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

Yu Sun, Qingfeng Li, James L. Kirkland

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Life Medicine ›› 2022, Vol. 1 ›› Issue (2) : 103-119. DOI: 10.1093/lifemedi/lnac030
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Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging

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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

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Yu Sun, Qingfeng Li, James L. Kirkland. Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging. Life Medicine, 2022, 1(2): 103‒119 https://doi.org/10.1093/lifemedi/lnac030

References

[1]
Lopez-OtinC, BlascoMA, PartridgeL, et al. The hallmarks of aging. Cell 2013;153:1194–217.
CrossRef Google scholar
[2]
ChanASL, NaritaM. Short-term gain, long-term pain: the senescence life cycle and cancer. Genes Dev 2019;33:127–43.
CrossRef Google scholar
[3]
GorgoulisV, AdamsPD, AlimontiA, et al. Cellular senescence: defining a path forward. Cell 2019;179:813–27.
CrossRef Google scholar
[4]
Munoz-EspinD, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 2014;15:482–96.
CrossRef Google scholar
[5]
Paez-RibesM, Gonzalez-Gualda E, DohertyGJ, et al. Targeting senescent cells in translational medicine. EMBO Mol Med 2019;11:e10234.
CrossRef Google scholar
[6]
van DeursenJM. Senolytic therapies for healthy longevity. Science 2019;364:636–7.
CrossRef Google scholar
[7]
NiccoliT, Partridge L. Ageing as a risk factor for disease. Curr Biol 2012;22:R741–52.
CrossRef Google scholar
[8]
FerrucciL, KuchelGA. Heterogeneity of aging: individual risk factors, mechanisms, patient priorities, and outcomes. J Am Geriatr Soc 2021;69:610–2.
CrossRef Google scholar
[9]
ConineCC, RandoOJ. Soma-to-germline RNA communication. Nat Rev Genet 2022;23:73–88.
CrossRef Google scholar
[10]
SongS, LamEW, TchkoniaT, et al. Senescent cells: emerging targets for human aging and age-related diseases. Trends Biochem Sci 2020;45:578–92.
CrossRef Google scholar
[11]
GasekNS, KuchelGA, KirklandJL, et al. Strategies for targeting senescent cells in human disease. Nat Aging 2021;1:870–9.
CrossRef Google scholar
[12]
HayflickL, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res 1961;25:585–621.
CrossRef Google scholar
[13]
KirklandJL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med 2020;288:518–36.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[16]
Martinez-ZamudioRI, Robinson L, RouxPF, et al. SnapShot: cellular senescence pathways. Cell 2017;170:816.
CrossRef Google scholar
[17]
GiacintiC, Giordano A. RB and cell cycle progression. Oncogene 2006;25:5220–7.
CrossRef Google scholar
[18]
Hernandez-SeguraA, de Jong TV, MelovS, et al. Unmasking transcriptional heterogeneity in senescent cells. Curr Biol 2017;27:2652–60.
CrossRef Google scholar
[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.
CrossRef Google scholar
[20]
CasellaG, MunkR, KimKM, et al. Transcriptome signature of cellular senescence. Nucleic Acids Res 2019;47:11476.
CrossRef Google scholar
[21]
BiranA, ZadaL, Abou KaramP, et al. Quantitative identification of senescent cells in aging and disease. Aging Cell 2017;16:661–71.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[24]
SalmonowiczH, PassosJF. Detecting senescence: a new method for an old pigment. Aging Cell 2017;16:432–4.
CrossRef Google scholar
[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.
CrossRef Google scholar
[26]
ChapmanJ, Fielder E, PassosJF. Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett 2019;593:1566–79.
CrossRef Google scholar
[27]
AndersonR, Lagnado A, MaggioraniD, et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J 2019;38:e100492.
CrossRef Google scholar
[28]
BuenoM, Papazoglou A, ValenziE, et al. Mitochondria, aging, and cellular senescence: implications for scleroderma. Curr Rheumatol Rep 2020;22:37.
CrossRef Google scholar
[29]
WileyCD, Velarde MC, LecotP, et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 2016;23:303–14.
CrossRef Google scholar
[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.
CrossRef Google scholar
[31]
SahinE, CollaS, LiesaM, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011;470:359–65.
CrossRef Google scholar
[32]
BakalovaR, AokiI, ZhelevZ, et al. Cellular redox imbalance on the crossroad between mitochondrial dysfunction, senescence, and proliferation. Redox Biol 2022;53:102337.
CrossRef Google scholar
[33]
