Browse > Article
http://dx.doi.org/10.4062/biomolther.2022.114

Senotherapeutics and Their Molecular Mechanism for Improving Aging  

Park, Jooho (Department of Applied Life Science, Graduate School, BK21 Program, Konkuk University)
Shin, Dong Wook (College of Biomedical and Health Science, Konkuk University)
Publication Information
Biomolecules & Therapeutics / v.30, no.6, 2022 , pp. 490-500 More about this Journal
Abstract
Aging is defined as physiological dysfunction of the body and a key risk factor for human diseases. During the aging process, cellular senescence occurs in response to various extrinsic and intrinsic factors such as radiation-induced DNA damage, the activation of oncogenes, and oxidative stress. These senescent cells accumulate in many tissues and exhibit diverse phenotypes, such as resistance to apoptosis, production of senescence-associated secretory phenotype, cellular flattening, and cellular hypertrophy. They also induce abnormal dysfunction of the microenvironment and damage neighboring cells, eventually causing harmful effects in the development of various chronic diseases such as diabetes, cancer, and neurodegenerative diseases. Thus, pharmacological interventions targeting senescent cells, called senotherapeutics, have been extensively studied. These senotherapeutics provide a novel strategy for extending the health span and improving age-related diseases. In this review, we discuss the current progress in understanding the molecular mechanisms of senotherapeutics and provide insights for developing senotherapeutics.
Keywords
Senotherapeutics; Senescence; Aging; Molecular mechanism;
Citations & Related Records
Times Cited By KSCI : 4  (Citation Analysis)
연도 인용수 순위
1 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
2 Cleary, J. M., Lima, C. M., Hurwitz, H. I., Montero, A. J., Franklin, C., Yang, J., Graham, A., Busman, T., Mabry, M., Holen, K., Shapiro, G. I. and Uronis, H. (2014) A phase I clinical trial of navitoclax, a targeted high-affinity Bcl-2 family inhibitor, in combination with gemcitabine in patients with solid tumors. Invest. New Drugs 32, 937-945.   DOI
3 Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A. M., Alston, S., Academia, E. C., Kilmarx, S., Valdovinos, A., Wang, B., de Bruin, A., Kennedy, B. K., Melov, S., Zhou, D., Sharpless, N. E., Muss, H. and Campisi, J. (2017) Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165-176.   DOI
4 Yun, S. P., Han, Y. S., Lee, J. H., Kim, S. M. and Lee, S. H. (2018) Melatonin rescues mesenchymal stem cells from senescence induced by the uremic toxin p-cresol via inhibiting mTOR-dependent autophagy. Biomol. Ther. (Seoul) 26, 389-398.   DOI
5 Zhang, C., Xie, Y., Chen, H., Lv, L., Yao, J., Zhang, M., Xia, K., Feng, X., Li, Y., Liang, X., Sun, X., Deng, C. and Liu, G. (2020) FOXO4- DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging 12, 1272-1284.   DOI
6 Vicente, R., Mausset-Bonnefont, A. L., Jorgensen, C., Louis-Plence, P. and Brondello, J. M. (2016) Cellular senescence impact on immune cell fate and function. Aging Cell 15, 400-406.   DOI
7 Di Mitri, D., Azevedo, R. I., Henson, S. M., Libri, V., Riddell, N. E., Macaulay, R., Kipling, D., Soares, M. V., Battistini, L. and Akbar, A. N. (2011) Reversible senescence in human CD4+CD45RA+CD27-memory T cells. J. Immunol. 187, 2093-2100.   DOI
