Molecules and Cells

  • 제44권7호
  • /
  • Pages.425-432
  • /
  • 2021
  • /
  • 1016-8478(pISSN)
  • /
  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지
DOI QR코드

DOI QR Code

Combinatorial Approach Using Caenorhabditis elegans and Mammalian Systems for Aging Research

  • Lee, Gee-Yoon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Sohn, Jooyeon (Department of Biological Sciences, Korea Advanced Institute of Science and Technology) ;
  • Lee, Seung-Jae V. (Department of Biological Sciences, Korea Advanced Institute of Science and Technology)
  • 투고 : 2021.04.06
  • 심사 : 2021.05.23
  • 발행 : 2021.07.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Aging is associated with functional and structural declines in organisms over time. Organisms as diverse as the nematode Caenorhabditis elegans and mammals share signaling pathways that regulate aging and lifespan. In this review, we discuss recent combinatorial approach to aging research employing C. elegans and mammalian systems that have contributed to our understanding of evolutionarily conserved aging-regulating pathways. The topics covered here include insulin/IGF-1, mechanistic target of rapamycin (mTOR), and sirtuin signaling pathways; dietary restriction; autophagy; mitochondria; and the nervous system. A combinatorial approach employing high-throughput, rapid C. elegans systems, and human model mammalian systems is likely to continue providing mechanistic insights into aging biology and will help develop therapeutics against age-associated disorders.

키워드

과제정보

We thank all Lee laboratory members for helpful discussion and comments. This study is supported by the Korean Government (MSICT) through the National Research Foundation of Korea (NRF-2017R1A5A1015366) to S.J.V.L.

참고문헌

  1. An, S.W.A., Artan, M., Park, S., Altintas, O., and Lee, S.J.V. (2017). Longevity regulation by insulin/IGF-1 signalling. In Ageing: Lessons from C. elegans, A. Olsen and M.S. Gill, eds. (Cham: Springer International Publishing), pp. 63-81.
  2. Antebi, A. (2013). Steroid regulation of C. elegans diapause, developmental timing, and longevity. Curr. Top. Dev. Biol. 105, 181-212. https://doi.org/10.1016/B978-0-12-396968-2.00007-5
  3. Bishop, N.A., Lu, T., and Yankner, B.A. (2010). Neural mechanisms of ageing and cognitive decline. Nature 464, 529-535. https://doi.org/10.1038/nature08983
  4. Bluher, M., Kahn, B.B., and Kahn, C.R. (2003). Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299, 572-574. https://doi.org/10.1126/science.1078223
  5. Brenner, S. (1974). The genetics of Caenorhabditis elegans. Genetics 77, 71-94. https://doi.org/10.1093/genetics/77.1.71
  6. Brooks-Wilson, A.R. (2013). Genetics of healthy aging and longevity. Hum. Genet. 132, 1323-1338. https://doi.org/10.1007/s00439-013-1342-z
