now been amended.

References

  1. 1.

    Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease. Cell 132, 27–42 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. 2.

    Huang, J. & Klionsky, D. J. Autophagy and human disease. Cell Cycle 6, 1837–1849 (2007).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Feng, Y., He, D., Yao, Z. & Klionsky, D. J. The machinery of macroautophagy. Cell Res. 24, 24–41 (2014).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

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

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1–222 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Johansen, T. & Lamark, T. Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279–296 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Khaminets, A., Behl, C. & Dikic, I. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol. 26, 6–16 (2016).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    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).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    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). This study is the first to show that overexpression of an autophagy gene is sufficient to extend lifespan (neuronal overexpression of Atg8 in D. melanogaster ).

    PubMed  Article  CAS  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). This study is the first to link loss of proteostasis during muscle ageing to autophagy and organismal ageing.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Bai, H., Kang, P., Hernandez, A. M. & Tatar, M. Activin signaling targeted by insulin/dFOXO regulates aging and muscle proteostasis in Drosophila. PLOS Genet. 9, e1003941 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. 13.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. 14.

    Carnio, S. et al. Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep. 8, 1509–1521 (2014). This study shows that autophagy inhibition in the muscle of mice impairs muscle function, possibly via impairing mitochondrial function, and shortens lifespan.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Cuervo, A. M. & Dice, J. F. Age-related decline in chaperone-mediated autophagy. J. Biol. Chem. 275, 31505–31513 (2000).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    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). This study is the first comprehensive spatiotemporal analysis of autophagy activity in a living organism, C. elegans . It indicates an age-dependent decrease in autophagy as well as tissue-specific regulation and functions of autophagy in two different longevity models.

    PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    Del Roso, A. et al. Ageing-related changes in the in vivo function of rat liver macroautophagy and proteolysis. Exp. Gerontol. 38, 519–527 (2003).

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Terman, A. The effect of age on formation and elimination of autophagic vacuoles in mouse hepatocytes. Gerontology 41 (Suppl. 2), 319–326 (1995).

    PubMed  Article  Google Scholar 

  20. 20.

    Donati, A. et al. Age-related changes in the regulation of autophagic proteolysis in rat isolated hepatocytes. J. Gerontol. A Biol. Sci. Med. Sci. 56, B288–B293 (2001).

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Cavallini, G., Donati, A., Gori, Z., Pollera, M. & Bergamini, E. The protection of rat liver autophagic proteolysis from the age-related decline co-varies with the duration of anti-ageing food restriction. Exp. Gerontol. 36, 497–506 (2001).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Donati, A. et al. Age-related changes in the autophagic proteolysis of rat isolated liver cells: effects of antiaging dietary restrictions. J. Gerontol. A Biol. Sci. Med. Sci. 56, B375–B383 (2001).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Hansen, M. in Ageing: Lessons from C. elegans Ch. 15 (eds Olsen, A. & Gill, M. S. (Springer, Cham, Switzerland, 2016).

  24. 24.

    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). This study is the first to show that neuronal Atg1 overexpression improves intestinal barrier function and extends D. melanogaster lifespan.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Rana, A. et al. Promoting Drp1-mediated mitochondrial fission in midlife prolongs healthy lifespan of Drosophila melanogaster. Nat. Commun. 8, 448 (2017). This study shows that increased expression of Drp1 in midlife facilitates mitophagy and extends D. melanogaster lifespan.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Karsli-Uzunbas, G. et al. Autophagy is required for glucose homeostasis and lung tumor maintenance. Cancer Discov. 4, 914–927 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Zhang, H. et al. Guidelines for monitoring autophagy in Caenorhabditis elegans. Autophagy 11, 9–27 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Pyo, J. O. et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4, 2300 (2013). This is the first study to show that overexpression of an autophagy gene ( ATG5 ) can extend mammalian lifespan.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Settembre, C. et al. TFEB links autophagy to lysosomal biogenesis. Science 332, 1429–1433 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Lapierre, L. R. et al. The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267 (2013). This study shows that overexpression of hlh-30 ( TFEB in mammals) is sufficient to extend the lifespan of C. elegans in an autophagy-dependent manner.

