Browse > Article
http://dx.doi.org/10.14348/molcells.2017.0151

Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot  

Kwon, Yoojin (School of Biological Sciences, Seoul National University)
Kim, Ji Wook (School of Biological Sciences, Seoul National University)
Jeoung, Jo Ae (School of Biological Sciences, Seoul National University)
Kim, Mi-Sung (School of Biological Sciences, Seoul National University)
Kang, Chanhee (School of Biological Sciences, Seoul National University)
Publication Information
Molecules and Cells / v.40, no.9, 2017 , pp. 607-612 More about this Journal
Abstract
When mammalian cells and animals face a variety of internal or external stresses, they need to make homeostatic changes so as to cope with various stresses. To this end, mammalian cells are equipped with two critical stress responses, autophagy and cellular senescence. Autophagy and cellular senescence share a number of stimuli including telomere shortening, DNA damage, oncogenic stress and oxidative stress, suggesting their intimate relationship. Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. These seemingly opposite roles of autophagy may reflect a complex picture of autophagic regulation on cellular senescence, including different types of autophagy or a unique spatiotemporal activation of autophagy. Thus, a better understanding of autophagy process will lead us to not only elucidate the conundrum how autophagy plays dual roles in the regulation of cellular senescence but also helps the development of new therapeutic strategies for many human diseases associated with cellular senescence. We address the pro-senescence and anti-senescence roles of autophagy while focusing on the potential mechanistic aspects of this complex relationship between autophagy and cellular senescence.
Keywords
aging; autophagy; cellular senescence; selective autophagy; senescence-associated secretory phenotype;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Dalle Pezze, P., Nelson, G., Otten, E.G., Korolchuk, V.I., Kirkwood, T.B., von Zglinicki, T., and Shanley, D.P. (2014). Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions. PLoS Comput. Biol. 10, e1003728.   DOI
2 Dou, Z., Xu, C., Donahue, G., Shimi, T., Pan, J.A., Zhu, J., Ivanov, A., Capell, B.C., Drake, A.M., Shah, P.P., et al. (2015). Autophagy mediates degradation of nuclear lamina. Nature 527, 105-109.   DOI
3 Dou, Z., Ivanov, A., Adams, P.D., and Berger, S.L. (2016). Mammalian autophagy degrades nuclear constituents in response to tumorigenic stress. Autophagy 12, 1416-1417.   DOI
4 Galluzzi, L., Kepp, O., Vander Heiden, M.G., and Kroemer, G. (2013). Metabolic targets for cancer therapy. Nat. Rev. Drug Dis. 12, 829-846.   DOI
5 Garcia-Prat, L., Martinez-Vicente, M., Perdiguero, E., Ortet, L., Rodriguez-Ubreva, J., Rebollo, E., Ruiz-Bonilla, V., Gutarra, S., Ballestar, E., Serrano, A.L., et al. (2016). Autophagy maintains stemness by preventing senescence. Nature 529, 37-42.   DOI
6 Gewirtz, D.A. (2013). Autophagy and senescence: a partnership in search of definition. Autophagy 9, 808-812.   DOI
7 Han, X., Tai, H., Wang, X., Wang, Z., Zhou, J., Wei, X., Ding, Y., Gong, H., Mo, C., Zhang, J., et al. (2016). AMPK activation protects cells from oxidative stress-induced senescence via autophagic flux restoration and intracellular NAD(+). elevation. Aging Cell 15, 416-427.   DOI
8 He, S., and Sharpless, N.E. (2017). Senescence in health and disease. Cell 169, 1000-1011.   DOI
9 Horikawa, I., Fujita, K., Jenkins, L.M., Hiyoshi, Y., Mondal, A.M., Vojtesek, B., Lane, D.P., Appella, E., and Harris, C.C. (2014). Autophagic degradation of the inhibitory p53 isoform Delta133p53alpha as a regulatory mechanism for p53-mediated senescence. Nat. Commun. 5, 4706.   DOI
10 Huang, Y.H., Yang, P.M., Chuah, Q.Y., Lee, Y.J., Hsieh, Y.F., Peng, C.W., and Chiu, S.J. (2014). Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells. Autophagy 10, 1212-1228.   DOI
