Browse > Article
http://dx.doi.org/10.14348/molcells.2019.0298

Senolytics and Senostatics: A Two-Pronged Approach to Target Cellular Senescence for Delaying Aging and Age-Related Diseases  

Kang, Chanhee (School of Biological Sciences, Seoul National University)
Publication Information
Molecules and Cells / v.42, no.12, 2019 , pp. 821-827 More about this Journal
Abstract
Aging is the most important single risk factor for many chronic diseases such as cancer, metabolic syndrome, and neurodegenerative disorders. Targeting aging itself might, therefore, be a better strategy than targeting each chronic disease individually for enhancing human health. Although much should be achieved for completely understanding the biological basis of aging, cellular senescence is now believed to mainly contribute to organismal aging via two independent, yet not mutually exclusive mechanisms: on the one hand, senescence of stem cells leads to exhaustion of stem cells and thus decreases tissue regeneration. On the other hand, senescent cells secrete many proinflammatory cytokines, chemokines, growth factors, and proteases, collectively termed as the senescence-associated secretory phenotype (SASP), which causes chronic inflammation and tissue dysfunction. Much effort has been recently made to therapeutically target detrimental effects of cellular senescence including selectively eliminating senescent cells (senolytics) and modulating a proinflammatory senescent secretome (senostatics). Here, we discuss current progress and limitations in understanding molecular mechanisms of senolytics and senostatics and therapeutic strategies for applying them. Furthermore, we propose how these novel interventions for aging treatment could be improved, based on lessons learned from cancer treatment.
Keywords
age-associated inflammation; aging; cellular senescence; senescence-associated secretory phenotype; senolytics; senostatics;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Gorgoulis, V., Adams, P.D., Alimonti, A., Bennett, D.C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019). Cellular senescence: defining a path forward. Cell 179, 813-827.   DOI
2 He, S. and Sharpless, N.E. (2017). Senescence in health and disease. Cell 169, 1000-1011.   DOI
3 Helman, A., Klochendler, A., Azazmeh, N., Gabai, Y., Horwitz, E., Anzi, S., Swisa, A., Condiotti, R., Granit, R.Z., Nevo, Y., et al. (2016). p16(Ink4a)-induced senescence of pancreatic beta cells enhances insulin secretion. Nat. Med. 22, 412-420.   DOI
4 Hernandez-Segura, A., de Jong, T.V., Melov, S., Guryev, V., Campisi, J., and Demaria, M. (2017). Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652-2660.e4.   DOI
5 Hernandez-Segura, A., Nehme, J., and Demaria, M. (2018). Hallmarks of cellular senescence. Trends Cell Biol. 28, 436-453.   DOI
6 Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C.J., Raguz, S., Acosta, J.C., Innes, A.J., Banito, A., et al. (2015). mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat. Cell Biol. 17, 1205-1217.   DOI
7 Hoare, M., Ito, Y., Kang, T.W., Weekes, M.P., Matheson, N.J., Patten, D.A., Shetty, S., Parry, A.J., Menon, S., Salama, R., et al. (2016). NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979-992.   DOI
8 Janzen, V., Forkert, R., Fleming, H.E., Saito, Y., Waring, M.T., Dombkowski, D.M., Cheng, T., DePinho, R.A., Sharpless, N.E., and Scadden, D.T. (2006). Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443, 421-426.   DOI
9 Kang, C. and Elledge, S.J. (2016). How autophagy both activates and inhibits cellular senescence. Autophagy 12, 898-899.   DOI
10 Jeon, O.H., Kim, C., Laberge, R.M., Demaria, M., Rathod, S., Vasserot, A.P., Chung, J.W., Kim, D.H., Poon, Y., David, N., et al. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775-781.   DOI
11 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
12 Krizhanovsky, V., Yon, M., Dickins, R.A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., and Lowe, S.W. (2008). Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657-667.   DOI
13 Kuilman, T., Michaloglou, C., Mooi, W.J., and Peeper, D.S. (2010). The essence of senescence. Genes Dev. 24, 2463-2479.   DOI
14 Kuilman, T., Michaloglou, C., Vredeveld, L.C., Douma, S., van Doorn, R., Desmet, C.J., Aarden, L.A., Mooi, W.J., and Peeper, D.S. (2008). Oncogeneinduced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019-1031.   DOI
15 McHugh, D. and Gil, J. (2018). Senescence and aging: causes, consequences, and therapeutic avenues. J. Cell Biol. 217, 65-77.   DOI
16 Luo, J., Emanuele, M.J., Li, D., Creighton, C.J., Schlabach, M.R., Westbrook, T.F., Wong, K.K., and Elledge, S.J. (2009a). A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene. Cell 137, 835-848.   DOI
17 Luo, J., Solimini, N.L., and Elledge, S.J. (2009b). Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136, 823-837.   DOI
18 Mazzucco, A.E., Smogorzewska, A., Kang, C., Luo, J., Schlabach, M.R., Xu, Q., Patel, R., and Elledge, S.J. (2017). Genetic interrogation of replicative senescence uncovers a dual role for USP28 in coordinating the p53 and GATA4 branches of the senescence program. Genes Dev. 31, 1933-1938.   DOI
