Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging

Abstract

Aging is a natural but relentless process of physiological decline, leading to physical frailty, reduced ability to respond to physical stresses (resilience) and, ultimately, organismal death. Cellular senescence, a self-defensive mechanism activated in response to intrinsic stimuli and/or exogenous stress, is one of the central hallmarks of aging. Senescent cells cease to proliferate, while remaining metabolically active and secreting numerous extracellular factors, a feature known as the senescence-associated secretory phenotype. Senescence is physiologically important for embryonic development, tissue repair, and wound healing, and prevents carcinogenesis. However, chronic accumulation of persisting senescent cells contributes to a host of pathologies including age-related morbidities. By paracrine and endocrine mechanisms, senescent cells can induce inflammation locally and systemically, thereby causing tissue dysfunction, and organ degeneration. Agents including those targeting damaging components of the senescence-associated secretory phenotype or inducing apoptosis of senescent cells exhibit remarkable benefits in both preclinical models and early clinical trials for geriatric conditions. Here we summarize features of senescent cells and outline strategies holding the potential to be developed as clinical interventions. In the long run, there is an increasing demand for safe, effective, and clinically translatable senotherapeutics to address healthcare needs in current settings of global aging.

Keywords

aging / senescent cell / senescence-associated secretory phenotype / senotherapeutics / clinical trial

References

[1] Lopez-OtinC, BlascoMA, PartridgeL, et al. The hallmarks of aging. Cell 2013;153:1194–217.

[2] ChanASL, NaritaM. Short-term gain, long-term pain: the senescence life cycle and cancer. Genes Dev 2019;33:127–43.

[3] GorgoulisV, AdamsPD, AlimontiA, et al. Cellular senescence: defining a path forward. Cell 2019;179:813–27.

[4] Munoz-EspinD, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 2014;15:482–96.

[5] Paez-RibesM, Gonzalez-Gualda E, DohertyGJ, et al. Targeting senescent cells in translational medicine. EMBO Mol Med 2019;11:e10234.

[6] van DeursenJM. Senolytic therapies for healthy longevity. Science 2019;364:636–7.

[7] NiccoliT, Partridge L. Ageing as a risk factor for disease. Curr Biol 2012;22:R741–52.

[8] FerrucciL, KuchelGA. Heterogeneity of aging: individual risk factors, mechanisms, patient priorities, and outcomes. J Am Geriatr Soc 2021;69:610–2.

[9] ConineCC, RandoOJ. Soma-to-germline RNA communication. Nat Rev Genet 2022;23:73–88.

[10] SongS, LamEW, TchkoniaT, et al. Senescent cells: emerging targets for human aging and age-related diseases. Trends Biochem Sci 2020;45:578–92.

[11] GasekNS, KuchelGA, KirklandJL, et al. Strategies for targeting senescent cells in human disease. Nat Aging 2021;1:870–9.

[12] HayflickL, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585–621.

[13] KirklandJL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med 2020;288:518–36.

[14] TchkoniaT, PalmerAK, KirklandJL. New horizons: novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J Clin Endocrinol Metab 2021;106:e1481–7.

[15] Wissler GerdesEO, Misra A, NettoJME, et al. Strategies for late phase preclinical and early clinical trials of senolytics. Mech Ageing Dev 2021;200:111591.

[16] Martinez-ZamudioRI, Robinson L, RouxPF, et al. SnapShot: cellular senescence pathways. Cell 2017;170:816.

[17] GiacintiC, Giordano A. RB and cell cycle progression. Oncogene 2006;25:5220–7.

[18] Hernandez-SeguraA, de Jong TV, MelovS, et al. Unmasking transcriptional heterogeneity in senescent cells. Curr Biol 2017;27:2652–60.

[19] TripathiU, MisraA, TchkoniaT, et al. Impact of senescent cell subtypes on tissue dysfunction and repair: importance and research questions. Mech Ageing Dev 2021;198:111548.

[20] CasellaG, MunkR, KimKM, et al. Transcriptome signature of cellular senescence. Nucleic Acids Res 2019;47:11476.

[21] BiranA, ZadaL, Abou KaramP, et al. Quantitative identification of senescent cells in aging and disease. Aging Cell 2017;16:661–71.

