DOI QR코드

DOI QR Code

Autophagy and Longevity

  • Nakamura, Shuhei (Department of Genetics, Graduate School of Medicine, Osaka University) ;
  • Yoshimori, Tamotsu (Department of Genetics, Graduate School of Medicine, Osaka University)
  • 투고 : 2017.12.05
  • 심사 : 2017.12.29
  • 발행 : 2018.01.31

초록

Autophagy is an evolutionally conserved cytoplasmic degradation system in which varieties of materials are sequestered by a double membrane structure, autophagosome, and delivered to the lysosomes for the degradation. Due to the wide varieties of targets, autophagic activity is essential for cellular homeostasis. Recent genetic evidence indicates that autophagy has a crucial role in the regulation of animal lifespan. Basal level of autophagic activity is elevated in many longevity paradigms and the activity is required for lifespan extension. In most cases, genes involved in autophagy and lysosomal function are induced by several transcription factors including HLH-30/TFEB, PHA-4/FOXA and MML-1/Mondo in long-lived animals. Pharmacological treatments have been shown to extend lifespan through activation of autophagy, indicating autophagy could be a potential and promising target to modulate animal lifespan. Here we summarize recent progress regarding the role of autophagy in lifespan regulation.

키워드

E1BJB7_2018_v41n1_65_f0001.png 이미지

Fig. 1. Overview of macroautophagy. Upon induction of autophagy by stress, cytoplasmic materials are sequestered by a double-membraned structure, called an autophagosome. These autophagosomes fuse with lysosomes to become autolysosomes, in which thesequestered cargos are degraded and recycled for the maintenance of cellular homeostasis.

E1BJB7_2018_v41n1_65_f0002.png 이미지

Fig. 2. Autophagy is a convergent mechanism of multiple longevi-ty paradigms. Autophagic activity is commonly elevated in manylong-lived animals and is essential for their longevity, suggestingthat autophagy is one of convergent mechanisms mediatingdifferent longevity paradigms.