8 Dutta Gupta, S. and Pan, C. H. (2020) Recent update on discovery and development of Hsp90 inhibitors as senolytic agents. Int. J. Biol. Macromol. 161, 1086-1098.   DOI
9 Fausti, F., Di Agostino, S., Cioce, M., Bielli, P., Sette, C., Pandolfi, P. P., Oren, M., Sudol, M., Strano, S. and Blandino, G. (2013) ATM kinase enables the functional axis of YAP, PML and p53 to ameliorate loss of Werner protein-mediated oncogenic senescence. Cell Death Differ. 20, 1498-1509.   DOI
10 van Deursen, J. M. (2014) The role of senescent cells in ageing. Nature 509, 439-446.   DOI
11 Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., Zhou, D. and Zheng, G. (2016) Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging 8, 2915-2926.   DOI
12 Kim, K. M., Noh, J. H., Bodogai, M., Martindale, J. L., Yang, X., Indig, F. E., Basu, S. K., Ohnuma, K., Morimoto, C., Johnson, P. F., Biragyn, A., Abdelmohsen, K. and Gorospe, M. (2017) Identification of senescent cell surface targetable protein DPP4. Genes Dev. 31, 1529-1534.   DOI
13 Hoang, N. M. H., Kim, S., Nguyen, H. D., Kim, M., Kim, J., Kim, B. C., Park, D., Lee, S., Yu, B. P., Chung, H. Y. and Kim, M. S. (2021) Age-dependent sensitivity to the neurotoxic environmental metabolite, 1,2-diacetylbenzene. Biomol. Ther. (Seoul) 29, 399-409.   DOI
14 Huang, S., Mills, L., Mian, B., Tellez, C., McCarty, M., Yang, X. D., Gudas, J. M. and Bar-Eli, M. (2002) Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am. J. Pathol. 161, 125-134.   DOI
15 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
16 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) Oncogene-induced senescence relayed by an interleukindependent inflammatory network. Cell 133, 1019-1031.   DOI
17 Waugh, D. J. and Wilson, C. (2008) The interleukin-8 pathway in cancer. Clin. Cancer Res. 14, 6735-6741.   DOI
18 Fu, W., Ma, Q., Chen, L., Li, P., Zhang, M., Ramamoorthy, S., Nawaz, Z., Shimojima, T., Wang, H., Yang, Y., Shen, Z., Zhang, Y., Zhang, X., Nicosia, S. V., Zhang, Y., Pledger, J. W., Chen, J. and Bai, W. (2009) MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J. Biol. Chem. 284, 13987-14000.   DOI
19 Fuhrmann-Stroissnigg, H., Ling, Y. Y., Zhao, J., McGowan, S. J., Zhu, Y., Brooks, R. W., Grassi, D., Gregg, S. Q., Stripay, J. L., Dorronsoro, A., Corbo, L., Tang, P., Bukata, C., Ring, N., Giacca, M., Li, X., Tchkonia, T., Kirkland, J. L., Niedernhofer, L. J. and Robbins, P. D. (2017) Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422.   DOI
20 Garrido, A. M., Kaistha, A., Uryga, A. K., Oc, S., Foote, K., Shah, A., Finigan, A., Figg, N., Dobnikar, L., Jorgensen, H. and Bennett, M. (2022) Efficacy and limitations of senolysis in atherosclerosis. Cardiovasc. Res. 118, 1713-1727.   DOI
21 Wiley, C. D., Schaum, N., Alimirah, F., Lopez-Dominguez, J. A., Orjalo, A. V., Scott, G., Desprez, P. Y., Benz, C., Davalos, A. R. and Campisi, J. (2018) Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. Sci. Rep. 8, 2410.   DOI
22 Wissler Gerdes, E. O., Zhu, Y., Tchkonia, T. and Kirkland, J. L. (2020) Discovery, development, and future application of senolytics: theories and predictions. FEBS J. 287, 2418-2427.   DOI
23 Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., Curran, G. L., Ogrodnik, M., Jurk, D., Johnson, K. O., Lowe, V., Tchkonia, T., Westendorf, J. J. and Kirkland, J. L. (2017) Transplanted senescent cells induce an osteoarthritis-like condition in mice. J. Gerontol. A Biol. Sci. Med. Sci. 72, 780-785.