[22] Debacq-ChainiauxF, Erusalimsky JD, CampisiJ, et al. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 2009;4:1798–806.

[23] DimriGP, LeeXH, BasileG, et al. A biomarker that identifies senescent human-cells in culture and in aging skin in-vivo. Proc Natl Acad Sci USA 1995;92:9363–7.

[24] SalmonowiczH, PassosJF. Detecting senescence: a new method for an old pigment. Aging Cell 2017;16:432–4.

[25] SummerR, Shaghaghi H, SchrinerD, et al. Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium. Am J Physiol Lung Cell Mol Physiol 2019;316:L1049–60.

[26] ChapmanJ, Fielder E, PassosJF. Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett 2019;593:1566–79.

[27] AndersonR, Lagnado A, MaggioraniD, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J 2019;38:e100492.

[28] BuenoM, Papazoglou A, ValenziE, et al. Mitochondria, aging, and cellular senescence: implications for scleroderma. Curr Rheumatol Rep 2020;22:37.

[29] WileyCD, Velarde MC, LecotP, et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 2016;23:303–14.

[30] Correia-MeloC, Marques FD, AndersonR, et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J 2016;35:724–42.

[31] SahinE, CollaS, LiesaM, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011;470:359–65.

[32] BakalovaR, AokiI, ZhelevZ, et al. Cellular redox imbalance on the crossroad between mitochondrial dysfunction, senescence, and proliferation. Redox Biol 2022;53:102337.

[33] BonnerWM, RedonCE, DickeyJS, et al. GammaH2AX and cancer. Nat Rev Cancer 2008;8:957–67.

[34] FreundA, Laberge RM, DemariaM, et al. Lamin B1 loss is a senescence- associated biomarker. Mol Biol Cell 2012;23:2066–75.

[35] AirdKM, ZhangR. Detection of senescence-associated heterochromatin foci (SAHF). Methods Mol Biol 2013;965:185–96.

[36] ZhangBY, FuD, XuQX, et al. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat Commun 2018;9:1723.

[37] WangW, ZhengY, SunS, et al. A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence. Sci Transl Med 2021;13:eabd2655.

[38] De CeccoM, ItoT, PetrashenAP, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 2019;566:73–8.

[39] CoppeJP, PatilCK, RodierF, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008;6:2853–68.

[40] AcostaJC, O’Loghlen A, BanitoA, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 2008;133:1006–18.

[41] KuilmanT, Michaloglou C, VredeveldLCW, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008;133:1019–31.

[42] BorghesanM, Fafian-Labora J, EleftheriadouO, et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3. Cell Rep 2019;27:3956–71.

[43] HanL, LongQL, LiSJ, et al. Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles. Cancer Res 2020;80:3383–98.

[44] IskeJ, SeydaM, HeinbokelT, et al. Senolytics prevent mt-DNA-induced inflammation and promote the survival of aged organs following transplantation. Nat Commun 2020;11:4289.

[45] KangC, XuQ, MartinTD, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 2015;349:aaa5612.

[46] SalminenA, Kauppinen A, KaarnirantaK. Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal 2012;24:835–45.

[47] HugginsCJ, MalikR, LeeS, et al. C/EBPgamma suppresses senescence and inflammatory gene expression by heterodimerizing with C/EBPbeta. Mol Cell Biol 2013;33:3242–58.

[48] XuM, Tchkonia T, DingH, et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci USA 2015;112:E6301–10.

[49] FreundA, PatilCK, CampisiJ. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J 2011;30:1536–48.

[50] YangH, WangHZ, RenJY, et al. cGAS is essential for cellular senescence. Proc Natl Acad Sci USA 2017;114:E4612–20.

[51] GluckS, GueyB, GulenMF, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol 2017;19:1061–70.

[52] TasdemirN, BanitoA, RoeJS, et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov 2016;6:612–29.

[53] CamellCD, Yousefzadeh MJ, ZhuY, et al. Senolytics reduce coronavirus- related mortality in old mice. Science 2021;373:eabe4832.

[54] TripathiU, Nchioua R, PrataL, et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 2021;13:21838–54.