Table 1. Longevity through activation of autophagy

E1BJB7_2018_v41n1_65_t0001.png 이미지

참고문헌

  1. Alvers, A.L., Fishwick, L.K., Wood, M.S., Hu, D., Chung, H.S., Dunn, W.A., Jr., and Aris, J.P. (2009a). Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiae. Aging Cell 8, 353-369. https://doi.org/10.1111/j.1474-9726.2009.00469.x
  2. Alvers, A.L., Wood, M.S., Hu, D., Kaywell, A.C., Dunn, W.A., Jr., and Aris, J.P. (2009b). Autophagy is required for extension of yeast chronological life span by rapamycin. Autophagy 5, 847-849. https://doi.org/10.4161/auto.8824
  3. Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P.S., and Curtis, R. (2004). The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 18, 3004-3009. https://doi.org/10.1101/gad.1255404
  4. Bjedov, I., Toivonen, J.M., Kerr, F., Slack, C., Jacobson, J., Foley, A., and Partridge, L. (2010). Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab. 11, 35-46. https://doi.org/10.1016/j.cmet.2009.11.010
  5. Chan, S.N., and Tang, B.L. (2013). Location and membrane sources for autophagosome formation - from ER-mitochondria contact sites to Golgi-endosome-derived carriers. Mol. Membr. Biol. 30, 394-402. https://doi.org/10.3109/09687688.2013.850178
  6. Chang, J.T., Kumsta, C., Hellman, A.B., Adams, L.M., and Hansen, M. (2017). Spatiotemporal regulation of autophagy during Caenorhabditis elegans aging. Elife 6.
  7. Del Roso, A., Vittorini, S., Cavallini, G., Donati, A., Gori, Z., Masini, M., Pollera, M., and Bergamini, E. (2003). Ageing-related changes in the in vivo function of rat liver macroautophagy and proteolysis. Exp. Gerontol. 38, 519-527. https://doi.org/10.1016/S0531-5565(03)00002-0
  8. Donati, A., Cavallini, G., Paradiso, C., Vittorini, S., Pollera, M., Gori, Z., and Bergamini, E. (2001). 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, B375-383. https://doi.org/10.1093/gerona/56.9.B375
  9. Egan, D.F., Shackelford, D.B., Mihaylova, M.M., Gelino, S., Kohnz, R.A., Mair, W., Vasquez, D.S., Joshi, A., Gwinn, D.M., Taylor, R., et al. (2011). Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456-461. https://doi.org/10.1126/science.1196371
  10. Eisenberg, T., Knauer, H., Schauer, A., Buttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., Ring, J., Schroeder, S., Magnes, C., Antonacci, L., et al. (2009). Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305-U1102. https://doi.org/10.1038/ncb1975
  11. Eisenberg, T., Abdellatif, M., Schroeder, S., Primessnig, U., Stekovic, S., Pendl, T., Harger, A., Schipke, J., Zimmermann, A., Schmidt, A., et al. (2016). Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428-1438. https://doi.org/10.1038/nm.4222
  12. Fang, E.F., Waltz, T.B., Kassahun, H., Lu, Q., Kerr, J.S., Morevati, M., Fivenson, E.M., Wollman, B.N., Marosi, K., Wilson, M.A., et al. (2017). Tomatidine enhances lifespan and healthspan in C. elegans through mitophagy induction via the SKN-1/Nrf2 pathway. Sci. Rep. 7, 46208. https://doi.org/10.1038/srep46208
  13. Fujita, N., Hayashi-Nishino, M., Fukumoto, H., Omori, H., Yamamoto, A., Noda, T., and Yoshimori, T. (2008). An Atg4B mutant hampers the lipidation of LC3 paralogues and causes defects in autophagosome closure. Mol. Biol. Cell 19, 4651-4659. https://doi.org/10.1091/mbc.E08-03-0312
  14. Fullgrabe, J., Klionsky, D.J., and Joseph, B. (2014). The return of the nucleus: transcriptional and epigenetic control of autophagy. Nat. Rev. Mol. Cell Biol. 15, 65-74.
  15. Gelino, S., Chang, J.T., Kumsta, C., She, X.Y., Davis, A., Nguyen, C., Panowski, S., and Hansen, M. (2016). Intestinal autophagy improves healthspan and longevity in C. elegans during dietary restriction. Plos Genet. 12.