  7. Burkewitz, K., Weir, H.J., and Mair, W.B. (2016). AMPK as a pro-longevity target. Exp. Suppl. 107, 227-256.
  8. Carmona, J.J. and Michan, S. (2016). Biology of healthy aging and longevity. Rev. Invest. Clin. 68, 7-16.
  9. Chew, Y.L., Fan, X., Gotz, J., and Nicholas, H.R. (2013). Aging in the nervous system of Caenorhabditis elegans. Commun. Integr. Biol. 6, e25288. https://doi.org/10.4161/cib.25288
  10. Chun, Y. and Kim, J. (2018). Autophagy: an essential degradation program for cellular homeostasis and life. Cells 7, 278. https://doi.org/10.3390/cells7120278
  11. Covarrubias, A.J., Perrone, R., Grozio, A., and Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol. 22, 119-141. https://doi.org/10.1038/s41580-020-00313-x
  12. Dell'agnello, C., Leo, S., Agostino, A., Szabadkai, G., Tiveron, C., Zulian, A., Prelle, A., Roubertoux, P., Rizzuto, R., and Zeviani, M. (2007). Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431-444. https://doi.org/10.1093/hmg/ddl477
  13. Dickinson, D.J. and Goldstein, B. (2016). CRISPR-based methods for Caenorhabditis elegans genome engineering. Genetics 202, 885-901. https://doi.org/10.1534/genetics.115.182162
  14. Fang, E.F., Kassahun, H., Croteau, D.L., Scheibye-Knudsen, M., Marosi, K., Lu, H., Shamanna, R.A., Kalyanasundaram, S., Bollineni, R.C., Wilson, M.A., et al. (2016). NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab. 24, 566-581. https://doi.org/10.1016/j.cmet.2016.09.004
  15. Folgueras, A.R., Freitas-Rodriguez, S., Velasco, G., and Lopez-Otin, C. (2018). Mouse models to disentangle the hallmarks of human aging. Circ. Res. 123, 905-924. https://doi.org/10.1161/circresaha.118.312204
  16. Fontana, L. and Partridge, L. (2015). Promoting health and longevity through diet: from model organisms to humans. Cell 161, 106-118. https://doi.org/10.1016/j.cell.2015.02.020
  17. Friedman, D.B. and Johnson, T.E. (1988). A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75-86. https://doi.org/10.1093/genetics/118.1.75
  18. Gelino, S. and Hansen, M. (2012). Autophagy - an emerging anti-aging mechanism. J. Clin. Exp. Pathol. Suppl 4, 006.
  19. Gems, D. and Partridge, L. (2013). Genetics of longevity in model organisms: debates and paradigm shifts. Annu. Rev. Physiol. 75, 621-644. https://doi.org/10.1146/annurev-physiol-030212-183712
  20. Guerra, B.A., Brandao, B.B., Pinto, S.S., Salgueiro, W.G., De-Souza, E.A., Reis, F.C.G., Batista, T.M., Cavalcante-Silva, V., D'Almeida, V., Castilho, B.A., et al. (2019). Dietary sulfur amino acid restriction upregulates DICER to confer beneficial effects. Mol. Metab. 29, 124-135. https://doi.org/10.1016/j.molmet.2019.08.017
  21. Guo, Y., Li, P., Gao, L., Zhang, J., Yang, Z., Bledsoe, G., Chang, E., Chao, L., and Chao, J. (2017). Kallistatin reduces vascular senescence and aging by regulating microRNA-34a-SIRT1 pathway. Aging Cell 16, 837-846. https://doi.org/10.1111/acel.12615
  22. Gurkar, A.U., Robinson, A.R., Cui, Y., Li, X., Allani, S.K., Webster, A., Muravia, M., Fallahi, M., Weissbach, H., Robbins, P.D., et al. (2018). Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging. Redox Biol. 18, 191-199. https://doi.org/10.1016/j.redox.2018.06.005
  23. Hahm, J.H., Kim, S., DiLoreto, R., Shi, C., Lee, S.J., Murphy, C.T., and Nam, H.G. (2015). C. elegans maximum velocity correlates with healthspan and is maintained in worms with an insulin receptor mutation. Nat. Commun. 6, 8919. https://doi.org/10.1038/ncomms9919
  24. Hansen, M., Taubert, S., Crawford, D., Libina, N., Lee, S.J., and Kenyon, C. (2007). Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell 6, 95-110. https://doi.org/10.1111/j.1474-9726.2006.00267.x
  25. Heintz, C., Doktor, T.K., Lanjuin, A., Escoubas, C., Zhang, Y., Weir, H.J., Dutta, S., Silva-Garcia, C.G., Bruun, G.H., Morantte, I., et al. (2017). Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans. Nature 541, 102-106. https://doi.org/10.1038/nature20789
  26. Hekimi, S. and Guarente, L. (2003). Genetics and the specificity of the aging process. Science 299, 1351-1354. https://doi.org/10.1126/science.1082358
