Acknowledgement
This research was supported by "Regional Innovation Strategy (RIS)" through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) (2021RIS-001) and the Ministry of Science and ICT (grants NRF-2020R1A2C1102831 and NRF-2022R1A4A3034038).
References
- Akbar, A. N. (2017) The convergence of senescence and nutrient sensing during lymphocyte ageing. Clin. Exp. Immunol. 187, 4-5. https://doi.org/10.1111/cei.12876
- 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. https://doi.org/10.1038/s41586-020-2403-9
- 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. https://doi.org/10.1016/j.cell.2017.02.031
- 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. https://doi.org/10.1038/nature16932
- 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. https://doi.org/10.1038/nature10600
- Banerjee, K. and Resat, H. (2016) Constitutive activation of STAT3 in breast cancer cells: a review. Int. J. Cancer 138, 2570-2578. https://doi.org/10.1002/ijc.29923
- 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. https://doi.org/10.4062/biomolther.2018.107
- 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. https://doi.org/10.1016/j.cmet.2016.05.011
- 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 https://doi.org/10.1101/gad.343129.120
- Demaria, M. (2020) A senescence-centric view of aging: implications for longevity and disease. Trends Cell Biol. 30, 777-791. https://doi.org/10.1016/j.tcb.2020.07.002
- Burton, D. G. A. and Stolzing, A. (2018) Cellular senescence: immunosurveillance and future immunotherapy. Ageing Res. Rev. 43, 17-25. https://doi.org/10.1016/j.arr.2018.02.001
- Campisi, J. (2013) Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685-705. https://doi.org/10.1146/annurev-physiol-030212-183653
- 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. https://doi.org/10.1038/nm.4010
- 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.
- 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. https://doi.org/10.1021/jf502500t
- 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. https://doi.org/10.1126/science.aaf6659
- 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. https://doi.org/10.1038/nrd.2017.116
- 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. https://doi.org/10.1007/s10637-014-0110-9
- 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. https://doi.org/10.1146/annurev-pathol-121808-102144
- 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. https://doi.org/10.1158/2159-8290.CD-16-0241
- 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. https://doi.org/10.4049/jimmunol.1100978
- 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. https://doi.org/10.1038/nrd3800
- 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. https://doi.org/10.1016/j.ijbiomac.2020.06.115
- 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. https://doi.org/10.1038/cdd.2013.101
- Ferrucci, L. and Fabbri, E. (2018) Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505-522. https://doi.org/10.1038/s41569-018-0064-2
- 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. https://doi.org/10.1074/jbc.M901758200
- 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. https://doi.org/10.1038/s41467-017-00314-z
- 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. https://doi.org/10.1080/15384101.2018.1475828
- 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. https://doi.org/10.1093/cvr/cvab208
- 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. https://doi.org/10.1016/j.cell.2019.10.005
- 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. https://doi.org/10.1080/10428194.2016.1195501
- He, S. and Sharpless, N. E. (2017) Senescence in health and disease. Cell 169, 1000-1011. https://doi.org/10.1016/j.cell.2017.05.015
- 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. https://doi.org/10.1172/JCI75051
- Hernandez-Segura, A., Nehme, J. and Demaria, M. (2018) Hallmarks of cellular senescence. Trends Cell Biol. 28, 436-453. https://doi.org/10.1016/j.tcb.2018.02.001
- 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. https://doi.org/10.4062/biomolther.2020.208
- 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. https://doi.org/10.1016/S0002-9440(10)64164-8
- 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. https://doi.org/10.1038/nm.4324
- 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. https://doi.org/10.1038/nchembio.2342
- 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. https://doi.org/10.1016/j.cell.2014.10.039
- Khan, N., Syed, D. N., Ahmad, N. and Mukhtar, H. (2013) Fisetin: a dietary antioxidant for health promotion. Antioxid. Redox Signal. 19, 151-162. https://doi.org/10.1089/ars.2012.4901
- 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. https://doi.org/10.1101/gad.302570.117
- Kirkland, J. L. and Tchkonia, T. (2017) Cellular senescence: a translational perspective. EBioMedicine 21, 21-28. https://doi.org/10.1016/j.ebiom.2017.04.013
- Krimpenfort, P. and Berns, A. (2017) Rejuvenation by therapeutic elimination of senescent cells. Cell 169, 3-5. https://doi.org/10.1016/j.cell.2017.03.014
- 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. https://doi.org/10.1016/j.cell.2008.03.039
- Kulkarni, A. S., Gubbi, S. and Barzilai, N. (2020) Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 32, 15-30. https://doi.org/10.1016/j.cmet.2020.04.001