  16. Giblin, W., Skinner, M.E., and Lombard, D.B. (2014). Sirtuins: guardians of mammalian healthspan. Trends Genet. 30, 271-286. https://doi.org/10.1016/j.tig.2014.04.007
  17. Greer, E.L., and Brunet, A. (2009). Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans. Aging Cell 8, 113-127. https://doi.org/10.1111/j.1474-9726.2009.00459.x
  18. Gupta, V.K., Scheunemann, L., Eisenberg, T., Mertel, S., Bhukel, A., Koemans, T.S., Kramer, J.M., Liu, K.S.Y., Schroeder, S., Stunnenberg, H.G., et al. (2013). Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 16, 1453-1460. https://doi.org/10.1038/nn.3512
  19. Hamasaki, M., Furuta, N., Matsuda, A., Nezu, A., Yamamoto, A., Fujita, N., Oomori, H., Noda, T., Haraguchi, T., Hiraoka, Y., et al. (2013). Autophagosomes form at ER-mitochondria contact sites. Nature 495, 389-393. https://doi.org/10.1038/nature11910
  20. 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
  21. Hansen, M., Chandra, A., Mitic, L.L., Onken, B., Driscoll, M., and Kenyon, C. (2008). A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. Plos Genet. 4, e24. https://doi.org/10.1371/journal.pgen.0040024
  22. Harrison, D.E., Strong, R., Sharp, Z.D., Nelson, J.F., Astle, C.M., Flurkey, K., Nadon, N.L., Wilkinson, J.E., Frenkel, K., Carter, C.S., et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392-395. https://doi.org/10.1038/nature08221
  23. Heestand, B.N., Shen, Y., Liu, W., Magner, D.B., Storm, N., Meharg, C., Habermann, B., and Antebi, A. (2013). Dietary restriction induced longevity is mediated by nuclear receptor NHR-62 in Caenorhabditis elegans. Plos Genet. 9, e1003651. https://doi.org/10.1371/journal.pgen.1003651
  24. Hur, J.H., Cho, J., and Walker, D.W. (2010). Aging: dial M for mitochondria. Aging (Albany NY) 2, 69-73.
  25. Jia, K.L., and Levine, B. (2007). Autophagy is required for dietary restriction-mediated life span extension in C-elegans. Autophagy 3, 597-599. https://doi.org/10.4161/auto.4989
  26. Jia, K.L., Thomas, C., Akbar, M., Sun, Q.H., Adams-Huet, B., Gilpin, C., and Levine, B. (2009). Autophagy genes protect against Salmonella typhimurium infection and mediate insulin signalingregulated pathogen resistance. Proc. Natl. Acad. Sci. USA 106, 14564-14569. https://doi.org/10.1073/pnas.0813319106
  27. Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., Kominami, E., Ohsumi, Y., and Yoshimori, T. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720-5728. https://doi.org/10.1093/emboj/19.21.5720
  28. Kenyon, C.J. (2010). The genetics of ageing. Nature 464, 504-512. https://doi.org/10.1038/nature08980
  29. Kirchman, P.A., Kim, S., Lai, C.Y., and Jazwinski, S.M. (1999). Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics 152, 179-190.
  30. Lamming, D.W., Ye, L., Sabatini, D.M., and Baur, J.A. (2013). Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980-989. https://doi.org/10.1172/JCI64099
  31. Lapierre, L.R., Gelino, S., Melendez, A., and Hansen, M. (2011). Autophagy and lipid metabolism coordinately modulate life span in germline-less C. elegans. Curr. Biol. 21, 1507-1514. https://doi.org/10.1016/j.cub.2011.07.042
  32. 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.
  33. Lee, I.H., Cao, L., Mostoslavsky, R., Lombard, D.B., Liu, J., Bruns, N.E., Tsokos, M., Alt, F.W., and Finkel, T. (2008). A role for the NADdependent deacetylase Sirt1 in the regulation of autophagy. Proc. Natl. Acad. Sci. USA 105, 3374-3379. https://doi.org/10.1073/pnas.0712145105