  27. Holzenberger, M., Dupont, J., Ducos, B., Leneuve, P., Geloen, A., Even, P.C., Cervera, P., and Le Bouc, Y. (2003). IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182-187. https://doi.org/10.1038/nature01298
  28. Houtkooper, R.H., Mouchiroud, L., Ryu, D., Moullan, N., Katsyuba, E., Knott, G., Williams, R.W., and Auwerx, J. (2013). Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451-457. https://doi.org/10.1038/nature12188
  29. Hsieh, P.N., Zhou, G., Yuan, Y., Zhang, R., Prosdocimo, D.A., Sangwung, P., Borton, A.H., Boriushkin, E., Hamik, A., Fujioka, H., et al. (2017). A conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction. Nat. Commun. 8, 914. https://doi.org/10.1038/s41467-017-00899-5
  30. Hu, C.K. and Brunet, A. (2018). The African turquoise killifish: a research organism to study vertebrate aging and diapause. Aging Cell 17, e12757. https://doi.org/10.1111/acel.12757
  31. Hughes, B.G. and Hekimi, S. (2011). A mild impairment of mitochondrial electron transport has sex-specific effects on lifespan and aging in mice. PLoS One 6, e26116. https://doi.org/10.1371/journal.pone.0026116
  32. Jeong, D.E., Artan, M., Seo, K., and Lee, S.J. (2012). Regulation of lifespan by chemosensory and thermosensory systems: findings in invertebrates and their implications in mammalian aging. Front. Genet. 3, 218. https://doi.org/10.3389/fgene.2012.00218
  33. Johnson, S.C., Rabinovitch, P.S., and Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. Nature 493, 338-345. https://doi.org/10.1038/nature11861
  34. Johnson, S.C., Sangesland, M., Kaeberlein, M., and Rabinovitch, P.S. (2015). Modulating mTOR in aging and health. Interdiscip. Top. Gerontol. 40, 107-127. https://doi.org/10.1159/000364974
  35. Kamath, R.S. and Ahringer, J. (2003). Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30, 313-321. https://doi.org/10.1016/S1046-2023(03)00050-1
  36. Kapahi, P., Kaeberlein, M., and Hansen, M. (2017). Dietary restriction and lifespan: lessons from invertebrate models. Ageing Res. Rev. 39, 3-14. https://doi.org/10.1016/j.arr.2016.12.005
  37. Katsyuba, E., Mottis, A., Zietak, M., De Franco, F., van der Velpen, V., Gariani, K., Ryu, D., Cialabrini, L., Matilainen, O., Liscio, P., et al. (2018). De novo NAD+ synthesis enhances mitochondrial function and improves health. Nature 563, 354-359. https://doi.org/10.1038/s41586-018-0645-6
  38. Kenyon, C., Chang, J., Gensch, E., Rudner, A., and Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature 366, 461-464. https://doi.org/10.1038/366461a0
  39. Kenyon, C.J. (2010). The genetics of ageing. Nature 464, 504-512. https://doi.org/10.1038/nature08980
  40. Kim, E.J.E., Son, H.G., Park, H.H., Jung, Y., Kwon, S., and Lee, S.V. (2020). Caenorhabditis elegans algn-2 is critical for longevity conferred by enhanced nonsense-mediated mRNA decay. iScience 23, 101713. https://doi.org/10.1016/j.isci.2020.101713
  41. Kim, S.S. and Lee, S.V. (2019). Non-coding RNAs in Caenorhabditis elegans aging. Mol. Cells 42, 379-385. https://doi.org/10.14348/molcells.2019.0077
  42. Lapierre, L.R., De Magalhaes Filho, C.D., McQuary, P.R., Chu, C.C., Visvikis, O., Chang, J.T., Gelino, S., Ong, B., Davis, A.E., Irazoqui, J.E., et al. (2013). The TFEB orthologue HLH-30 regulates autophagy and modulates longevity in Caenorhabditis elegans. Nat. Commun. 4, 2267. https://doi.org/10.1038/ncomms3267
  43. Lapointe, J., Stepanyan, Z., Bigras, E., and Hekimi, S. (2009). Reversal of the mitochondrial phenotype and slow development of oxidative biomarkers of aging in long-lived Mclk1+/- mice. J. Biol. Chem. 284, 20364-20374. https://doi.org/10.1074/jbc.M109.006569
  44. Lee, B.P., Pilling, L.C., Emond, F., Flurkey, K., Harrison, D.E., Yuan, R., Peters, L.L., Kuchel, G.A., Ferrucci, L., Melzer, D., et al. (2016). Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans. Aging Cell 15, 903-913. https://doi.org/10.1111/acel.12499
  45. Lee, Y., An, S.W.A., Artan, M., Seo, M., Hwang, A.B., Jeong, D.E., Son, H.G., Hwang, W., Lee, D., Seo, K., et al. (2015). Genes and pathways that influence longevity in Caenorhabditis elegans. In Aging Mechanisms: Longevity, Metabolism, and Brain Aging, N. Mori and I. Mook-Jung, eds. (Tokyo: Springer Japan), pp. 123-169.