24 Mato-Basalo, R., Morente-Lopez, M., Arntz, O. J., van de Loo, F. A. J., Fafian-Labora, J. and Arufe, M. C. (2021) Therapeutic potential for regulation of the nuclear factor kappa-B transcription factor p65 to prevent cellular senescence and activation of pro-inflammatory in mesenchymal stem cells. Int. J. Mol. Sci. 22, 3367.   DOI
25 Lewis-McDougall, F. C., Ruchaya, P. J., Domenjo-Vila, E., Shin Teoh, T., Prata, L., Cottle, B. J., Clark, J. E., Punjabi, P. P., Awad, W., Torella, D., Tchkonia, T., Kirkland, J. L. and Ellison-Hughes, G. M. (2019) Aged-senescent cells contribute to impaired heart regeneration. Aging Cell 18, e12931.   DOI
26 Liang, J., Nagahashi, M., Kim, E. Y., Harikumar, K. B., Yamada, A., Huang, W. C., Hait, N. C., Allegood, J. C., Price, M. M., Avni, D., Takabe, K., Kordula, T., Milstien, S. and Spiegel, S. (2013) Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell 23, 107-120.   DOI
27 Marofi, F., Motavalli, R., Safonov, V. A., Thangavelu, L., Yumashev, A. V., Alexander, M., Shomali, N., Chartrand, M. S., Pathak, Y., Jarahian, M., Izadi, S., Hassanzadeh, A., Shirafkan, N., Tahmasebi, S. and Khiavi, F. M. (2021) CAR T cells in solid tumors: challenges and opportunities. Stem Cell Res. Ther. 12, 81.   DOI
28 Moiseeva, O., Deschenes-Simard, X., St-Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N. and Ferbeyre, G. (2013) Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 12, 489-498.   DOI
29 Mun, G. I. and Boo, Y. C. (2010) Identification of CD44 as a senescence-induced cell adhesion gene responsible for the enhanced monocyte recruitment to senescent endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 298, H2102- H2111.   DOI
30 Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., Gil, J., Hara, E., Krizhanovsky, V., Jurk, D., Maier, A. B., Narita, M., Niedernhofer, L., Passos, J. F., Robbins, P. D., Schmitt, C. A., Sedivy, J., Vougas, K., von Zglinicki, T., Zhou, D., Serrano, M. and Demaria, M. (2019) Cellular senescence: defining a path forward. Cell 179, 813-827.   DOI
31 He, S. and Sharpless, N. E. (2017) Senescence in health and disease. Cell 169, 1000-1011.   DOI
32 Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., Puleston, D. J., Watson, A. S., Simon, A. K., Tooze, S. A. and Akbar, A. N. (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8(+) T cells. J. Clin. Invest. 124, 4004-4016.   DOI
33 Samaraweera, L., Adomako, A., Rodriguez-Gabin, A. and McDaid, H. M. (2017) A novel indication for panobinostat as a senolytic drug in NSCLC and HNSCC. Sci. Rep. 7, 1900.   DOI
34 Dinarello, C. A., Simon, A. and van der Meer, J. W. (2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 11, 633-652.   DOI
35 Xu, M., Palmer, A. K., Ding, H., Weivoda, M. M., Pirtskhalava, T., White, T. A., Sepe, A., Johnson, K. O., Stout, M. B., Giorgadze, N., Jensen, M. D., LeBrasseur, N. K., Tchkonia, T. and Kirkland, J. L. (2015a) Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4, e12997.   DOI
36 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., Onken, J. L., Johnson, K. O., Verzosa, G. C., Langhi, L. G. P., Weigl, M., Giorgadze, N., LeBrasseur, N. K., Miller, J. D., Jurk, D., Singh, R. J., Allison, D. B., Ejima, K., Hubbard, G. B., Ikeno, Y., Cubro, H., Garovic, V. D., Hou, X., Weroha, S. J., Robbins, P. D., Niedernhofer, L. J., Khosla, S., Tchkonia, T. and Kirkland, J. L. (2018) Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246-1256.
37 Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White, T. A., Johnson, K. O., Stout, M. B., Mezera, V., Giorgadze, N., Jensen, M. D., LeBrasseur, N. K. and Kirkland, J. L. (2015b) JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl. Acad. Sci. U. S. A. 112, E6301-E6310.