  34. Liu, N., Landreh, M., Cao, K.J., Abe, M., Hendriks, G.J., Kennerdell, J.R., Zhu, Y.Q., Wang, L.S., and Bonini, N.M. (2012). The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 482, 519-U240. https://doi.org/10.1038/nature10810
  35. Mair, W., and Dillin, A. (2008). Aging and survival: the genetics of life span extension by dietary restriction. Annu. Rev. Biochem. 77, 727-754. https://doi.org/10.1146/annurev.biochem.77.061206.171059
  36. Matecic, M., Smith, D.L., Pan, X., Maqani, N., Bekiranov, S., Boeke, J.D., and Smith, J.S. (2010). A microarray-based genetic screen for yeast chronological aging factors. Plos Genet. 6, e1000921. https://doi.org/10.1371/journal.pgen.1000921
  37. Melendez, A., Talloczy, Z., Seaman, M., Eskelinen, E.L., Hall, D.H., and Levine, B. (2003). Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science 301, 1387-1391. https://doi.org/10.1126/science.1087782
  38. Mizushima, N., and Levine, B. (2010). Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12, 823-830. https://doi.org/10.1038/ncb0910-823
  39. Morselli, E., Maiuri, M.C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S.A., Vitale, I., et al. (2010). Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 1.
  40. Morselli, E., Marino, G., Bennetzen, M.V., Eisenberg, T., Megalou, E., Schroeder, S., Cabrera, S., Benit, P., Rustin, P., Criollo, A., et al. (2011). Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615-629. https://doi.org/10.1083/jcb.201008167
  41. Nakamura, S., and Yoshimori, T. (2017). New insights into autophagosome-lysosome fusion. J. Cell Sci. 130, 1209-1216. https://doi.org/10.1242/jcs.196352
  42. Nakamura, S., Karalay, O., Jager, P.S., Horikawa, M., Klein, C., Nakamura, K., Latza, C., Templer, S.E., Dieterich, C., and Antebi, A. (2016). Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals. Nat. Commun. 7, 10944. https://doi.org/10.1038/ncomms10944
  43. Palikaras, K., Lionaki, E., and Tavernarakis, N. (2015). Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525-528. https://doi.org/10.1038/nature14300
  44. Park, S., Mori, R., and Shimokawa, I. (2013). Do sirtuins promote mammalian longevity? A critical review on its relevance to the longevity effect induced by calorie restriction. Mol. Cells 35, 474-480. https://doi.org/10.1007/s10059-013-0130-x
  45. Pyo, J.O., Yoo, S.M., Ahn, H.H., Nah, J., Hong, S.H., Kam, T.I., Jung, S., and Jung, Y.K. (2013). Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat. Commun. 4.
  46. Rubinsztein, D.C., Marino, G., and Kroemer, G. (2011). Autophagy and aging. Cell 146, 682-695. https://doi.org/10.1016/j.cell.2011.07.030
  47. Ryu, D., Mouchiroud, L., Andreux, P.A., Katsyuba, E., Moullan, N., Nicolet-dit-Felix, A.A., Williams, E.G., Jha, P., Lo Sasso, G., Huzard, D., et al. (2016). Urolithin A induces mitophagy and prolongs lifespan in C-elegans and increases muscle function in rodents. Nat. Med. 22, 879-888. https://doi.org/10.1038/nm.4132
  48. Sardiello, M., Palmieri, M., di Ronza, A., Medina, D.L., Valenza, M., Gennarino, V.A., Di Malta, C., Donaudy, F., Embrione, V., Polishchuk, R.S., et al. (2009). A gene network regulating lysosomal biogenesis and function. Science 325, 473-477.
  49. Schiavi, A., Torgovnick, A., Kell, A., Megalou, E., Castelein, N., Guccini, I., Marzocchella, L., Gelino, S., Hansen, M., Malisan, F., et al. (2013). Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans. Exp. Gerontol. 48, 191-201. https://doi.org/10.1016/j.exger.2012.12.002
  50. Schiavi, A., Maglioni, S., Palikaras, K., Shaik, A., Strappazzon, F., Brinkmann, V., Torgovnick, A., Castelein, N., De Henau, S., Braeckman, B.P., et al. (2015). Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans. Curr. Biol. 25, 1810-1822. https://doi.org/10.1016/j.cub.2015.05.059