    PubMed  Article  CAS  Google Scholar 

  32. 32.

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

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Oz-Levi, D. et al. Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis. Am. J. Hum. Genet. 91, 1065–1072 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Hanein, S. et al. Identification of the SPG15 gene, encoding spastizin, as a frequent cause of complicated autosomal-recessive spastic paraplegia, including Kjellin syndrome. Am. J. Hum. Genet. 82, 992–1002 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Kim, M. et al. Mutation in ATG5 reduces autophagy and leads to ataxia with developmental delay. Elife 5, e12245 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

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

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Attardo, G. et al. [The follow-up of malformation uropathies diagnosed “in utero”]. Pediatr. Med. Chir. 14, 119–126 (1992).

    PubMed  CAS  Google Scholar 

  38. 38.

    Laurin, N., Brown, J. P., Morissette, J. & Raymond, V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70, 1582–1588 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Rubino, E. et al. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79, 1556–1562 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

    PubMed  Article  CAS  Google Scholar 

  41. 41.

    Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525–528 (2015). This study is the first to indicate a requirement for mitophagy in several conserved longevity paradigms in C. elegans.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Pickrell, A. M. & Youle, R. J. The roles of PINK1, Parkin, and mitochondrial fidelity in Parkinson’s disease. Neuron 85, 257–273 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Ashrafi, G. & Schwarz, T. L. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 20, 31–42 (2013).

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    Dutta, D., Calvani, R., Bernabei, R., Leeuwenburgh, C. & Marzetti, E. Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ. Res. 110, 1125–1138 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Singh, L. P., Devi, T. S. & Yumnamcha, T. The role of Txnip in mitophagy dysregulation and inflammasome activation in diabetic retinopathy: a new perspective. JOJ Ophthalmol. 4, 555–643 (2017).

  51. 51.

    Pang, L. et al. Differential effects of reticulophagy and mitophagy on nonalcoholic fatty liver disease. Cell Death Dis. 9, 90 (2018).

  52. 52.

    Marshall, J. D., Bazan, I., Zhang, Y., Fares, W. H. & Lee, P. J. Mitochondrial dysfunction and pulmonary hypertension: cause, effect or both. Am. J. Physiol. Lung Cell. Mol. Physiol. https://doi.org/10.1152/ajplung.00331.2017 (2018).

  53. 53.

    Chen, K. et al. Optineurin-mediated mitophagy protects renal tubular epithelial cells against accelerated senescence in diabetic nephropathy. Cell Death Dis. 9, 105 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    Khalil, B. & Lievens, J. C. Mitochondrial quality control in amyotrophic lateral sclerosis: towards a common pathway? Neural Regen Res. 12, 1052–1061 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Martinez-Vicente, M. Neuronal mitophagy in neurodegenerative diseases. Front. Mol. Neurosci. 10, 64 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Drummond, M. J. et al. Downregulation of E3 ubiquitin ligases and mitophagy-related genes in skeletal muscle of physically inactive, frail older women: a cross-sectional comparison. J. Gerontol. A Biol. Sci. Med. Sci. 69, 1040–1048 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Sun, N. et al. Measuring in vivo mitophagy. Mol. Cell 60, 685–696 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Clark, I. E. et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441, 1162–1166 (2006).

  59. 59.

    Greene, J. C. et al. Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proc. Natl Acad. Sci. USA 100, 4078–4083 (2003).

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Schiavi, A. et al. Iron-starvation-induced mitophagy mediates lifespan extension upon mitochondrial stress in C. elegans. Curr. Biol. 25, 1810–1822 (2015).

    PubMed  Article  CAS  Google Scholar 

  61. 61.