19 van Deursen, J.M. (2019). Senolytic therapies for healthy longevity. Science 364, 636-637.   DOI
20 Valentijn, F.A., Falke, L.L., Nguyen, T.Q., and Goldschmeding, R. (2018). Cellular senescence in the aging and diseased kidney. J. Cell Commun. Signal. 12, 69-82.   DOI
21 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 Metab. 23, 303-314.   DOI
22 Xu, M., Pirtskhalava, T., Farr, J.N., Weigand, B.M., Palmer, A.K., Weivoda, M.M., Inman, C.L., Ogrodnik, M.B., Hachfeld, C.M., Fraser, D.G., et al. (2018). Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246-1256.   DOI
23 Yang, H., Wang, H., Ren, J., Chen, Q., and Chen, Z.J. (2017). cGAS is essential for cellular senescence. Proc. Natl. Acad. Sci. U. S. A. 114, E4612-E4620.   DOI
24 Zhu, Y., Doornebal, E.J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., Niedernhofer, L.J., Robbins, P.D., Tchkonia, T., and Kirkland, J.L. (2017). New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY) 9, 955-963.   DOI
25 Zhu, Y., Tchkonia, T., Fuhrmann-Stroissnigg, H., Dai, H.M., Ling, Y.Y., Stout, M.B., Pirtskhalava, T., Giorgadze, N., Johnson, K.O., Giles, C.B., et al. (2016). Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428-435.   DOI
26 Mosteiro, L., Pantoja, C., Alcazar, N., Marion, R.M., Chondronasiou, D., Rovira, M., Fernandez-Marcos, P.J., Munoz-Martin, M., Blanco-Aparicio, C., Pastor, J., et al. (2016). Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 354, aaf4445.   DOI
27 Kwon, Y., Kim, J.W., Jeoung, J.A., Kim, M.S., and Kang, C. (2017). Autophagy is pro-senescence when seen in close-up, but anti-senescence in longshot. Mol. Cells 40, 607-612.   DOI
28 Laberge, R.M., Sun, Y., Orjalo, A.V., Patil, C.K., Freund, A., Zhou, L., Curran, S.C., Davalos, A.R., Wilson-Edell, K.A., Liu, S., et al. (2015). MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17, 1049-1061.   DOI
29 Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., and Kroemer, G. (2013). The hallmarks of aging. Cell 153, 1194-1217.   DOI
30 Molkentin, J.D., Lin, Q., Duncan, S.A., and Olson, E.N. (1997). Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev. 11, 1061-1072.   DOI
31 Munoz-Espin, D. and Serrano, M. (2014). Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482-496.   DOI
32 Niedernhofer, L.J. and Robbins, P.D. (2018). Senotherapeutics for healthy ageing. Nat. Rev. Drug Discov. 17, 377.   DOI
33 Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C.L., Lahat, A., Day, C.P., Burt, A., Palmer, A., Anstee, Q.M., et al. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691.   DOI
34 Baker, D.J., Childs, B.G., Durik, M., Wijers, M.E., Sieben, C.J., Zhong, J., Saltness, R.A., Jeganathan, K.B., Verzosa, G.C., Pezeshki, A., et al. (2016). Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184-189.   DOI
35 Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A.C., Ding, H., Giorgadze, N., Palmer, A.K., Ikeno, Y., Hubbard, G.B., Lenburg, M., et al. (2015). The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644-658.   DOI
36 Acosta, J.C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J.P., Athineos, D., Kang, T.W., Lasitschka, F., Andrulis, M., et al. (2013). A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978-990.   DOI
37 Acosta, J.C., O'Loghlen, A., Banito, A., Guijarro, M.V., Augert, A., Raguz, S., Fumagalli, M., Da Costa, M., Brown, C., Popov, N., et al. (2008). Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006-1018.   DOI
38 Al-Lazikani, B., Banerji, U., and Workman, P. (2012). Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol. 30, 679-692.   DOI
39 Baar, M.P., Brandt, R.M.C., Putavet, D.A., Klein, J.D.D., Derks, K.W.J., Bourgeois, B.R.M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D.A., et al. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132-147.e16.   DOI
40 Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L., and van Deursen, J.M. (2011). Clearance of p16Ink4apositive senescent cells delays ageing-associated disorders. Nature 479, 232-236.   DOI
41 Campisi, J. (2013). Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685-705.   DOI
42 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
43 Campisi, J., Kapahi, P., Lithgow, G.J., Melov, S., Newman, J.C., and Verdin, E. (2019). From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183-192.   DOI
44 Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J.E., Premsrirut, P., Luo, W., Chicas, A., Lee, C.S., et al. (2011). Control of the senescence-associated secretory phenotype by NF-kappaB promotes senescence and enhances chemosensitivity. Genes Dev. 25, 2125-2136.   DOI
45 Childs, B.G., Baker, D.J., Wijshake, T., Conover, C.A., Campisi, J., and van Deursen, J.M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472-477.   DOI
46 Childs, B.G., Gluscevic, M., Baker, D.J., Laberge, R.M., Marquess, D., Dananberg, J., and van Deursen, J.M. (2017). Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718-735.   DOI
47 Coppe, J.P., Patil, C.K., Rodier, F., Sun, Y., Munoz, D.P., Goldstein, J., Nelson, P.S., Desprez, P.Y., and Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853-2868.