[55] CoppeJP, PatilCK, RodierF, et al. A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS One 2010;5:e9188.

[56] ErenM, BoeAE, MurphySB, et al. PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. Proc Natl Acad Sci USA 2014;111:7090–5.

[57] OzcanS, Alessio N, AcarMB, et al. Unbiased analysis of senescence associated secretory phenotype (SASP) to identify common components following different genotoxic stresses. Aging 2016;8:1316–29.

[58] ChenF, LongQ, FuD, et al. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat Commun 2018;9:4315.

[59] ZhuY, PrataL, GerdesEOW, et al. Orally-active, clinically-translatable senolytics restore alpha-Klotho in mice and humans. EBioMedicine 2022;77:103912.

[60] FranceschiC, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014;69:S4–9.

[61] KaleA, SharmaA, StolzingA, et al. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing 2020;17:16.

[62] AcostaJC, BanitoA, WuestefeldT, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 2013;15:978–90.

[63] NelsonG, Wordsworth J, WangC, et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 2012;11:345–9.

[64] PereiraBI, DevineOP, Vukmanovic-StejicM, et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8(+) T cell inhibition. Nat Commun 2019;10:2387.

[65] Desdin-MicoG, Soto-Heredero G, ArandaJF, et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 2020;368:1371–6.

[66] FranceschiC, BonafeM, ValensinS, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244–54.

[67] LiberaleL, Montecucco F, TardifJC, et al. Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease. Eur Heart J 2020;41:2974–82.

[68] MehdizadehM, Aguilar M, ThorinE, et al. The role of cellular senescence in cardiac disease: basic biology and clinical relevance. Nat Rev Cardiol 2022;19:250–64.

[69] LeeS, YuY, TrimpertJ, et al. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature 2021;599:283–9.

[70] ZhangX, TanY, LingY, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature 2020;583:437–40.

[71] AckermannM, Verleden SE, KuehnelM, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;383:120–8.

[72] MiddletonEA, HeXY, DenormeF, et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020;136:1169–79.

[73] CohenJ, TorresC. Astrocyte senescence: evidence and significance. Aging Cell 2019;18:e12937.

[74] DaiX, HongL, ShenH, et al. Estradiol-induced senescence of hypothalamic astrocytes contributes to aging-related reproductive function declines in female mice. Aging 2020;12:6089–108.

[75] CaoD, LiXH, LuoXG, et al. Phorbol myristate acetate induces cellular senescence in rat microglia in vitro. Int J Mol Med 2020;46:415–26.

[76] SierraA, Gottfried-Blackmore AC, McEwenBS, et al. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 2007;55:412–24.

[77] OgrodnikM, EvansSA, FielderE, et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 2021;20:e13296.

[78] Fernandez-RebolloE, Franzen J, GoetzkeR, et al. Senescenceassociated metabolomic phenotype in primary and iPSC-derived mesenchymal stromal cells. Stem Cell Rep 2020;14:201–9.

[79] HeS, Sharpless NE. Senescence in health and disease. Cell 2017;169:1000–11.

[80] SongS, Tchkonia T, JiangJ, et al. Targeting senescent cells for a healthier aging: challenges and opportunities. Adv Sci (Weinh) 2020;7:2002611.

[81] BakerDJ, Wijshake T, TchkoniaT, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011;479:232–6.

[82] JeonOH, KimC, LabergeRM, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 2017;23:775–81.

[83] PalmerAK, XuM, ZhuY, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 2019;18:e12950.

[84] WangL, WangB, GasekNS, et al. Targeting p21(Cip1) highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab 2022;34:75–89.

[85] Di MiccoR, Krizhanovsky V, BakerD, et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 2021;22:75–95.

[86] HerranzN, Gallage S, MelloneM, et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol 2015;17:1205–17.

[87] LabergeRM, SunY, OrjaloAV, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 2015;17:1049–61.

[88] ThapaRK, NguyenHT, JeongJH, et al. Progressive slowdown/prevention of cellular senescence by CD9-targeted delivery of rapamycin using lactose-wrapped calcium carbonate nanoparticles. Sci Rep 2017;7:43299.

[89] HarrisonDE, StrongR, SharpZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392–5.