    Rana, A., Rera, M. & Walker, D. W. Parkin overexpression during aging reduces proteotoxicity, alters mitochondrial dynamics, and extends lifespan. Proc. Natl Acad. Sci. USA 110, 8638–8643 (2013). This study is the first to show a direct link between Parkin, a key regulator of mitophagy, and longevity by showing that parkin overexpression is sufficient to extend D. melanogaster lifespan.

    PubMed  Article  Google Scholar 

  62. 62.

    Palikaras, K., Daskalaki, I., Markaki, M. & Tavernarakis, N. Mitophagy and age-related pathologies: development of new therapeutics by targeting mitochondrial turnover. Pharmacol. Ther. 178, 157–174 (2017).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016).This study describes a natural compound that induces mitophagy and promotes health in diverse species.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Hansen, M., Flatt, T. & Aguilaniu, H. Reproduction, fat metabolism, and life span: what is the connection? Cell Metab. 17, 10–19 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Schulze, R. J., Sathyanarayan, A. & Mashek, D. G. Breaking fat: the regulation and mechanisms of lipophagy. Biochim. Biophys. Acta 1862, 1178–1187 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  66. 66.

    Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  67. 67.

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

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Singh, R. & Cuervo, A. M. Lipophagy: connecting autophagy and lipid metabolism. Int. J. Cell Biol. 2012, 282041 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Maan, M., Peters, J. M., Dutta, M. & Patterson, A. D. Lipid metabolism and lipophagy in cancer. Biochem. Biophys. Res. Commun. https://doi.org/10.1016/j.bbrc.2018.02.097 (2018).

  70. 70.

    Chen, K., Yuan, R., Zhang, Y., Geng, S. & Li, L. Tollip deficiency alters atherosclerosis and steatosis by disrupting lipophagy. J. Am. Heart Assoc. 6, e004078 (2017).

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Wang, M. C., O’Rourke, E. J. & Ruvkun, G. Fat metabolism links germline stem cells and longevity in C. elegans. Science 322, 957–960 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. 72.

    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). This study is the first to indicate a role for selective autophagy, namely, lipophagy, in organismal lifespan ( C. elegans ).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    O’Rourke, E. J., Kuballa, P., Xavier, R. & Ruvkun, G. Omega-6 polyunsaturated fatty acids extend life span through the activation of autophagy. Genes Dev. 27, 429–440 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    O’Rourke, E. J. & Ruvkun, G. MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability. Nat. Cell Biol. 15, 668–676 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Folick, A. et al. Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans. Science 347, 83–86 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Palikaras, K. et al. Ectopic fat deposition contributes to age-associated pathology in Caenorhabditis elegans. J. Lipid Res. 58, 72–80 (2017).

    PubMed  Article  CAS  Google Scholar 

  77. 77.

    Ravikumar, B., Duden, R. & Rubinsztein, D. C. Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy. Hum. Mol. Genet. 11, 1107–1117 (2002). This study is the first to show that aggregate-prone proteins causing neurodegeneration are autophagy substrates.

    PubMed  Article  CAS  Google Scholar 

  78. 78.

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

    PubMed  Article  CAS  Google Scholar 

  79. 79.

    Berger, Z. et al. Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum. Mol. Genet. 15, 433–442 (2006).

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004). This is the first report suggesting that autophagy upregulation can ameliorate neurodegenerative disease caused by mutant HTT in model organisms like D. melanogaster and mice.

    PubMed  Article  CAS  Google Scholar 

  81. 81.

    Lopez, A. et al. A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain 140, 1128–1146 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Menzies, F. M. et al. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron 93, 1015–1034 (2017).

    PubMed  Article  CAS  Google Scholar 

  84. 84.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Ashkenazi, A. et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 545, 108–111 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Maejima, I. et al. Autophagy sequesters damaged lysosomes to control lysosomal biogenesis and kidney injury. EMBO J. 32, 2336–2347 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. 87.

    Yamamoto, T. et al. Time-dependent dysregulation of autophagy: implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy 12, 801–813 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Lenoir, O., Tharaux, P. L. & Huber, T. B. Autophagy in kidney disease and aging: lessons from rodent models. Kidney Int. 90, 950–964 (2016).