  46. Lee, Y., Jung, Y., Jeong, D.E., Hwang, W., Ham, S., Park, H.H., Kwon, S., Ashraf, J.M., Murphy, C.T., and Lee, S.V. (2021). Reduced insulin/IGF1 signaling prevents immune aging via ZIP-10/bZIP-mediated feedforward loop. J. Cell Biol. 220, e202006174. https://doi.org/10.1083/jcb.202006174
  47. Levine, B. and Kroemer, G. (2019). Biological functions of autophagy genes: a disease perspective. Cell 176, 11-42. https://doi.org/10.1016/j.cell.2018.09.048
  48. Li, T.Y., Sleiman, M.B., Li, H., Gao, A.W., Mottis, A., Bachmann, A.M., Alam, G.E., Li, X., Goeminne, L.J.E., Schoonjans, K., et al. (2021). The transcriptional coactivator CBP/p300 is an evolutionarily conserved node that promotes longevity in response to mitochondrial stress. Nat. Aging 1, 165-178. https://doi.org/10.1038/s43587-020-00025-z
  49. Lin, S.J., Defossez, P.A., and Guarente, L. (2000). Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae. Science 289, 2126-2128. https://doi.org/10.1126/science.289.5487.2126
  50. Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2013). The hallmarks of aging. Cell 153, 1194-1217. https://doi.org/10.1016/j.cell.2013.05.039
  51. Lu, T., Aron, L., Zullo, J., Pan, Y., Kim, H., Chen, Y., Yang, T.H., Kim, H.M., Drake, D., Liu, X.S., et al. (2014). REST and stress resistance in ageing and Alzheimer's disease. Nature 507, 448-454. https://doi.org/10.1038/nature13163
  52. Maeder, C.I., Kim, J.I., Liang, X., Kaganovsky, K., Shen, A., Li, Q., Li, Z., Wang, S., Xu, X.Z.S., Li, J.B., et al. (2018). The THO complex coordinates transcripts for synapse development and dopamine neuron survival. Cell 174, 1436-1449.e20. https://doi.org/10.1016/j.cell.2018.07.046
  53. Maxwell, S., Harding, J., Brabin, C., Appleford, P.J., Brown, R., Delaney, C., Brown, G., and Woollard, A. (2013). The SFT-1 and OXA-1 respiratory chain complex assembly factors influence lifespan by distinct mechanisms in C. elegans. Longev. Healthspan 2, 9. https://doi.org/10.1186/2046-2395-2-9
  54. McCay, C.M., Crowell, M.F., and Maynard, L.A. (1935). The effect of retarded growth upon the length of life span and upon the ultimate body size: one figure. J. Nutr. 10, 63-79. https://doi.org/10.1093/jn/10.1.63
  55. Merkwirth, C., Jovaisaite, V., Durieux, J., Matilainen, O., Jordan, S.D., Quiros, P.M., Steffen, K.K., Williams, E.G., Mouchiroud, L., Tronnes, S.U., et al. (2016). Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165, 1209-1223. https://doi.org/10.1016/j.cell.2016.04.012
  56. Mitchell, S.J., Scheibye-Knudsen, M., Longo, D.L., and de Cabo, R. (2015). Animal models of aging research: implications for human aging and agerelated diseases. Annu. Rev. Anim. Biosci. 3, 283-303. https://doi.org/10.1146/annurev-animal-022114-110829
  57. Mori, M.A., Raghavan, P., Thomou, T., Boucher, J., Robida-Stubbs, S., Macotela, Y., Russell, S.J., Kirkland, J.L., Blackwell, T.K., and Kahn, C.R. (2012). Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab. 16, 336-347. https://doi.org/10.1016/j.cmet.2012.07.017
  58. Mouchiroud, L., Houtkooper, R.H., Moullan, N., Katsyuba, E., Ryu, D., Canto, C., Mottis, A., Jo, Y.S., Viswanathan, M., Schoonjans, K., et al. (2013). The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430-441. https://doi.org/10.1016/j.cell.2013.06.016