  51. Settembre, C., Di Malta, C., Polito, V.A., Garcia Arencibia, M., Vetrini, F., Erdin, S., Erdin, S.U., Huynh, T., Medina, D., Colella, P., et al. (2011). TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433. https://doi.org/10.1126/science.1204592
  52. Settembre, C., De Cegli, R., Mansueto, G., Saha, P.K., Vetrini, F., Visvikis, O., Huynh, T., Carissimo, A., Palmer, D., Klisch, T.J., et al. (2013a). TFEB controls cellular lipid metabolism through a starvationinduced autoregulatory loop. Nat. Cell Biol. 15, 647-658. https://doi.org/10.1038/ncb2718
  53. Settembre, C., Fraldi, A., Medina, D.L., and Ballabio, A. (2013b). Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283-296. https://doi.org/10.1038/nrm3565
  54. Sheaffer, K.L., Updike, D.L., and Mango, S.E. (2008). The Target of Rapamycin pathway antagonizes pha-4/FoxA to control development and aging. Curr. Biol. 18, 1355-1364. https://doi.org/10.1016/j.cub.2008.07.097
  55. Simonsen, A., Cumming, R.C., Brech, A., Isakson, P., Schubert, D.R., and Finley, K.D. (2008). Promoting basal levels of autophagy in the nervous system enhances longevity and oxidant resistance in adult Drosophila. Autophagy 4, 176-184. https://doi.org/10.4161/auto.5269
  56. Smith, D.L., Jr., McClure, J.M., Matecic, M., and Smith, J.S. (2007). Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the Sirtuins. Aging Cell 6, 649-662. https://doi.org/10.1111/j.1474-9726.2007.00326.x
  57. Tang, F., Watkins, J.W., Bermudez, M., Gray, R., Gaban, A., Portie, K., Grace, S., Kleve, M., and Craciun, G. (2008). A life-span extending form of autophagy employs the vacuole-vacuole fusion machinery. Autophagy 4, 874-886. https://doi.org/10.4161/auto.6556
  58. Toth, M.L., Sigmond, T., Borsos, E., Barna, J., Erdelyi, P., Takacs-Vellai, K., Orosz, L., Kovacs, A.L., Csikos, G., Sass, M., et al. (2008). Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy 4, 330-338. https://doi.org/10.4161/auto.5618
  59. Uddin, M.N., Nishio, N., Ito, S., Suzuki, H., and Isobe, K. (2012). Autophagic activity in thymus and liver during aging. Age 34, 75-85. https://doi.org/10.1007/s11357-011-9221-9
  60. Ulgherait, M., Rana, A., Rera, M., Graniel, J., and Walker, D.W. (2014). AMPK modulates tissue and organismal aging in a non-cellautonomous manner. Cell Rep. 8, 1767-1780. https://doi.org/10.1016/j.celrep.2014.08.006
  61. Vellai, T., Takacs-Vellai, K., Zhang, Y., Kovacs, A.L., Orosz, L., and Muller, F. (2003). Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 426, 620.
  62. Wang, M.C., O'Rourke, E.J., and Ruvkun, G. (2008). Fat metabolism links germline stem cells and longevity in C. elegans. Science 322, 957-960. https://doi.org/10.1126/science.1162011
  63. Wang, C., Niederstrasser, H., Douglas, P.M., Lin, R., Jaramillo, J., Li, Y., Olswald, N.W., Zhou, A., McMillan, E.A., Mendiratta, S., et al. (2017). Small-molecule TFEB pathway agonists that ameliorate metabolic syndrome in mice and extend C. elegans lifespan. Nat. Commun. 8, 2270. https://doi.org/10.1038/s41467-017-02332-3
  64. Wilhelm, T., Byrne, J., Medina, R., Kolundzic, E., Geisinger, J., Hajduskova, M., Tursun, B., and Richly, H. (2017). Neuronal inhibition of the autophagy nucleation complex extends life span in postreproductive C. elegans. Genes Dev. 31, 1561-1572. https://doi.org/10.1101/gad.301648.117
  65. Yang, J.R., Chen, D.P., He, Y.N., Melendez, A., Feng, Z., Hong, Q., Bai, X.Y., Li, Q.G., Cai, G.Y., Wang, J.Z., et al. (2013). MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9. Age 35, 11-22. https://doi.org/10.1007/s11357-011-9324-3