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Papadopoulos, C. et al. VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy. EMBO J. 36, 135–150 (2017).

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Hu, D. J. & Jasper, H. Epithelia: understanding the cell biology of intestinal barrier dysfunction. Curr. Biol. 27, R185–R187 (2017).

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Clark, R. I. et al. Distinct shifts in microbiota composition during Drosophila aging impair intestinal function and drive mortality. Cell Rep. 12, 1656–1667 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  92. 92.

    Rera, M., Clark, R. I. & Walker, D. W. Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc. Natl Acad. Sci. USA 109, 21528–21533 (2012).

    PubMed  Article  Google Scholar 

  93. 93.

    Rera, M., Azizi, M. J. & Walker, D. W. Organ-specific mediation of lifespan extension: more than a gut feeling? Ageing Res. Rev. 12, 436–444 (2013).

    PubMed  Article  CAS  Google Scholar 

  94. 94.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    Regan, J. C. et al. Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction. Elife 5, e10956 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Fan, P., Liu, P., Song, P., Chen, X. & Ma, X. Moderate dietary protein restriction alters the composition of gut microbiota and improves ileal barrier function in adult pig model. Sci. Rep. 7, 43412 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Minnerly, J., Zhang, J., Parker, T., Kaul, T. & Jia, K. The cell non-autonomous function of ATG-18 is essential for neuroendocrine regulation of Caenorhabditis elegans lifespan. PLOS Genet. 13, e1006764 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Grumati, P. et al. Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat. Med. 16, 1313–1320 (2010).

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    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).

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Donati, A., Recchia, G., Cavallini, G. & Bergamini, E. Effect of aging and anti-aging caloric restriction on the endocrine regulation of rat liver autophagy. J. Gerontol. A Biol. Sci. Med. Sci. 63, 550–555 (2008).

    PubMed  Article  Google Scholar 

  101. 101.

    Resnik-Docampo, M. et al. Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis. Nat. Cell Biol. 19, 52–59 (2017).

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Spalinger, M. R., Rogler, G. & Scharl, M. Crohn’s disease: loss of tolerance or a disorder of autophagy? Dig. Dis. 32, 370–377 (2014).

    PubMed  Article  Google Scholar 

  103. 103.

    Nighot, P. K., Hu, C. A. & Ma, T. Y. Autophagy enhances intestinal epithelial tight junction barrier function by targeting claudin-2 protein degradation. J. Biol. Chem. 290, 7234–7246 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104.

    Broughton, S. J. et al. Longer lifespan, altered metabolism, and stress resistance in Drosophila from ablation of cells making insulin-like ligands. Proc. Natl Acad. Sci. USA 102, 3105–3110 (2005).

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Broughton, S. & Partridge, L. Insulin/IGF-like signalling, the central nervous system and aging. Biochem. J. 418, 1–12 (2009).

    PubMed  Article  CAS  Google Scholar 

  106. 106.

    Zhang, Y. et al. Hypothalamic stem cells control ageing speed partly through exosomal miRNAs. Nature 548, 52–57 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Saha, S. et al. Mutations in LRRK2 potentiate age-related impairment of autophagic flux. Mol. Neurodegener. 10, 26 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    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).

    PubMed  Article  Google Scholar 

  109. 109.

    Bishop, N. A., Lu, T. & Yankner, B. A. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009). This study shows beneficial effects of the autophagy inducer spermidine on longevity in multiple organisms.

    PubMed  Article  CAS  Google Scholar 

  111. 111.

    Gupta, V. K. et al. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 16, 1453–1460 (2013).

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Gupta, V. K. et al. Spermidine suppresses age-associated memory impairment by preventing adverse increase of presynaptic active zone size and release. PLOS Biol. 14, e1002563 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Demontis, F., Piccirillo, R., Goldberg, A. L. & Perrimon, N. The influence of skeletal muscle on systemic aging and lifespan. Aging Cell 12, 943–949 (2013).