11 Ito, S., Araya, J., Kurita, Y., Kobayashi, K., Takasaka, N., Yoshida, M., Hara, H., Minagawa, S., Wakui, H., Fujii, S., et al. (2015). PARK2- mediated mitophagy is involved in regulation of HBEC senescence in COPD pathogenesis. Autophagy 11, 547-559.   DOI
12 Jin, M., Liu, X., and Klionsky, D.J. (2013). SnapShot: selective autophagy. Cell 152, 368-368 e362.   DOI
13 Johansen, T., and Lamark, T. (2011). Selective autophagy mediated by autophagic adapter proteins. Autophagy 7, 279-296.   DOI
14 Kang, C., and Avery, L. (2008). To be or not to be, the level of autophagy is the question: dual roles of autophagy in the survival response to starvation. Autophagy 4, 82-84.   DOI
15 Kang, C., and Avery, L. (2009a). Systemic regulation of autophagy in Caenorhabditis elegans. Autophagy 5, 565-566.   DOI
16 Kang, C., and Avery, L. (2009b). Systemic regulation of starvation response in Caenorhabditis elegans. Genes Dev. 23, 12-17.   DOI
17 Kang, C., and Elledge, S.J. (2016). How autophagy both activates and inhibits cellular senescence. Autophagy 12, 898-899.   DOI
18 Kang, C., You, Y.J., and Avery, L. (2007). Dual roles of autophagy in the survival of Caenorhabditis elegans during starvation. Genes Dev. 21, 2161-2171.   DOI
19 Kang, H.T., Park, J.T., Choi, K., Kim, Y., Choi, H.J.C., Jung, C.W., Lee, Y.S., and Park, S.C. (2017). Chemical screening identifies ATM as a target for alleviating senescence. Nat. Chem. Biol. 13, 616-623.   DOI
20 Kang, H.T., Lee, K.B., Kim, S.Y., Choi, H.R., and Park, S.C. (2011). Autophagy impairment induces premature senescence in primary human fibroblasts. PloS One 6, e23367.   DOI
21 Kang, C., Xu, Q., Martin, T.D., Li, M.Z., Demaria, M., Aron, L., Lu, T., Yankner, B.A., Campisi, J., and Elledge, S.J. (2015). The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 349, aaa5612.   DOI
22 Klionsky, D.J., and Codogno, P. (2013). The mechanism and physiological function of macroautophagy. J. Innate Immun. 5, 427-433.   DOI
23 Korolchuk, V.I., Miwa, S., Carroll, B., and von Zglinicki, T. (2017). Mitochondria in cell senescence: is mitophagy the weakest link? EBioMedicine 21, 7-13.   DOI
24 Kroemer, G. (2015). Autophagy: a druggable process that is deregulated in aging and human disease. J. Clin. Invest. 125, 1-4.   DOI
25 Kroemer, G., Marino, G., and Levine, B. (2010). Autophagy and the integrated stress response. Mol. Cell 40, 280-293.   DOI
26 Kuilman, T., Michaloglou, C., Mooi, W.J., and Peeper, D.S. (2010). The essence of senescence. Genes Dev. 24, 2463-2479.   DOI
27 Lapierre, L.R., Kumsta, C., Sandri, M., Ballabio, A., and Hansen, M. (2015). Transcriptional and epigenetic regulation of autophagy in aging. Autophagy 11, 867-880.   DOI
28 Levine, B., and Kroemer, G. (2008). Autophagy in the pathogenesis of disease. Cell 132, 27-42.   DOI
29 Liu, H., He, Z., and Simon, H.U. (2014). Autophagy suppresses melanoma tumorigenesis by inducing senescence. Autophagy 10, 372-373.   DOI
30 Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2013). The hallmarks of aging. Cell 153, 1194-1217.   DOI
31 Nam, H.Y., Han, M.W., Chang, H.W., Kim, S.Y., and Kim, S.W. (2013). Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence. Autophagy 9, 1631-1632.   DOI
32 Luo, J., Solimini, N.L., and Elledge, S.J. (2009). Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823-837.   DOI
33 Munoz-Espin, D., and Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nature reviews. Mol. Cell Biol. 15, 482-496.   DOI
34 Nah, J., Yuan, J., and Jung, Y.K. (2015). Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach. Mol. Cells 38, 381-389.   DOI
35 Narita, M., Young, A.R., Arakawa, S., Samarajiwa, S.A., Nakashima, T., Yoshida, S., Hong, S., Berry, L.S., Reichelt, S., Ferreira, M., et al. (2011). Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 332, 966-970.   DOI
36 Nopparat, C., Sinjanakhom, P., and Govitrapong, P. (2017). Melatonin reverses H2 O2 -induced senescence in SH-SY5Y cells by enhancing autophagy via sirtuin 1 deacetylation of the RelA/p65 subunit of NF-kappaB. J. Pineal Res. 63.