38 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
39 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
40 Ferrucci, L. and Fabbri, E. (2018) Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505-522.   DOI
41 Fuhrmann-Stroissnigg, H., Niedernhofer, L. J. and Robbins, P. D. (2018) Hsp90 inhibitors as senolytic drugs to extend healthy aging. Cell Cycle 17, 1048-1055.   DOI
42 Harrison, C. N., Talpaz, M. and Mead, A. J. (2016) Ruxolitinib is effective in patients with intermediate-1 risk myelofibrosis: a summary of recent evidence. Leuk. Lymphoma 57, 2259-2267.   DOI
43 Yu, H., Pardoll, D. and Jove, R. (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat. Rev. Cancer 9, 798-809.   DOI
44 Novakova, Z., Hubackova, S., Kosar, M., Janderova-Rossmeislova, L., Dobrovolna, J., Vasicova, P., Vancurova, M., Horejsi, Z., Hozak, P., Bartek, J. and Hodny, Z. (2010) Cytokine expression and signaling in drug-induced cellular senescence. Oncogene 29, 273-284.   DOI
45 Ogrodnik, M., Evans, S. A., Fielder, E., Victorelli, S., Kruger, P., Salmonowicz, H., Weigand, B. M., Patel, A. D., Pirtskhalava, T., Inman, C. L., Johnson, K. O., Dickinson, S. L., Rocha, A., Schafer, M. J., Zhu, Y., Allison, D. B., von Zglinicki, T., LeBrasseur, N. K., Tchkonia, T., Neretti, N., Passos, J. F., Kirkland, J. L. and Jurk, D. (2021) Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296.   DOI
46 Shaw, S., Bourne, T., Meier, C., Carrington, B., Gelinas, R., Henry, A., Popplewell, A., Adams, R., Baker, T., Rapecki, S., Marshall, D., Moore, A., Neale, H. and Lawson, A. (2014) Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs 6, 774-782.
47 Taipale, M., Jarosz, D. F. and Lindquist, S. (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nat. Rev. Mol. Cell Biol. 11, 515-528.   DOI
48 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., Huard, J., Clemens, P. R., Stolz, D. B., Guttridge, D. C., Watkins, S. C., Garinis, G. A., Wang, Y., Niedernhofer, L. J. and Robbins, P. D. (2012) NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. J. Clin. Invest. 122, 2601-2612.   DOI
49 Yosef, R., Pilpel, N., Tokarsky-Amiel, R., Biran, A., Ovadya, Y., Cohen, S., Vadai, E., Dassa, L., Shahar, E., Condiotti, R., Ben-Porath, I. and Krizhanovsky, V. (2016) Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190.   DOI
50 Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., FuhrmannStroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., McGuckian, C., Wade, E. A., Kato, J. I., Grassi, D., Wentworth, M., Burd, C. E., Arriaga, E. A., Ladiges, W. L., Tchkonia, T., Kirkland, J. L., Robbins, P. D. and Niedernhofer, L. J. (2018) Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18-28.   DOI
51 Kirkland, J. L. and Tchkonia, T. (2017) Cellular senescence: a translational perspective. EBioMedicine 21, 21-28.   DOI
52 Orjalo, A. V., Bhaumik, D., Gengler, B. K., Scott, G. K. and Campisi, J. (2009) Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc. Natl. Acad. Sci. U. S. A. 106, 17031-17036.   DOI
53 O'Sullivan Coyne, G. and Burotto, M. (2017) MABp1 for the treatment of colorectal cancer. Expert Opin. Biol. Ther. 17, 1155-1161.   DOI
54 Timper, K., Seelig, E., Tsakiris, D. A. and Donath, M. Y. (2015) Safety, pharmacokinetics, and preliminary efficacy of a specific anti-IL-1alpha therapeutic antibody (MABp1) in patients with type 2 diabetes mellitus. J. Diabetes Complications 29, 955-960.   DOI
55 Toso, A., Revandkar, A., Di Mitri, D., Guccini, I., Proietti, M., Sarti, M., Pinton, S., Zhang, J., Kalathur, M., Civenni, G., Jarrossay, D., Montani, E., Marini, C., Garcia-Escudero, R., Scanziani, E., Grassi, F., Pandolfi, P. P., Catapano, C. V. and Alimonti, A. (2014) Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep. 9, 75-89.   DOI
56 Akbar, A. N. (2017) The convergence of senescence and nutrient sensing during lymphocyte ageing. Clin. Exp. Immunol. 187, 4-5.   DOI
57 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., Khazaie, K., Miller, J. D. and van Deursen, J. M. (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184-189.   DOI