BonnerWM, RedonCE, DickeyJS, et al. GammaH2AX and cancer. Nat Rev Cancer 2008;8:957–67.
CrossRef Google scholar
[34]
FreundA, Laberge RM, DemariaM, et al. Lamin B1 loss is a senescence- associated biomarker. Mol Biol Cell 2012;23:2066–75.
CrossRef Google scholar
[35]
AirdKM, ZhangR. Detection of senescence-associated heterochromatin foci (SAHF). Methods Mol Biol 2013;965:185–96.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[38]
De CeccoM, ItoT, PetrashenAP, et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 2019;566:73–8.
CrossRef Google scholar
[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.
CrossRef Google scholar
[40]
AcostaJC, O’Loghlen A, BanitoA, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 2008;133:1006–18.
CrossRef Google scholar
[41]
KuilmanT, Michaloglou C, VredeveldLCW, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 2008;133:1019–31.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[45]
KangC, XuQ, MartinTD, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science 2015;349:aaa5612.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[50]
YangH, WangHZ, RenJY, et al. cGAS is essential for cellular senescence. Proc Natl Acad Sci USA 2017;114:E4612–20.
CrossRef Google scholar
[51]
GluckS, GueyB, GulenMF, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol 2017;19:1061–70.
CrossRef Google scholar
[52]
TasdemirN, BanitoA, RoeJS, et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov 2016;6:612–29.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[58]
ChenF, LongQ, FuD, et al. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat Commun 2018;9:4315.
CrossRef Google scholar
[59]
ZhuY, PrataL, GerdesEOW, et al. Orally-active, clinically-translatable senolytics restore alpha-Klotho in mice and humans. EBioMedicine 2022;77:103912.
CrossRef Google scholar
[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.
CrossRef Google scholar
[61]
KaleA, SharmaA, StolzingA, et al. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing 2020;17:16.
CrossRef Google scholar
[62]
AcostaJC, BanitoA, WuestefeldT, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 2013;15:978–90.
CrossRef Google scholar
[63]
NelsonG, Wordsworth J, WangC, et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 2012;11:345–9.
CrossRef Google scholar
[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.
CrossRef Google scholar
[65]
Desdin-MicoG, Soto-Heredero G, ArandaJF, et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 2020;368:1371–6.
CrossRef Google scholar
[66]
FranceschiC, BonafeM, ValensinS, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000;908:244–54.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[69]
LeeS, YuY, TrimpertJ, et al. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature 2021;599:283–9.
CrossRef Google scholar
[70]
ZhangX, TanY, LingY, et al. Viral and host factors related to the clinical outcome of COVID-19. Nature 2020;583:437–40.
CrossRef Google scholar
[71]
AckermannM, Verleden SE, KuehnelM, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 2020;383:120–8.
CrossRef Google scholar
[72]
MiddletonEA, HeXY, DenormeF, et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020;136:1169–79.
CrossRef Google scholar
[73]
CohenJ, TorresC. Astrocyte senescence: evidence and significance. Aging Cell 2019;18:e12937.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[76]
SierraA, Gottfried-Blackmore AC, McEwenBS, et al. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 2007;55:412–24.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[79]
HeS, Sharpless NE. Senescence in health and disease. Cell 2017;169:1000–11.
CrossRef Google scholar
[80]
SongS, Tchkonia T, JiangJ, et al. Targeting senescent cells for a healthier aging: challenges and opportunities. Adv Sci (Weinh) 2020;7:2002611.
CrossRef Google scholar
[81]
BakerDJ, Wijshake T, TchkoniaT, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011;479:232–6.
CrossRef Google scholar
[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.
CrossRef Google scholar
[83]
PalmerAK, XuM, ZhuY, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 2019;18:e12950.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[89]
HarrisonDE, StrongR, SharpZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392–5.
CrossRef Google scholar
[90]
OubahaM, Miloudi K, DejdaA, et al. Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy. Sci Transl Med 2016;8:362–ra144.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[94]