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Miller, R. A. ‘Accelerated aging’: a primrose path to insight? Aging Cell 3, 47–51 (2004).

    PubMed  Article  CAS  Google Scholar 

  115. 115.

    Nair, K. S. Aging muscle. Am. J. Clin. Nutr. 81, 953–963 (2005).

    PubMed  Article  CAS  Google Scholar 

  116. 116.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Fiacco, E. et al. Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles. Cell Death Differ. 23, 1839–1849 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

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

    PubMed  Article  CAS  Google Scholar 

  119. 119.

    Zhang, H., Puleston, D. J. & Simon, A. K. Autophagy and immune senescence. Trends Mol. Med. 22, 671–686 (2016).

    PubMed  Article  CAS  Google Scholar 

  120. 120.

    Raz, Y. et al. Activation-induced autophagy is preserved in CD4+ T-cells in familial longevity. J. Gerontol. A Biol. Sci. Med. Sci. 72, 1201–1206 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Doulatov, S. & Daley, G. Q. Autophagy: it’s in your blood. Dev. Cell 40, 518–520 (2017).

    PubMed  Article  CAS  Google Scholar 

  122. 122.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123.

    Baar, E. L., Carbajal, K. A., Ong, I. M. & Lamming, D. W. Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell 15, 155–166 (2016).

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    Hughes, A. L. & Gottschling, D. E. An early age increase in vacuolar pH limits mitochondrial function and lifespan in yeast. Nature 492, 261–265 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  125. 125.

    Maday, S. & Holzbaur, E. L. Autophagosome assembly and cargo capture in the distal axon. Autophagy 8, 858–860 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. 126.

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

    PubMed  Article  CAS  Google Scholar 

  127. 127.

    Heintz, C. & Mair, W. You are what you host: microbiome modulation of the aging process. Cell 156, 408–411 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  128. 128.

    Clark, R. I. & Walker, D. W. Role of gut microbiota in aging-related health decline: insights from invertebrate models. Cell. Mol. Life Sci. 75, 93–101 (2018).

    PubMed  Article  CAS  Google Scholar 

  129. 129.

    Martinez, J. et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat. Cell Biol. 17, 893–906 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  130. 130.

    Lee, C. & Longo, V. Dietary restriction with and without caloric restriction for healthy aging. F1000Res 5, 117 (2016).

    Google Scholar 

  131. 131.

    Kennedy, B. K. & Lamming, D. W. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell. Metabolism 23, 990–1003 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132.

    Piper, M. D., Selman, C., McElwee, J. J. & Partridge, L. Separating cause from effect: how does insulin/IGF signalling control lifespan in worms, flies and mice? J. Intern. Med. 263, 179–191 (2008).

    PubMed  Article  CAS  Google Scholar 

  133. 133.

    Burkewitz, K., Weir, H. J. & Mair, W. B. AMPK as a pro-longevity target. EXS 107, 227–256 (2016).

    PubMed  CAS  Google Scholar 

  134. 134.

    Munkacsy, E. & Rea, S. L. The paradox of mitochondrial dysfunction and extended longevity. Exp. Gerontol. 56, 221–233 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. 135.

    Gems, D. & Partridge, L. Stress-response hormesis and aging: “that which does not kill us makes us stronger”. Cell Metab. 7, 200–203 (2008).

    PubMed  Article  CAS  Google Scholar 

  136. 136.

    Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

    PubMed  Article  CAS  Google Scholar 

  137. 137.

    Pallauf, K., Rimbach, G., Rupp, P. M., Chin, D. & Wolf, I. M. Resveratrol and lifespan in model organisms. Curr. Med. Chem. 23, 4639–4680 (2016).

    PubMed  Article  CAS  Google Scholar 

  138. 138.

    Shaw, W. M., Luo, S., Landis, J., Ashraf, J. & Murphy, C. T. The C. elegans TGF-beta Dauer pathway regulates longevity via insulin signaling. Curr. Biol. 17, 1635–1645 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  139. 139.

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Shoji-Kawata, S. et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 494, 201–206 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. 141.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  142. 142.