[90] OubahaM, Miloudi K, DejdaA, et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med 2016;8:362–ra144.

[91] MoiseevaO, Deschenes-Simard X, St-GermainE, et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell 2013;12:489–98.

[92] LimH, ParkH, KimHP. Effects of flavonoids on senescence-associated secretory phenotype formation from bleomycin-induced senescence in BJ fibroblasts. Biochem Pharmacol 2015;96:337–48.

[93] HariP, MillarFR, TarratsN, et al. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci Adv 2019;5:eaaw0254.

[94] NacarelliT, LauL, FukumotoT, et al. NAD(+) metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol 2019;21:397–407.

[95] Fuhrmann-StroissniggH, Ling YY, ZhaoJ, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 2017;8:422.

[96] HarrisonDE, StrongR, AllisonDB, et al. Acarbose, 17-alpha-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 2014;13:273–82.

[97] WeichhartT. mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology 2018;64:127–34.

[98] CavinatoM, Madreiter-Sokolowski CT, ButtnerS, et al. Targeting cellular senescence based on interorganelle communication, multilevel proteostasis, and metabolic control. FEBS J 2021;288:3834–54.

[99] ParkJH, LeeNK, LimHJ, et al. Pharmacological inhibition of mTOR attenuates replicative cell senescence and improves cellular function via regulating the STAT3-PIM1 axis in human cardiac progenitor cells. Exp Mol Med 2020;52:615–28.

[100] Noren HootenN, Martin-Montalvo A, DluzenDF, et al. Metforminmediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell 2016;15:572–81.

[101] MacipS, Igarashi M, FangL, et al. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J 2002;21:2180–8.

[102] Il’yasovaD, Fontana L, BhapkarM, et al. Effects of 2 years of caloric restriction on oxidative status assessed by urinary F2-isoprostanes: the CALERIE 2 randomized clinical trial. Aging Cell 2018;17:e12719.

[103] YangL, Licastro D, CavaE, et al. Long-term calorie restriction enhances cellular quality-control processes in human skeletal muscle. Cell Rep 2016;14:422–8.

[104] NelsonG, Kucheryavenko O, WordsworthJ, et al. The senescent bystander effect is caused by ROS-activated NF-kappaB signalling. Mech Ageing Dev 2018;170:30–6.

[105] KangHT, ParkJT, ChoiK, et al. Chemical screening identifies ATM as a target for alleviating senescence. Nat Chem Biol 2017;13:616–23.

[106] LiuS, UppalH, DemariaM, et al. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells. Sci Rep 2015;5:17895.

[107] LabergeRM, ZhouL, SarantosMR, et al. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 2012;11:569–78.

[108] NiklanderSE, CraneHL, DardaL, et al. The role of icIL-1RA in keratinocyte senescence and development of the senescence-associated secretory phenotype. J Cell Sci 2021;134:jcs252080.

[109] YuanB, Clowers MJ, VelascoWV, et al. Targeting IL-1beta as an immune preventive and therapeutic modality for K-ras mutant lung cancer. JCI Insight 2022;7:e157788.

[110] TianCC, AiXC, MaJC, et al. Etanercept treatment of Stevens- Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol 2022;129:360–55.

[111] LangE, SandeB, BrodkinS, et al. . Idiopathic multicentric Castleman disease treated with siltuximab for 15 years: a case report. Ther Adv Hematol 2022;13:20406207221082552.

[112] Moreno-TorresV, Sanchez-Chica E, CastejonR, et al. Red blood cell distribution width as a marker of hyperinflammation and mortality in COVID-19. Ann Palliat Med 2022;apm-22–119.

[113] ZhuY, Tchkonia T, PirtskhalavaT, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015;14:644–58.

[114] ZhuY, Doornebal EJ, PirtskhalavaT, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging 2017;9:955–63.

[115] PeiF, PeiH, SuC, et al. Fisetin alleviates neointimal hyperplasia via PPARgamma/PON2 antioxidative pathway in SHR rat artery injury model. Oxid Med Cell Longev 2021;2021:6625517.

[116] Hernandez-SeguraA, Brandenburg S, DemariaM. Induction and validation of cellular senescence in primary human cells. J Vis Exp 2018;136:57782.