  59. Pan, K.Z., Palter, J.E., Rogers, A.N., Olsen, A., Chen, D., Lithgow, G.J., and Kapahi, P. (2007). Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans. Aging Cell 6, 111-119. https://doi.org/10.1111/j.1474-9726.2006.00266.x
  60. Park, H.H., Jung, Y., and Lee, S.V. (2017). Survival assays using Caenorhabditis elegans. Mol. Cells 40, 90-99. https://doi.org/10.14348/molcells.2017.0017
  61. Park, S., Artan, M., Han, S.H., Park, H.H., Jung, Y., Hwang, A.B., Shin, W.S., Kim, K.T., and Lee, S.V. (2020). VRK-1 extends life span by activation of AMPK via phosphorylation. Sci. Adv. 6, eaaw7824. https://doi.org/10.1126/sciadv.aaw7824
  62. Perez-Jimenez, M.M., Monje-Moreno, J.M., Brokate-Llanos, A.M., VenegasCaleron, M., Sanchez-Garcia, A., Sansigre, P., Valladares, A., Esteban-Garcia, S., Suarez-Pereira, I., Vitorica, J., et al. (2021). Steroid hormones sulfatase inactivation extends lifespan and ameliorates age-related diseases. Nat. Commun. 12, 49. https://doi.org/10.1038/s41467-020-20269-y
  63. Pitt, J.N. and Kaeberlein, M. (2015). Why is aging conserved and what can we do about it? PLoS Biol. 13, e1002131. https://doi.org/10.1371/journal.pbio.1002131
  64. Riera, C.E., Huising, M.O., Follett, P., Leblanc, M., Halloran, J., Van Andel, R., de Magalhaes Filho, C.D., Merkwirth, C., and Dillin, A. (2014). TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell 157, 1023-1036. https://doi.org/10.1016/j.cell.2014.03.051
  65. Robida-Stubbs, S., Glover-Cutter, K., Lamming, D.W., Mizunuma, M., Narasimhan, S.D., Neumann-Haefelin, E., Sabatini, D.M., and Blackwell, T.K. (2012). TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab. 15, 713-724. https://doi.org/10.1016/j.cmet.2012.04.007
  66. Santos, J., Leitao-Correia, F., Sousa, M.J., and Leao, C. (2016). Dietary restriction and nutrient balance in aging. Oxid. Med. Cell. Longev. 2016, 4010357. https://doi.org/10.1155/2016/4010357
  67. Selman, C., Tullet, J.M., Wieser, D., Irvine, E., Lingard, S.J., Choudhury, A.I., Claret, M., Al-Qassab, H., Carmignac, D., Ramadani, F., et al. (2009). Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140-144. https://doi.org/10.1126/science.1177221
  68. Shao, L.W., Peng, Q., Dong, M., Gao, K., Li, Y., Li, Y., Li, C.Y., and Liu, Y. (2020). Histone deacetylase HDA-1 modulates mitochondrial stress response and longevity. Nat. Commun. 11, 4639. https://doi.org/10.1038/s41467-020-18501-w
  69. Son, H.G., Seo, M., Ham, S., Hwang, W., Lee, D., An, S.W., Artan, M., Seo, K., Kaletsky, R., Arey, R.N., et al. (2017). RNA surveillance via nonsensemediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans. Nat. Commun. 8, 14749. https://doi.org/10.1038/ncomms14749
  70. Sorrentino, V., Romani, M., Mouchiroud, L., Beck, J.S., Zhang, H., D'Amico, D., Moullan, N., Potenza, F., Schmid, A.W., Rietsch, S., et al. (2017). Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature 552, 187-193. https://doi.org/10.1038/nature25143
  71. Swindell, W.R. (2009). Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse. BMC Genomics 10, 585. https://doi.org/10.1186/1471-2164-10-585
