Academic Journal
Cellular senescence and inflammageing: from mechanisms to senotherapeutic interventions.
| Τίτλος: | Cellular senescence and inflammageing: from mechanisms to senotherapeutic interventions. |
|---|---|
| Συγγραφείς: | Chmielewski PP; Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 6a Chałubińskiego Street, 50-368, Wrocław, Poland. piotr.chmielewski@umw.edu.pl. |
| Πηγή: | Biogerontology [Biogerontology] 2026 Jul 23; Vol. 27 (4). Date of Electronic Publication: 2026 Jul 23. |
| Τύπος έκδοσης: | Journal Article; Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Kluwer Academic Country of Publication: Netherlands NLM ID: 100930043 Publication Model: Electronic Cited Medium: Internet ISSN: 1573-6768 (Electronic) Linking ISSN: 13895729 NLM ISO Abbreviation: Biogerontology Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Dordrecht ; Boston : Kluwer Academic, c2000- |
| Ιατρικοί όροι (MeSH): | Cellular Senescence*/drug effects , Cellular Senescence*/physiology , Senotherapeutics*/therapeutic use , Senotherapeutics*/pharmacology , Inflammation*/pathology , Inflammation*/drug therapy , Aging*/pathology, Humans ; Animals ; Senescence-Associated Secretory Phenotype |
| Περίληψη: | Cellular senescence is a context-dependent cellular state characterised by persistent cell-cycle arrest, epigenetic remodelling, metabolic reprogramming and acquisition of a senescence-associated secretory phenotype. Transient senescence contributes to embryogenesis, tissue repair and tumour suppression, whereas persistent senescent cell populations accumulate with advancing age across multiple tissues, in part owing to declining immune-mediated clearance and intrinsic resistance to apoptosis, thereby promoting chronic systemic inflammation, tissue fibrosis, stem-cell dysfunction and propagation of secondary senescence. Experimental genetic and pharmacological evidence supports a contributory and in several contexts causal role for senescent cells in cardiovascular, metabolic, musculoskeletal, fibrotic and neurodegenerative disorders. These findings have accelerated the development of senotherapeutic strategies, including senolytics, senomorphics and immune-mediated clearance approaches, with early clinical studies showing preliminary evidence of functional benefit in idiopathic pulmonary fibrosis and diabetic kidney disease. However, clinical translation remains constrained by senescence heterogeneity, limited biomarker specificity and unresolved long-term safety concerns. Improved molecular, spatial and functional resolution of senescent states will be essential for developing biomarker-guided and tissue-specific interventions that preserve the beneficial functions of transient senescence while limiting its chronic deleterious effects. (© 2026. The Author(s).) |
| Competing Interests: | Declarations. Conflict of interest: The authors declare no competing interests. |
| References: | Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J (2013) A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990. (PMID: 10.1038/ncb2784237706763732483) Adewoye AB, Tampakis D, Follenzi A, Stolzing A (2020) Multiparameter flow cytometric detection and quantification of senescent cells in vitro. Biogerontology 21:773–786. (PMID: 10.1007/s10522-020-09893-9327762627541365) Aguayo-Mazzucato C, Andle J, Lee TB Jr, Midha A, Talemal L, Chipashvili V, Hollister-Lock J, van Deursen J, Weir G, Bonner-Weir S (2019) Acceleration of β cell aging determines diabetes and senolysis improves disease outcomes. Cell Metab 30:129-142.e4. (PMID: 31155496661072010.1016/j.cmet.2019.05.006) Aird KM, Iwasaki O, Kossenkov AV, Tanizawa H, Fatkhutdinov N, Bitler BG, Le L, Alicea G, Yang