    Alvers, A. L. et al. Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy 5, 847–849 (2009). This is the first study to show a requirement for autophagy genes in a conserved longevity paradigm in yeasts.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  143. 143.

    Ruckenstuhl, C. et al. Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. PLOS Genet. 10, e1004347 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  144. 144.

    Tang, F. et al. A life-span extending form of autophagy employs the vacuole-vacuole fusion machinery. Autophagy 4, 874–886 (2008).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

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

    PubMed  Article  CAS  Google Scholar 

  146. 146.

    Melendez, A. et al. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387–1391 (2003). This study is the first to show a direct role for an autophagy gene in a conserved longevity paradigm in C. elegans ( bec-1 ( Becn1 in mammals and ATG6 in yeasts) in long-lived daf-2 mutants).

    PubMed  Article  CAS  Google Scholar 

  147. 147.

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

    PubMed  Article  CAS  Google Scholar 

  148. 148.

    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  Article  CAS  Google Scholar 

  149. 149.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  150. 150.

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

    PubMed  Article  Google Scholar 

  151. 151.

    Yang, J. et al. MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9. Age 35, 11–22 (2013).

    PubMed  Article  CAS  Google Scholar 

  152. 152.

    McQuary, P. R. et al. C. elegans S6K mutants require a creatine-kinase-like effector for lifespan extension. Cell Rep. 14, 2059–2067 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. 153.

    McColl, G. et al. Insulin-like signaling determines survival during stress via posttranscriptional mechanisms in C. elegans. Cell Metab. 12, 260–272 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  154. 154.

    Bjedov, I. et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35–46 (2010). This study is the first to show a requirement for autophagy in a conserved longevity paradigm in D. melanogaster through mTOR inhibition.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. 155.

    Tang, H. et al. Decreased BECN1 mRNA expression in human breast cancer is associated with estrogen receptor-negative subtypes and poor prognosis. EBioMedicine 2, 255–263 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Haack, T. B. et al. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA. Am. J. Hum. Genet. 91, 1144–1149 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. 157.

    Saitsu, H. et al. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat. Genet. 45, 445–449 (2013).

    PubMed  CAS  Article  Google Scholar 

  158. 158.

    Metzger, S. et al. The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients. PLOS ONE 8, e68951 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  159. 159.

    Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207–211 (2007).

    PubMed  Article  CAS  Google Scholar 

  160. 160.

    Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596–604 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  161. 161.

    Cullup, T. et al. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy. Nat. Genet. 45, 83–87 (2013). This study shows how a mutation in an autophagy regulator causes a Mendelian neurodegenerative disease.

    PubMed  Article  CAS  Google Scholar 

  162. 162.

    Fernandez, A. F. et al. Disruption of the beclin 1–BCL2 autophagy-regulatory complex promotes longevity in mice. Nature 558, 136–140 (2018). This study shows that decreased interaction between beclin 1 and its negative regulator BCL-2 increases autophagic flux and extends healthspan and lifespan in mice.

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Acknowledgements

The authors apologize to the colleagues whose work they were unable to discuss owing to space limitations. The authors are grateful to the assistance of C. Karabiyc with the figures. Work in M.H.’s laboratory is funded by the National Institute on Aging (R01AG038664) and National Institute of General Medical Sciences (R01GM117466). Work in D.W.W.’s laboratory is funded by the National Institute on Aging (R01AG037514, R01AG049157 and R01AG040288). M.H. and D.W.W. are both Julie Martin Mid-Career Awardees in Aging Research supported by The Ellison Medical Foundation and the American Federation for Aging Research. Work in D.C.R.’s laboratory is funded by the UK Dementia Research Institute (funded by the Medical Research Council, Alzheimer Disease Research UK and the Alzheimer Disease Society), the Wellcome Trust (Principal Research Fellowship to D.C.R. (095317/Z/11/Z)), the Rosetrees Trust, Strategic Grant to Cambridge Institute for Medical Research (100140/Z/12/Z), Alzheimer Disease Research UK, the Tau Consortium and the Biomedical Research Centre at Addenbrooke’s Hospital.