NacarelliT, LauL, FukumotoT, et al. NAD(+) metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol 2019;21:397–407.
CrossRef Google scholar
[95]
Fuhrmann-StroissniggH, Ling YY, ZhaoJ, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 2017;8:422.
CrossRef Google scholar
[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.
CrossRef Google scholar
[97]
WeichhartT. mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology 2018;64:127–34.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[101]
MacipS, Igarashi M, FangL, et al. Inhibition of p21-mediated ROS accumulation can rescue p21-induced senescence. EMBO J 2002;21:2180–8.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[105]
KangHT, ParkJT, ChoiK, et al. Chemical screening identifies ATM as a target for alleviating senescence. Nat Chem Biol 2017;13:616–23.
CrossRef Google scholar
[106]
LiuS, UppalH, DemariaM, et al. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells. Sci Rep 2015;5:17895.
CrossRef Google scholar
[107]
LabergeRM, ZhouL, SarantosMR, et al. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 2012;11:569–78.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[110]
TianCC, AiXC, MaJC, et al. Etanercept treatment of Stevens- Johnson syndrome and toxic epidermal necrolysis. Ann Allergy Asthma Immunol 2022;129:360–55.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[113]
ZhuY, Tchkonia T, PirtskhalavaT, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015;14:644–58.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[116]
Hernandez-SeguraA, Brandenburg S, DemariaM. Induction and validation of cellular senescence in primary human cells. J Vis Exp 2018;136:57782.
CrossRef Google scholar
[117]
KirklandJL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine 2017;21:21–8.
CrossRef Google scholar
[118]
XuM, Pirtskhalava T, FarrJN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med 2018;24:1246–56.
CrossRef Google scholar
[119]
RobertsAW, DavidsMS, PagelJM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016;374:311–22.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[124]
Munoz-EspinD, RoviraM, GalianaI, et al. A versatile drug delivery system targeting senescent cells. EMBO Mol Med 2018;10:e9355.
CrossRef Google scholar
[125]
GuerreroA, GuihoR, HerranzN, et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell 2020;19:e13133.
CrossRef Google scholar
[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.
CrossRef Google scholar
[127]
GuerreroA, Herranz N, SunB, et al. Cardiac glycosides are broad-spectrum senolytics. Nat Metab 2019;1:1074–88.
CrossRef Google scholar
[128]
XuQ, FuQ, LiZ, et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat Metab 2021;3:1706–26.
CrossRef Google scholar
[129]
XuQ, FuQ, LiZ, et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat Metab 2021;12:1706–26.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[133]
LiW, HeY, ZhangR, et al. The curcumin analog EF24 is a novel senolytic agent. Aging 2019;11:771–82.
CrossRef Google scholar
[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.
CrossRef Google scholar
[135]
LiaoCM, Wulfmeyer VC, ChenR, et al. Induction of ferroptosis selectively eliminates senescent tubular cells. Am J Transplant 2022;22:2158–68.
CrossRef Google scholar
[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.
CrossRef Google scholar
[137]
ZhangX, ZhangS, LiuX, et al. Oxidation resistance 1 is a novel senolytic target. Aging Cell 2018;17:e12780.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[140]
SchaferMJ, WhiteTA, IijimaK, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 2017;8:14532.
CrossRef Google scholar
[141]
RoosCM, ZhangB, PalmerAK, et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 2016;15:973–7.
CrossRef Google scholar
[142]
FarrJN, XuM, WeivodaMM, et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 2017;23:1072–9.
CrossRef Google scholar
[143]
YousefzadehMJ, ZhuY, McGowanSJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. Ebiomedicine 2018;36:18–28.
CrossRef Google scholar
[144]
MaherP. Preventing and treating neurological disorders with the flavonol fisetin. Brain Plast 2021;6:155–66.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[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.
CrossRef Google scholar
[148]
DeVitoLM, Barzilai N, CuervoAM, et al. Extending human healthspan and longevity: a symposium report. Ann N Y Acad Sci 2022;1507:70–83.
CrossRef Google scholar

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