- 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. https://doi.org/10.1016/j.freeradbiomed.2021.05.003
- 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. https://doi.org/10.1111/acel.12931
- 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. https://doi.org/10.1016/j.ccr.2012.11.013
- 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
- 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. https://doi.org/10.1186/s13287-020-02128-1
- 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. https://doi.org/10.3390/ijms22073367
- 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. https://doi.org/10.1186/s13287-022-02901-4
- 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. https://doi.org/10.1111/acel.12075
- 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. https://doi.org/10.1152/ajpheart.00835.2009
- Munoz-Espin, D. and Serrano, M. (2014) Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482-496. https://doi.org/10.1038/nrm3823
- 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. https://doi.org/10.1038/onc.2009.318
- 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. https://doi.org/10.1111/acel.13296
- 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. https://doi.org/10.1038/ncomms15691
- 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. https://doi.org/10.1073/pnas.0905299106
- O'Sullivan Coyne, G. and Burotto, M. (2017) MABp1 for the treatment of colorectal cancer. Expert Opin. Biol. Ther. 17, 1155-1161. https://doi.org/10.1080/14712598.2017.1347631
- 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.
- 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. https://doi.org/10.1038/s41467-018-07825-3
- 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. https://doi.org/10.1111/php.12337
- 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. https://doi.org/10.1158/1078-0432.CCR-11-3090
- Salminen, A. (2021) Immunosuppressive network promotes immunosenescence associated with aging and chronic inflammatory conditions. J. Mol. Med. (Berl.) 99, 1553-1569. https://doi.org/10.1007/s00109-021-02123-w
- 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. https://doi.org/10.1016/j.cellsig.2011.12.006
- 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. https://doi.org/10.1038/s41598-017-01964-1
- Sanchez-Rangel, E. and Inzucchi, S. E. (2017) Metformin: clinical use in type 2 diabetes. Diabetologia 60, 1586-1593. https://doi.org/10.1007/s00125-017-4336-x
- 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. https://doi.org/10.3389/fcell.2020.00354
- 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.
- Sundarraj, K., Raghunath, A. and Perumal, E. (2018) A review on the chemotherapeutic potential of fisetin: In vitro evidences. Biomed. Pharmacother. 97, 928-940. https://doi.org/10.1016/j.biopha.2017.10.164
- 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. https://doi.org/10.1038/nrm2918
- 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. https://doi.org/10.1172/JCI45785
- 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. https://doi.org/10.1016/j.jdiacomp.2015.05.019
- 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. https://doi.org/10.1016/j.celrep.2014.08.044
- Trendowski, M. (2015) PU-H71: an improvement on nature's solutions to oncogenic Hsp90 addiction. Pharmacol. Res. 99, 202-216. https://doi.org/10.1016/j.phrs.2015.06.007
- van Deursen, J. M. (2014) The role of senescent cells in ageing. Nature 509, 439-446. https://doi.org/10.1038/nature13193
- van Deursen, J. M. (2019) Senolytic therapies for healthy longevity. Science 364, 636-637. https://doi.org/10.1126/science.aaw1299
- 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. https://doi.org/10.1111/acel.12455
- 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. https://doi.org/10.18632/aging.101100
- Waugh, D. J. and Wilson, C. (2008) The interleukin-8 pathway in cancer. Clin. Cancer Res. 14, 6735-6741. https://doi.org/10.1158/1078-0432.CCR-07-4843
- 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. https://doi.org/10.1038/s41598-018-20000-4
- 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. https://doi.org/10.1111/febs.15264
- 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.
- 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. https://doi.org/10.7554/eLife.12997
- 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.
- 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.
- 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. https://doi.org/10.1038/ncomms11190
- 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. https://doi.org/10.1016/j.ebiom.2018.09.015
- 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. https://doi.org/10.1038/nrc2734
- 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. https://doi.org/10.4062/biomolther.2017.071
- 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. https://doi.org/10.18632/aging.102682
- 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. https://doi.org/10.1111/acel.12780
- 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. https://doi.org/10.18632/aging.101202
- 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. https://doi.org/10.1111/acel.12445
- 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.