48 Salama, R., Sadaie, M., Hoare, M., and Narita, M. (2014). Cellular senescence and its effector programs. Genes Dev. 28, 99-114.   DOI
49 Pietras, E.M., Mirantes-Barbeito, C., Fong, S., Loeffler, D., Kovtonyuk, L.V., Zhang, S., Lakshminarasimhan, R., Chin, C.P., Techner, J.M., Will, B., et al. (2016). Chronic interleukin-1 exposure drives haematopoietic stem cells towards precocious myeloid differentiation at the expense of self-renewal. Nat. Cell Biol. 18, 607-618.   DOI
50 Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M.C., Morton, J.P., Sansom, O.J., Zender, L., and Keyes, W.M. (2017). The senescenceassociated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev. 31, 172-183.   DOI
51 Schafer, M.J., White, T.A., Iijima, K., Haak, A.J., Ligresti, G., Atkinson, E.J., Oberg, A.L., Birch, J., Salmonowicz, H., Zhu, Y., et al. (2017). Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532.   DOI
52 Sharma, P. and Allison, J.P. (2015). Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205-214.   DOI
53 Tasdemir, N., Banito, A., Roe, J.S., Alonso-Curbelo, D., Camiolo, M., Tschaharganeh, D.F., Huang, C.H., Aksoy, O., Bolden, J.E., Chen, C.C., et al. (2016). BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 6, 612-629.   DOI
54 Thompson, P.J., Shah, A., Ntranos, V., Van Gool, F., Atkinson, M., and Bhushan, A. (2019). Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab. 29, 1045-1060.e10.   DOI
55 Dorr, J.R., Yu, Y., Milanovic, M., Beuster, G., Zasada, C., Dabritz, J.H., Lisec, J., Lenze, D., Gerhardt, A., Schleicher, K., et al. (2013). Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421-425.   DOI
56 Tilstra, J.S., Robinson, A.R., Wang, J., Gregg, S.Q., Clauson, C.L., Reay, D.P., Nasto, L.A., St Croix, C.M., Usas, A., Vo, N., et al. (2012). NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. J. Clin. Invest. 122, 2601-2612.   DOI
57 De Cecco, M., Ito, T., Petrashen, A.P., Elias, A.E., Skvir, N.J., Criscione, S.W., Caligiana, A., Brocculi, G., Adney, E.M., Boeke, J.D., et al. (2019). L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73-78.   DOI
58 Demaria, M., O'Leary, M.N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A.M., et al. (2017). Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165-176.   DOI
59 Demaria, M., Ohtani, N., Youssef, S.A., Rodier, F., Toussaint, W., Mitchell, J.R., Laberge, R.M., Vijg, J., Van Steeg, H., Dolle, M.E., et al. (2014). An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722-733.   DOI
60 Doles, J., Storer, M., Cozzuto, L., Roma, G., and Keyes, W.M. (2012). Ageassociated inflammation inhibits epidermal stem cell function. Genes Dev. 26, 2144-2153.   DOI
61 Dou, Z., Ghosh, K., Vizioli, M.G., Zhu, J., Sen, P., Wangensteen, K.J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., et al. (2017). Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402-406.   DOI
62 Freund, A., Patil, C.K., and Campisi, J. (2011). p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536-1548.   DOI
63 Gluck, S., Guey, B., Gulen, M.F., Wolter, K., Kang, T.W., Schmacke, N.A., Bridgeman, A., Rehwinkel, J., Zender, L., and Ablasser, A. (2017). Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061-1070.   DOI