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All authors contributed equally to all aspects of article preparation, including researching data for article, discussion of content and writing and editing of manuscript.

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Correspondence to Malene Hansen or David C. Rubinsztein or David W. Walker.

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D.C.R. is a consultant for E3Bio and has consulted for GlaxoSmithKline and AstraZeneca. D.C.R. has grant support from AstraZeneca and AbbVie.

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Glossary

Autophagosomes

Cytosolic double-membrane-bound vesicles capable of sequestering cytoplasmic inclusions and organelles destined for degradation in the autolysosome.

Autolysosome

A cytosolic vesicle resulting from fusion between an autophagosome and acidic lysosomes in which degradation of the inner membrane and sequestered autophagosomal material takes place.

mTOR

An evolutionarily conserved protein kinase that negatively regulates autophagy.

Autophagy receptors

Proteins that facilitate recruitment of cargo to the phagophore for subsequent lysosomal degradation.

Hypothalamus

A region of forebrain that coordinates the autonomic nervous system and the activity of the pituitary, which controls various homeostatic systems, including body temperature.

Lysosomal-associated membrane glycoprotein 2a

(LAMP2A). A lysosomal protein with a key role in chaperone-mediated autophagy.

Insulin/IGF1 signalling

A multi-component signalling pathway that regulates metabolism and longevity in a conserved fashion.

Spastic paraplegia

An inherited disorder characterized by spasticity of the legs.

Ataxia

Loss of control over bodily movements.

Mitochondrial fission

The separation of a single mitochondrion into two or more daughter organelles.

Urolithin A

A metabolite produced by gut microorganisms from ellagic acid. Urolithin A induces mitophagy.

Lipid droplet

A cellular organelle that regulates the storage and hydrolysis of neutral lipids.

Lipid chaperone

A fatty acid-binding protein important in the transport of lipids inside and between cells.

Hormetic heat shock

An aspect of hormesis, meaning beneficial effects of a treatment for which higher intensity is harmful. During hormetic heat shock, non-lethal exposure to elevated temperature induces a response that results in increased stress resistance and longevity.

Proximal tubules

The segment of the kidney that is responsible for reabsorption of nearly two-thirds of all filtered water, sodium and chloride.

Podocytes

Highly specialized cells of the kidney glomerulus that wrap around capillaries.

Glomerulus

A key structure of a nephron, the functional unit of the kidney.

Microbial dysbiosis

The condition of having imbalances in the microbial communities either in or on the body.

Septate junction

An intercellular occluding junction found in invertebrate epithelia.

Crohn’s disease

A chronic inflammatory bowel disease.

Insulin-like peptide

A type of peptide with homology to insulin, a hormone produced in the pancreas that regulates glucose levels in the blood.

Chemosensory neurons

Sensory neurons responsive to chemical stimuli.

Presynaptic active zone

The part of the nerve terminal from which neurotransmitters are released by synaptic vesicle exocytosis.

Sarcopenia

The degenerative loss of muscle mass, quality and strength associated with ageing.

Senescence

Loss of the ability of a cell to divide, differentiate and grow.

Beclin 1

Mammalian orthologue of yeast autophagy-related 6 (Atg6), which forms part of the class III phosphatidylinositol 3-kinase complex involved in activating autophagy.

ERphagy

The selective degradation of the endoplasmic reticulum by autophagy.

Ribophagy

The selective degradation of ribosomes by autophagy.

Xenophagy

The selective degradation of intracellular pathogens by autophagy; xenophagy is part of the cell-autonomous innate immunity defence.

Nucleophagy

The selective removal of nuclear material from a cell by autophagy.

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Hansen, M., Rubinsztein, D.C. & Walker, D.W. Autophagy as a promoter of longevity: insights from model organisms. Nat Rev Mol Cell Biol 19, 579–593 (2018). https://doi.org/10.1038/s41580-018-0033-y

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