피인용 문헌

  1. What We Learned From Big Data for Autophagy Research vol.6, pp.2296-634X, 2018, https://doi.org/10.3389/fcell.2018.00092
  2. Hallmarks of Aging: An Autophagic Perspective vol.9, pp.1664-2392, 2018, https://doi.org/10.3389/fendo.2018.00790
  3. Molecular mechanisms regulating lifespan and environmental stress responses vol.38, pp.1, 2018, https://doi.org/10.1186/s41232-018-0080-y
  4. Overview of the Minireviews on Autophagy vol.41, pp.1, 2018, https://doi.org/10.14348/molcells.2018.0400
  5. NADPH Oxidases and Mitochondria in Vascular Senescence vol.19, pp.5, 2018, https://doi.org/10.3390/ijms19051327
  6. Proximal Cysteines that Enhance Lysine N-Acetylation of Cytosolic Proteins in Mice Are Less Conserved in Longer-Living Species vol.24, pp.6, 2018, https://doi.org/10.1016/j.celrep.2018.07.007
  7. Autophagy in Age-Associated Neurodegeneration vol.7, pp.5, 2018, https://doi.org/10.3390/cells7050037
  8. Targeting Autophagy in Aging and Aging-Related Cardiovascular Diseases vol.39, pp.12, 2018, https://doi.org/10.1016/j.tips.2018.10.005
  9. 6-Bromoindirubin-3′-Oxime (6BIO) Suppresses the mTOR Pathway, Promotes Autophagy, and Exerts Anti-aging Effects in Rodent Liver vol.10, pp.None, 2019, https://doi.org/10.3389/fphar.2019.00320
  10. mTOR: A Cellular Regulator Interface in Health and Disease vol.8, pp.1, 2018, https://doi.org/10.3390/cells8010018
  11. Is Autophagy Involved in the Diverse Effects of Antidepressants? vol.8, pp.1, 2018, https://doi.org/10.3390/cells8010044
  12. Influence of Normal Aging on Brain Autophagy: A Complex Scenario vol.11, pp.None, 2018, https://doi.org/10.3389/fnagi.2019.00049
  13. Chemical Screening Approaches Enabling Drug Discovery of Autophagy Modulators for Biomedical Applications in Human Diseases vol.7, pp.None, 2019, https://doi.org/10.3389/fcell.2019.00038
  14. Senotherapeutics: emerging strategy for healthy aging and age-related disease vol.52, pp.1, 2018, https://doi.org/10.5483/bmbrep.2019.52.1.293
  15. Is Gcn4-induced autophagy the ultimate downstream mechanism by which hormesis extends yeast replicative lifespan? vol.65, pp.3, 2019, https://doi.org/10.1007/s00294-019-00936-4
  16. Novel Genetic Locus of Visceral Fat and Systemic Inflammation vol.104, pp.9, 2018, https://doi.org/10.1210/jc.2018-02656
  17. Royal Jelly and Its Components Promote Healthy Aging and Longevity: From Animal Models to Humans vol.20, pp.19, 2018, https://doi.org/10.3390/ijms20194662
  18. miR-762 modulates thyroxine-induced cardiomyocyte hypertrophy by inhibiting Beclin-1 vol.66, pp.3, 2019, https://doi.org/10.1007/s12020-019-02048-y
  19. Accelerated Kidney Aging in Diabetes Mellitus vol.2020, pp.None, 2020, https://doi.org/10.1155/2020/1234059
  20. Nitrative Stress-Related Autophagic Insufficiency Participates in Hyperhomocysteinemia-Induced Renal Aging vol.2020, pp.None, 2018, https://doi.org/10.1155/2020/4252047
  21. Editorial: Autophagy and Ageing: Ideas, Methods, Molecules vol.8, pp.None, 2018, https://doi.org/10.3389/fcell.2020.00141
  22. Telomeres and Telomerase in Heart Ontogenesis, Aging and Regeneration vol.9, pp.2, 2020, https://doi.org/10.3390/cells9020503
  23. Vascular Calcification—New Insights into Its Mechanism vol.21, pp.8, 2018, https://doi.org/10.3390/ijms21082685
  24. Precision Medicine in Lifestyle Medicine: The Way of the Future? vol.14, pp.2, 2020, https://doi.org/10.1177/1559827619834527
  25. Autophagy Declines with Premature Skin Aging resulting in Dynamic Alterations in Skin Pigmentation and Epidermal Differentiation vol.21, pp.16, 2018, https://doi.org/10.3390/ijms21165708