37 Passos, J.F., Saretzki, G., Ahmed, S., Nelson, G., Richter, T., Peters, H., Wappler, I., Birket, M.J., Harold, G., Schaeuble, K., et al. (2007). Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol. 5, e110.   DOI
38 Rubinsztein, D.C., Marino, G., and Kroemer, G. (2011). Autophagy and aging. Cell 146, 682-695.   DOI
39 Soto-Gamez, A., and Demaria, M. (2017). Therapeutic interventions for aging: the case of cellular senescence. Drug Dis. Today 22, 786-795.   DOI
40 Shaid, S., Brandts, C.H., Serve, H., and Dikic, I. (2013). Ubiquitination and selective autophagy. Cell Death Differ. 20, 21-30.   DOI
41 Young, A.R., Narita, M., Ferreira, M., Kirschner, K., Sadaie, M., Darot, J.F., Tavare, S., Arakawa, S., Shimizu, S., Watt, F.M., et al. (2009). Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798-803.   DOI
42 Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., and Kirkland, J.L. (2013). Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966-972.   DOI
43 Wen, X., and Klionsky, D.J. (2016). Autophagy is a key factor in maintaining the regenerative capacity of muscle stem cells by promoting quiescence and preventing senescence. Autophagy 12, 617-618.   DOI
44 Wiley, C.D., Velarde, M.C., Lecot, P., Liu, S., Sarnoski, E.A., Freund, A., Shirakawa, K., Lim, H.W., Davis, S.S., Ramanathan, A., et al. (2016). Mitochondrial Dysfunction induces senescence with a distinct secretory phenotype. Cell Metabol. 23, 303-314.   DOI
45 Choi, A.M., Ryter, S.W., and Levine, B. (2013). Autophagy in human health and disease. N. Engl. J. Med. 368, 1845-1846.   DOI
46 Tai, H., Wang, Z., Gong, H., Han, X., Zhou, J., Wang, X., Wei, X., Ding, Y., Huang, N., Qin, J., et al. (2017). Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence. Autophagy 13, 99-113.   DOI
47 Amaravadi, R.K., Yu, D., Lum, J.J., Bui, T., Christophorou, M.A., Evan, G.I., Thomas-Tikhonenko, A., and Thompson, C.B. (2007). Autophagy inhibition enhances therapy-induced apoptosis in a Mycinduced model of lymphoma. J. Clin. Invest. 117, 326-336.   DOI
48 Boya, P., Reggiori, F., and Codogno, P. (2013). Emerging regulation and functions of autophagy. Nat. Cell Biol. 15, 713-720.   DOI
49 Capparelli, C., Chiavarina, B., Whitaker-Menezes, D., Pestell, T.G., Pestell, R.G., Hulit, J., Ando, S., Howell, A., Martinez-Outschoorn, U.E., Sotgia, F., et al. (2012). CDK inhibitors (p16/p19/p21). induce senescence and autophagy in cancer-associated fibroblasts, "fueling" tumor growth via paracrine interactions, without an increase in neoangiogenesis. Cell Cycle 11, 3599-3610.   DOI
50 Childs, B.G., Durik, M., Baker, D.J., and van Deursen, J.M. (2015). Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424-1435.   DOI
51 Coppe, J.P., Desprez, P.Y., Krtolica, A., and Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99-118.   DOI