TL, Johnson FB, Noma KI, Zhang R (2016) HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci. J Cell Biol 215:325–334. (PMID: 27799366510029610.1083/jcb.201608026) Ajoolabady A, Pratico D, Bahijri S, Tuomilehto J, Uversky VN, Ren J (2025) Hallmarks of cellular senescence: biology, mechanisms, regulations. Exp Mol Med 57:1482–1491. (PMID: 10.1038/s12276-025-01480-74063475312322015) Algire C, Moiseeva O, Deschenes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 5:536–543. (PMID: 10.1158/1940-6207.CAPR-11-0536) Ali I, Zhang H, Zaidi SAA, Zhou G (2024) Understanding the intricacies of cellular senescence in atherosclerosis: mechanisms and therapeutic implications. Ageing Res Rev 96:102273. (PMID: 3849281010.1016/j.arr.2024.102273) Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, Mansilla-Soto J, Boyer JA, Li X, Giavridis T, Kulick A, Houlihan S, Peerschke E, Friedman SL, Ponomarev V, Piersigilli A, Sadelain M, Lowe SW (2020) Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583:127–132. (PMID: 10.1038/s41586-020-2403-9325554597583560) Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Tyndyk ML, Yurova MV, Kovalenko IG, Poroshina TE, Semenchenko AV (2008) Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 7:2769–2773. (PMID: 1872838610.4161/cc.7.17.6625) Baker DJ, Perez-Terzic C, Jin F, Pitel KS, Niederlander NJ, Jeganathan K, Yamada S, Reyes S, Rowe L, Hiddinga HJ, Eberhardt NL, Terzic A, van Deursen JM (2008) Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol 10:825–836. (PMID: 10.1038/ncb1744185160912594014) Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. (PMID: 10.1038/nature10600220483123468323) Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–189. (PMID: 10.1038/nature16932268404894845101) Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou LV, Kolettas E, Niforou K, Zoumpourlis VC, Takaoka M, Nakagawa H, Tort F, Fugger K, Johansson F, Sehested M, Andersen CL, Dyrskjot L, Ørntoft T, Lukas J, Kittas C, Helleday T, Halazonetis TD, Bartek J, Gorgoulis VG (2006) Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444:633–637. (PMID: 10.1038/nature0526817136093) Basisty N, Kale A, Jeon OH, Kuehnemann C, Payne T, Rao C, Holtz A, Shah S, Sharma V, Ferrucci L, Campisi J, Schilling B (2020) A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol 18:e3000599. (PMID: 31945054696482110.1371/journal.pbio.3000599) Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, Johnson FB, Trojanowski JQ, Sell C, Torres C (2012) Astrocyte senescence as a component of Alzheimer’s disease. PLoS ONE 7:e45069. (PMID: 22984612344041710.1371/journal.pone.0045069) Birch J, Anderson RK, Correia-Melo C, Jurk D, Hewitt G, Marques FM, Green NJ, Moisey E, Birrell MA, Belvisi MG, Black F, Taylor JJ, Fisher AJ, De Soyza A, Passos JF (2015) DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol 309:L1124–L1137. (PMID: 26386121465215510.1152/ajplung.00293.2015) Borghesan M, Hoogaars WMH, Varela-Eirin M, Talma N, Demaria M (2020) A senescence-centric view of aging: implications for longevity and disease. Trends Cell Biol 30:777–791. (PMID: 3280065910.1016/j.tcb.2020.07.002) Burton DGA, Faragher RGA (2018) Obesity and type-2 diabetes as inducers of premature cellular senescence and ageing. Biogerontology 19:447–459. (PMID: 10.1007/s10522-018-9763-7300547616223730) Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562:578–582. (PMID: 10.1038/s41586-018-0543-y302324516206507) Chae JB, Jang H, Son C, Park CW, Choi H, Jin S, Lee HY, Lee H, Ryu JH, Kim N, Kim C, Chung H (2021) Targeting senescent retinal pigment epithelial cells facilitates retinal regeneration in mouse models of age-related macular degeneration. GeroScience 43:2809–2833. (PMID: 