58 Bang, M., Ryu, O., Kim, D. G., Mabunga, D. F., Cho, K. S., Kim, Y., Han, S. H., Kwon, K. J. and Shin, C. Y. (2019) Tenovin-1 induces senescence and decreases wound-healing activity in cultured rat primary astrocytes. Biomol. Ther. (Seoul) 27, 283-289.   DOI
59 Demaria, M. (2020) A senescence-centric view of aging: implications for longevity and disease. Trends Cell Biol. 30, 777-791.   DOI
60 Burton, D. G. A. and Stolzing, A. (2018) Cellular senescence: immunosurveillance and future immunotherapy. Ageing Res. Rev. 43, 17-25.   DOI
61 Krimpenfort, P. and Berns, A. (2017) Rejuvenation by therapeutic elimination of senescent cells. Cell 169, 3-5.   DOI
62 Kulkarni, A. S., Gubbi, S. and Barzilai, N. (2020) Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 32, 15-30.   DOI
63 Lagoumtzi, S. M. and Chondrogianni, N. (2021) Senolytics and senomorphics: natural and synthetic therapeutics in the treatment of aging and chronic diseases. Free Radic. Biol. Med. 171, 169-190.   DOI
64 Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. and Kroemer, G. (2013) The hallmarks of aging. Cell 153, 1194-1217.   DOI
65 Khan, N., Syed, D. N., Ahmad, N. and Mukhtar, H. (2013) Fisetin: a dietary antioxidant for health promotion. Antioxid. Redox Signal. 19, 151-162.   DOI
66 Hernandez-Segura, A., Nehme, J. and Demaria, M. (2018) Hallmarks of cellular senescence. Trends Cell Biol. 28, 436-453.   DOI
67 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., Baker, D. J., van Deursen, J. M., Campisi, J. and Elisseeff, J. H. (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
68 Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., Franceschi, C., Lithgow, G. J., Morimoto, R. I., Pessin, J. E., Rando, T. A., Richardson, A., Schadt, E. E., Wyss-Coray, T. and Sierra, F. (2014) Geroscience: linking aging to chronic disease. Cell 159, 709-713.   DOI
69 Ovadya, Y., Landsberger, T., Leins, H., Vadai, E., Gal, H., Biran, A., Yosef, R., Sagiv, A., Agrawal, A., Shapira, A., Windheim, J., Tsoory, M., Schirmbeck, R., Amit, I., Geiger, H. and Krizhanovsky, V. (2018) Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat. Commun. 9, 5435.   DOI
70 Oubaha, M., Miloudi, K., Dejda, A., Guber, V., Mawambo, G., Germain, M. A., Bourdel, G., Popovic, N., Rezende, F. A., Kaufman, R. J., Mallette, F. A. and Sapieha, P. (2016) Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci. Transl. Med. 8, 362ra144.
71 Pal, H. C., Athar, M., Elmets, C. A. and Afaq, F. (2015) Fisetin inhibits UVB-induced cutaneous inflammation and activation of PI3K/ AKT/NFkappaB signaling pathways in SKH-1 hairless mice. Photochem. Photobiol. 91, 225-234.   DOI
72 Salminen, A. (2021) Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions. J. Mol. Med. (Berl.) 99, 1553-1569.   DOI
73 Campisi, J. (2013) Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685-705.   DOI
74 Miura, Y., Endo, K., Komori, K. and Sekiya, I. (2022) Clearance of senescent cells with ABT-263 improves biological functions of synovial mesenchymal stem cells from osteoarthritis patients. Stem Cell Res. Ther. 13, 222.   DOI
75 Munoz-Espin, D. and Serrano, M. (2014) Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482-496.   DOI
76 Rudin, C. M., Hann, C. L., Garon, E. B., Ribeiro de Oliveira, M., Bonomi, P. D., Camidge, D. R., Chu, Q., Giaccone, G., Khaira, D., Ramalingam, S. S., Ranson, M. R., Dive, C., McKeegan, E. M., Chyla, B. J., Dowell, B. L., Chakravartty, A., Nolan, C. E., Rudersdorf, N., Busman, T. A., Mabry, M. H., Krivoshik, A. P., Humerickhouse, R. A., Shapiro, G. I. and Gandhi, L. (2012) Phase II study of singleagent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin. Cancer Res. 18, 3163-3169.   DOI
77 Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., Day, C. P., Burt, A., Palmer, A., Anstee, Q. M., Grellscheid, S. N., Hoeijmakers, J. H. J., Barnhoorn, S., Mann, D. A., Bird, T. G., Vermeij, W. P., Kirkland, J. L., Passos, J. F., von Zglinicki, T. and Jurk, D. (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691.   DOI