[117] KirklandJL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine 2017;21:21–8.

[118] XuM, Pirtskhalava T, FarrJN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 2018;24:1246–56.

[119] RobertsAW, DavidsMS, PagelJM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:311–22.

[120] de VosS, Leonard JP, FriedbergJW, et al. Safety and efficacy of navitoclax, a BCL-2 and BCL-XL inhibitor, in patients with relapsed or refractory lymphoid malignancies: results from a phase 2a study. Leuk Lymphoma 2021;62:810–8.

[121] WilsonWH, O’Connor OA, CzuczmanMS, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol 2010;11:1149–59.

[122] BaarMP, BrandtRMC, PutavetDA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017;169:132–47.

[123] HeY, LiW, LvD, et al. Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity. Aging Cell 2020;19:e13117.

[124] Munoz-EspinD, RoviraM, GalianaI, et al. A versatile drug delivery system targeting senescent cells. EMBO Mol Med 2018;10:e9355.

[125] GuerreroA, GuihoR, HerranzN, et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell 2020;19:e13133.

[126] Gonzalez-GualdaE, Paez-Ribes M, Lozano-TorresB, et al. Galactoconjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 2020;19:e13142.

[127] GuerreroA, Herranz N, SunB, et al. Cardiac glycosides are broad-spectrum senolytics. Nat Metab 2019;1:1074–88.

[128] XuQ, FuQ, LiZ, et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat Metab 2021;3:1706–26.

[129] XuQ, FuQ, LiZ, et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat Metab 2021;12:1706–26.

[130] ChangJ, WangY, ShaoL, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 2016;22:78–83.

[131] YosefR, PilpelN, Tokarsky-AmielR, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun 2016;7:11190.

[132] Triana-MartinezF, Picallos-Rabina P, Da Silva-AlvarezS, et al. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat Commun 2019;10:4731.

[133] LiW, HeY, ZhangR, et al. The curcumin analog EF24 is a novel senolytic agent. Aging 2019;11:771–82.

[134] OzsvariB, Nuttall JR, SotgiaF, et al. Azithromycin and Roxithromycin define a new family of „senolytic” drugs that target senescent human fibroblasts. Aging 2018;10:3294–307.

[135] LiaoCM, Wulfmeyer VC, ChenR, et al. Induction of ferroptosis selectively eliminates senescent tubular cells. Am J Transplant 2022;22:2158–68.

[136] HanSY, KoA, KitanoH, et al. Molecular chaperone HSP90 Is necessary to prevent cellular senescence via lysosomal degradation of p14ARF. Cancer Res 2017;77:343–54.

[137] ZhangX, ZhangS, LiuX, et al. Oxidation resistance 1 is a novel senolytic target. Aging Cell 2018;17:e12780.

[138] CaiY, ZhouH, ZhuY, et al. Elimination of senescent cells by beta-galactosidase- targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell Res 2020;1:16.

[139] ZhuY, Tchkonia T, Fuhrmann-StroissniggH, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 2016;15:428–35.

[140] SchaferMJ, WhiteTA, IijimaK, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 2017;8:14532.

[141] RoosCM, ZhangB, PalmerAK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 2016;15:973–7.

[142] FarrJN, XuM, WeivodaMM, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 2017;23:1072–9.

[143] YousefzadehMJ, ZhuY, McGowanSJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. Ebiomedicine 2018;36:18–28.

[144] MaherP. Preventing and treating neurological disorders with the flavonol fisetin. Brain Plast 2021;6:155–66.

[145] JusticeJN, Nambiar AM, TchkoniaT, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 2019;40:554–63.

[146] HicksonLJ, Langhi Prata LGP, BobartSA, et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 2019;47:446–56.

[147] GonzalesMM, Garbarino VR, Marques ZilliE, et al. Senolytic therapy to modulate the progression of Alzheimer’s disease (SToMP-AD): a pilot clinical trial. J Prev Alzheimers Dis 2022;9:22–9.

[148] DeVitoLM, Barzilai N, CuervoAM, et al. Extending human healthspan and longevity: a symposium report. Ann N Y Acad Sci 2022;1507:70–83.

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