10.1007/s11357-021-00457-4346017068602547) Chang J, Wang Y, Shao L, Laberge RM, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W, Luo Y, Wang X, Aykin-Burns N, Krager K, Ponnappan U, Hauer-Jensen M, Meng A, Zhou D (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22:78–83. (PMID: 10.1038/nm.401026657143) Chen X, Luo Y, Zhu Q, Zhang J, Huang H, Kan Y, Li D, Xu M, Liu S, Li J, Pan J, Zhang L, Guo Y, Wang B, Qi G, Zhou Z, Zhang CY, Fang L, Wang Y, Chen X (2024) Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism. Nat Aging 4:814–838. (PMID: 10.1038/s43587-024-00612-43862752411186790) Childs BG, Durik M, Baker DJ, van Deursen JM (2015) Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 21:1424–1435. (PMID: 10.1038/nm.4000266464994748967) Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM (2016) Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354:472–477. (PMID: 27789842511258510.1126/science.aaf6659) Chinta SJ, Lieu CA, Demaria M, Laberge RM, Campisi J, Andersen JK (2013) Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson’s disease? J Intern Med 273:429–436. (PMID: 23600398363308510.1111/joim.12029) Chinta SJ, Woods G, Demaria M, Rane A, Zou Y, McQuade A, Rajagopalan S, Limbad C, Madden DT, Campisi J, Andersen JK (2018) Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep 22:930–940. (PMID: 29386135580653410.1016/j.celrep.2017.12.092) Chmielewski P (2017) Rethinking modern theories of ageing and their classification: the proximate mechanisms and the ultimate explanations. Anthropol Rev 80:259–272. (PMID: 10.1515/anre-2017-0021) Chmielewski PP (2026) Ageing was never a singular problem in biology: implications for mechanisms, measurements and interventions. Biogerontology 27:87. (PMID: 10.1007/s10522-026-10436-x42008063) Chmielewski PP, Data K, Strzelec B, Farzaneh M, Anbiyaiee A, Zaheer U, Uddin S, Sheykhi-Sabzehpoush M, Mozdziak P, Zabel M, Dzięgiel P, Kempisty B (2025) Human aging and age-related diseases: from underlying mechanisms to pro-longevity interventions. Aging Dis 16:1853–1877. (PMID: 10.14336/AD.2024.0280) Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40:179–204. (PMID: 20965415298887710.1016/j.molcel.2010.09.019) Coppé JP, Desprez PY, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118. (PMID: 20078217416649510.1146/annurev-pathol-121808-102144) Demaria M, Ohtani N, Youssef SA, Rodier F, Toussaint W, Mitchell JR, Laberge RM, Vijg J, Van Steeg H, Dollé ME, Hoeijmakers JH, de Bruin A, Hara E, Campisi J (2014) An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 31:722–733. (PMID: 25499914434962910.1016/j.devcel.2014.11.012) Dhokia V, Albati A, Smith H, Thomas G, Macip S (2024) A second generation of senotherapies: the development of targeted senolytics, senoblockers and senoreversers for healthy ageing. Biochem Soc Trans 52:1661–1671. (PMID: 3894074610.1042/BST20231066) Di Micco R, Krizhanovsky V, Baker D, d’Adda di Fagagna F (2021) Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol 22:75–95. (PMID: 10.1038/s41580-020-00314-w33328614) Estévez-Souto V, Da Silva-Álvarez S, Collado M (2023) The role of extracellular vesicles in cellular senescence. FEBS J 290:1203–1211. (PMID: 3590446610.1111/febs.16585) Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl):S4–S9. (PMID: 2483358610.1093/gerona/glu057) Freund A, Laberge RM, Demaria M, Campisi J (2012) Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 23:2066–2075. (PMID: 22496421336417210.1091/mbc.e11-10-0884) Furman D, Campisi J, Verdin E, Carrera-Bastos P, Targ S, Franceschi C, Ferrucci L, Gilroy DW, Fasano A, Miller GW,Miller AH, Mantovani A, Weyand CM, Barzilai N, Goronzy JJ, Rando TA, Eff ros RB, Lucia A, Kleinstreuer N, Slavich GM (2019) Chronic