  72. Tabrez, S.S., Sharma, R.D., Jain, V., Siddiqui, A.A., and Mukhopadhyay, A. (2017). Differential alternative splicing coupled to nonsense-mediated decay of mRNA ensures dietary restriction-induced longevity. Nat. Commun. 8, 306. https://doi.org/10.1038/s41467-017-00370-5
  73. Taormina, G., Ferrante, F., Vieni, S., Grassi, N., Russo, A., and Mirisola, M.G. (2019). Longevity: lesson from model organisms. Genes (Basel) 10, 518. https://doi.org/10.3390/genes10070518
  74. Tiku, V., Jain, C., Raz, Y., Nakamura, S., Heestand, B., Liu, W., Spath, M., Suchiman, H.E.D., Muller, R.U., Slagboom, P.E., et al. (2017). Small nucleoli are a cellular hallmark of longevity. Nat. Commun. 8, 16083. https://doi.org/10.1038/ncomms16083
  75. Tissenbaum, H.A. (2015). Using C. elegans for aging research. Invertebr. Reprod. Dev. 59(sup1), 59-63. https://doi.org/10.1080/07924259.2014.940470
  76. Vatner, D.E., Zhang, J., Oydanich, M., Guers, J., Katsyuba, E., Yan, L., Sinclair, D., Auwerx, J., and Vatner, S.F. (2018). Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14. Aging Cell 17, e12751. https://doi.org/10.1111/acel.12751
  77. Weimer, S., Priebs, J., Kuhlow, D., Groth, M., Priebe, S., Mansfeld, J., Merry, T.L., Dubuis, S., Laube, B., Pfeiffer, A.F., et al. (2014). D-Glucosamine supplementation extends life span of nematodes and of ageing mice. Nat. Commun. 5, 3563. https://doi.org/10.1038/ncomms4563
  78. Wong, S.Q., Kumar, A.V., Mills, J., and Lapierre, L.R. (2020). Autophagy in aging and longevity. Hum. Genet. 139, 277-290. https://doi.org/10.1007/s00439-019-02031-7
  79. Wu, Z., Senchuk, M.M., Dues, D.J., Johnson, B.K., Cooper, J.F., Lew, L., Machiela, E., Schaar, C.E., DeJonge, H., Blackwell, T.K., et al. (2018). Mitochondrial unfolded protein response transcription factor ATFS1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways. BMC Biol. 16, 147. https://doi.org/10.1186/s12915-018-0615-3
  80. Xie, Q., Peng, S., Tao, L., Ruan, H., Yang, Y., Li, T.M., Adams, U., Meng, S., Bi, X., Dong, M.Q., et al. (2014). E2F transcription factor 1 regulates cellular and organismal senescence by inhibiting Forkhead box O transcription factors. J. Biol. Chem. 289, 34205-34213. https://doi.org/10.1074/jbc.M114.587170
  81. Yang, Y. and Klionsky, D.J. (2020). Autophagy and disease: unanswered questions. Cell Death Differ. 27, 858-871. https://doi.org/10.1038/s41418-019-0480-9
  82. Yuan, J., Chang, S.Y., Yin, S.G., Liu, Z.Y., Cheng, X., Liu, X.J., Jiang, Q., Gao, G., Lin, D.Y., Kang, X.L., et al. (2020). Two conserved epigenetic regulators prevent healthy ageing. Nature 579, 118-122. https://doi.org/10.1038/s41586-020-2037-y
  83. Zhou, B., Kreuzer, J., Kumsta, C., Wu, L., Kamer, K.J., Cedillo, L., Zhang, Y., Li, S., Kacergis, M.C., Webster, C.M., et al. (2019). Mitochondrial permeability uncouples elevated autophagy and lifespan extension. Cell 177, 299-314. e16. https://doi.org/10.1016/j.cell.2019.02.013
  84. Zullo, J.M., Drake, D., Aron, L., O'Hern, P., Dhamne, S.C., Davidsohn, N., Mao, C.A., Klein, W.H., Rotenberg, A., Bennett, D.A., et al. (2019). Regulation of lifespan by neural excitation and REST. Nature 574, 359-364. https://doi.org/10.1038/s41586-019-1647-8