78 Salminen, A., Kauppinen, A. and Kaarniranta, K. (2012) Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell. Signal. 24, 835-845.   DOI
79 Sanchez-Rangel, E. and Inzucchi, S. E. (2017) Metformin: clinical use in type 2 diabetes. Diabetologia 60, 1586-1593.   DOI
80 Sharma, A. K., Roberts, R. L., Benson, R. D., Jr., Pierce, J. L., Yu, K., Hamrick, M. W. and McGee-Lawrence, M. E. (2020) The senolytic drug navitoclax (ABT-263) causes trabecular bone loss and impaired osteoprogenitor function in aged mice. Front. Cell Dev. Biol. 8, 354.   DOI
81 Sundarraj, K., Raghunath, A. and Perumal, E. (2018) A review on the chemotherapeutic potential of fisetin: In vitro evidences. Biomed. Pharmacother. 97, 928-940.   DOI
82 Trendowski, M. (2015) PU-H71: an improvement on nature's solutions to oncogenic Hsp90 addiction. Pharmacol. Res. 99, 202-216.   DOI
83 van Deursen, J. M. (2019) Senolytic therapies for healthy longevity. Science 364, 636-637.   DOI
84 Banerjee, K. and Resat, H. (2016) Constitutive activation of STAT3 in breast cancer cells: a review. Int. J. Cancer 138, 2570-2578.   DOI
85 Zhang, X., Zhang, S., Liu, X., Wang, Y., Chang, J., Zhang, X., Mackintosh, S. G., Tackett, A. J., He, Y., Lv, D., Laberge, R. M., Campisi, J., Wang, J., Zheng, G. and Zhou, D. (2018) Oxidation resistance 1 is a novel senolytic target. Aging Cell 17, e12780.   DOI
86 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 9, 955-963.   DOI
87 Amor, C., Feucht, J., Leibold, J., Ho, Y. J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., Kulick, A., Houlihan, S., Peerschke, E., Friedman, S. L., Ponomarev, V., Piersigilli, A., Sadelain, M. and Lowe, S. W. (2020) Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127-132.   DOI
88 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., van der Pluijm, I., Essers, J., van Cappellen, W. A., van IJcken, W. F., Houtsmuller, A. B., Pothof, J., de Bruin, R. W. F., Madl, T., Hoeijmakers, J. H. J., Campisi, J. and de Keizer, P. L. J. (2017) Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132-147. e16.   DOI
89 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 p16Ink4a-positive senescent cells delays ageingassociated disorders. Nature 479, 232-236.   DOI
90 Chang, J., Wang, Y., Shao, L., Laberge, R. M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., Luo, Y., Wang, X., Aykin-Burns, N., Krager, K., Ponnappan, U., HauerJensen, M., Meng, A. and Zhou, D. (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78-83.   DOI
91 Chen, M., Fu, Y., Wang, X., Wu, R., Su, D., Zhou, N. and Qi, Y. (2022) Metformin protects lens epithelial cells against senescence in a naturally aged mouse model. Cell Death Discov. 8, 8.
92 Chiang, H. M., Chan, S. Y., Chu, Y. and Wen, K. C. (2015) Fisetin ameliorated photodamage by suppressing the mitogen-activated protein Kinase/Matrix metalloproteinase pathway and nuclear factor-kappaB pathways. J. Agric. Food Chem. 63, 4551-4560.   DOI
93 Birch, J. and Gil, J. (2020) Senescence and the SASP: many therapeutic avenues. Genes Dev. 34, 1565-1576. Borghesan, M., Hoogaars, W. M. H., Varela-Eirin, M., Talma, N. and   DOI
94 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., Wren, J. D., Niedernhofer, L. J., Robbins, P. D. and Kirkland, J. L. (2016) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428-435.   DOI
95 Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., O'Hara, S. P., LaRusso, N. F., Miller, J. D., Roos, C. M., Verzosa, G. C., LeBrasseur, N. K., Wren, J. D., Farr, J. N., Khosla, S., Stout, M. B., McGowan, S. J., Fuhrmann-Stroissnigg, H., Gurkar, A. U., Zhao, J., Colangelo, D., Dorronsoro, A., Ling, Y. Y., Barghouthy, A. S., Navarro, D. C., Sano, T., Robbins, P. D., Niedernhofer, L. J. and Kirkland, J. L. (2015) The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644-658.
96 Barzilai, N., Crandall, J. P., Kritchevsky, S. B. and Espeland, M. A. (2016) Metformin as a tool to target aging. Cell Metab. 23, 1060-1065.   DOI