infl ammation in the etiology of disease across the life span. Nat Med 25:1822–1832. Garrido AM, Kaistha A, Uryga AK, Oc S, Foote K, Shah A, Finigan A, Figg N, Dobnikar L, Jørgensen H, Bennett M (2022) Efficacy and limitations of senolysis in atherosclerosis. Cardiovasc Res 118:1713–1727. (PMID: 34142149921519710.1093/cvr/cvab208) González-Gualda E, Pàez-Ribes M, Lozano-Torres B, Macias D, Wilson JR 3rd, González-López C, Ou HL, Mirón-Barroso S, Zhang Z, Lérida-Viso A, Blandez JF, Bernardos A, Sancenón F, Rovira M, Fruk L, Martins CP, Serrano M, Doherty GJ, Martínez-Máñez R, Muñoz-Espín D (2020) Galacto-conjugation of Navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 19:e13142. (PMID: 32233024718999310.1111/acel.13142) Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, Campisi J, Collado M, Evangelou K, Ferbeyre G, Gil J, Hara E, Krizhanovsky V, Jurk D, Maier AB, Narita M, Niedernhofer L, Passos JF, Robbins PD, Schmitt CA, Sedivy J, Vougas K, von Zglinicki T, Zhou D, Serrano M, Demaria M (2019) Cellular senescence: defining a path forward. Cell 179:813–827. (PMID: 3167549510.1016/j.cell.2019.10.005) Gray DA, Woulfe J (2005) Lipofuscin and aging: a matter of toxic waste. Sci Aging Knowl Environ 2005(5):re1. (PMID: 10.1126/sageke.2005.5.re1) Grigorian Shamagian L, Rogers RG, Luther K, Angert D, Echavez A, Liu W, Middleton R, Antes T, Valle J, Fourier M, Sanchez L, Jaghatspanyan E, Mariscal J, Zhang R, Marbán E (2023) Rejuvenating effects of young extracellular vesicles in aged rats and in cellular models of human senescence. Sci Rep 13:12240. (PMID: 10.1038/s41598-023-39370-53750744810382547) Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460:392–395. (PMID: 10.1038/nature08221195876802786175) Hayflick L (1965) The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37:614–636. (PMID: 1431508510.1016/0014-4827(65)90211-9) Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621. (PMID: 1390565810.1016/0014-4827(61)90192-6) He S, Sharpless NE (2017) Senescence in health and disease. Cell 169:1000–1011. (PMID: 28575665564302910.1016/j.cell.2017.05.015) Hernandez-Segura A, Nehme J, Demaria M (2018) Hallmarks of cellular senescence. Trends Cell Biol 28:436–453. (PMID: 2947761310.1016/j.tcb.2018.02.001) Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, Raguz S, Acosta JC, Innes AJ, Banito A, Georgilis A, Montoya A, Wolter K, Dharmalingam G, Faull P, Carroll T, Martínez-Barbera JP, Cutillas P, Reisinger F, Heikenwalder M, Miller RA, Withers D, Zender L, Thomas GJ, Gil J (2015) mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol 17:1205–1217. (PMID: 10.1038/ncb3225262805354589897) Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL et al (2019) Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine 47:446–456. (PMID: 31542391679653010.1016/j.ebiom.2019.08.069) Hou J, Chen KX, He C, Li XX, Huang M, Jiang YZ, Jiao YR, Xiao QN, He WZ, Liu L, Zou NY, Huang M, Wei J, Xiao Y, Yang M, Luo XH, Zeng C, Lei GH, Li CJ (2024) Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence. Nat Aging 4:1562–1581. (PMID: 10.1038/s43587-024-00694-03926676811564114) Hu Q, Peng J, Jiang L, Li W, Su Q, Zhang J, Li H, Song M, Cheng B, Xia J, Wu T (2020) Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma. Cell Death Dis 11:925. (PMID: 10.1038/s41419-020-03126-0331161177595194) Hu C, Zhang X, Teng T, Ma ZG, Tang QZ (2022) Cellular senescence in cardiovascular diseases: a systematic review. Aging Dis 13:103–128. (PMID: 35111365878255410.14336/AD.2021.0927) Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461:1071–1078. (PMID: 10.1038/nature08467198472582906700) Jeon OH, Kim C, Laberge RM, Demaria M, Rathod S, Vasserot AP, Chung JW, Kim DH, Poon