  26. Systematic Surveys of Iron Homeostasis Mechanisms Reveal Ferritin Superfamily and Nucleotide Surveillance Regulation to be Modified by PINK1 Absence vol.9, pp.10, 2018, https://doi.org/10.3390/cells9102229
  27. The Aging Stress Response and Its Implication for AMD Pathogenesis vol.21, pp.22, 2020, https://doi.org/10.3390/ijms21228840
  28. Isobacachalcone induces autophagy and improves the outcome of immunogenic chemotherapy vol.11, pp.11, 2020, https://doi.org/10.1038/s41419-020-03226-x
  29. A natural product solution to aging and aging-associated diseases vol.216, pp.None, 2018, https://doi.org/10.1016/j.pharmthera.2020.107673
  30. A Bioactive compound Shatavarin IV-mediated longevity as revealed by dietary restriction-induced autophagy in Caenorhabditis elegans vol.21, pp.6, 2018, https://doi.org/10.1007/s10522-020-09897-5
  31. The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity vol.10, pp.1, 2018, https://doi.org/10.3390/cells10010079
  32. Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis vol.8, pp.None, 2018, https://doi.org/10.2147/jhc.s327339
  33. TFEB: A Emerging Regulator in Lipid Homeostasis for Atherosclerosis vol.12, pp.None, 2018, https://doi.org/10.3389/fphys.2021.639920
  34. Quality Matters? The Involvement of Mitochondrial Quality Control in Cardiovascular Disease vol.9, pp.None, 2021, https://doi.org/10.3389/fcell.2021.636295
  35. SIRT6 in Senescence and Aging-Related Cardiovascular Diseases vol.9, pp.None, 2018, https://doi.org/10.3389/fcell.2021.641315
  36. Autophagy and Aging: Roles in Skeletal Muscle, Eye, Brain and Hepatic Tissue vol.9, pp.None, 2018, https://doi.org/10.3389/fcell.2021.752962
  37. Cellular Senescence in Brain Aging vol.13, pp.None, 2018, https://doi.org/10.3389/fnagi.2021.646924
  38. Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and d-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging vol.22, pp.1, 2018, https://doi.org/10.1007/s10522-020-09900-z
  39. Lysosomal Functions in Glia Associated with Neurodegeneration vol.11, pp.3, 2018, https://doi.org/10.3390/biom11030400
  40. Ferulic Acid Supplementation Increases Lifespan and Stress Resistance via Insulin/IGF-1 Signaling Pathway in C. elegans vol.22, pp.8, 2018, https://doi.org/10.3390/ijms22084279
  41. Maternal high sugar and fat diet benefits offspring brain function via targeting on the gut-brain axis vol.13, pp.7, 2021, https://doi.org/10.18632/aging.202787
  42. Translational control of gene expression by eIF2 modulates proteostasis and extends lifespan vol.13, pp.8, 2018, https://doi.org/10.18632/aging.203018
  43. New Molecular Targets for Antidepressant Drugs vol.14, pp.9, 2018, https://doi.org/10.3390/ph14090894
  44. Genetic characteristics of Bursaphelenchus xylophilus third-stage dispersal juveniles vol.11, pp.1, 2018, https://doi.org/10.1038/s41598-021-82343-9
  45. Spermidine induces cytoprotective autophagy of female germline stem cells in vitro and ameliorates aging caused by oxidative stress through upregulated sequestosome-1/p62 expression vol.11, pp.1, 2018, https://doi.org/10.1186/s13578-021-00614-4
  46. Graptopetalum paraguayense Extract Ameliorates Proteotoxicity in Aging and Age-Related Diseases in Model Systems vol.13, pp.12, 2018, https://doi.org/10.3390/nu13124317
  47. 3,3’-Diindolylmethane induces apoptosis and autophagy in fission yeast vol.16, pp.12, 2018, https://doi.org/10.1371/journal.pone.0255758