Y, David N, Baker DJ, van Deursen JM, Campisi J, Elisseeff JH (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775–781. (PMID: 10.1038/nm.4324284369585785239) Jung T, Bader N, Grune T (2007) Lipofuscin: formation, distribution, and metabolic consequences. Ann N Y Acad Sci 1119:97–111. (PMID: 1805695910.1196/annals.1404.008) Kirkland JL, Tchkonia T (2020) Senolytic drugs: from discovery to translation. J Intern Med 288:518–536. (PMID: 32686219740539510.1111/joim.13141) Kowald A, Passos JF, Kirkwood TBL (2020) On the evolution of cellular senescence. Aging Cell 19:e13270. (PMID: 33166065774496010.1111/acel.13270) Krabbe KS, Pedersen M, Bruunsgaard H (2004) Inflammatory mediators in the elderly. Exp Gerontol 39:687–699. (PMID: 1513066310.1016/j.exger.2004.01.009) Kumar M, Yan P, Kuchel GA, Xu M (2024) Cellular senescence as a targetable risk factor for cardiovascular diseases: therapeutic implications: JACC family series. JACC Basic Transl Sci 9:522–534. (PMID: 386809571105520710.1016/j.jacbts.2023.12.003) Kuźniar J, Kozubek P, Czaja M, Sitka H, Kochman U, Leszek J (2025) Connections between cellular senescence and Alzheimer’s disease-a narrative review. Int J Mol Sci 26:8638. (PMID: 409435591242956810.3390/ijms26178638) Lee KS, Lin S, Copland DA, Dick AD, Liu J (2021) Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration. J Neuroinflamm 18:32. (PMID: 10.1186/s12974-021-02088-0) Liberale L, Badimon L, Montecucco F, Lüscher TF, Libby P, Camici GG (2022) Inflammation, aging, and cardiovascular disease: JACC review topic of the week. J Am Coll Cardiol 79:837–847. (PMID: 35210039888167610.1016/j.jacc.2021.12.017) Long E, Zhang J (2023) Evidence for the role of selection for reproductively advantageous alleles in human aging. Sci Adv 9:eadh4990. (PMID: 380645651070818510.1126/sciadv.adh4990) Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L (2015) Interventions to slow aging in humans: are we ready? Aging Cell 14:497–510. (PMID: 25902704453106510.1111/acel.12338) López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. (PMID: 23746838383617410.1016/j.cell.2013.05.039) López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2023) Hallmarks of aging: an expanding universe. Cell 186:243–278. (PMID: 3659934910.1016/j.cell.2022.11.001) Martínez-Cué C, Rueda N (2020) Cellular senescence in neurodegenerative diseases. Front Cell Neurosci 14:16. (PMID: 32116562702668310.3389/fncel.2020.00016) Matias I, Diniz LP, Damico IV, Araujo APB, Neves LDS, Vargas G, Leite REP, Suemoto CK, Nitrini R, Jacob-Filho W, Grinberg LT, Hol EM, Middeldorp J, Gomes FCA (2022) Loss of Lamin-B1 and defective nuclear morphology are hallmarks of astrocyte senescence in vitro and in the aging human hippocampus. Aging Cell 21:e13521. (PMID: 3489405610.1111/acel.13521) McHugh D, Gil J (2018) Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol 217:65–77. (PMID: 2911406610.1083/jcb.201708092) McHugh D, Durán I, Gil J (2025) Senescence as a therapeutic target in cancer and age-related diseases. Nat Rev Drug Discov 24:57–71. (PMID: 10.1038/s41573-024-01074-439548312) Melo Dos Santos LS, Trombetta-Lima M, Eggen B, Demaria M (2024) Cellular senescence in brain aging and neurodegeneration. Ageing Res Rev 93:102141. (PMID: 3803008810.1016/j.arr.2023.102141) Merkt W, Bueno M, Mora AL, Lagares D (2020) Senotherapeutics: targeting senescence in idiopathic pulmonary fibrosis. Semin Cell Dev Biol 101:104–110. (PMID: 3187926410.1016/j.semcdb.2019.12.008) Mirzayans R, Andrais B, Hansen G, Murray D (2012) Role of p16(INK4A) in replicative senescence and DNA damage-induced premature senescence in p53-deficient human cells. Biochem Res Int 2012:951574. (PMID: 22924132342464010.1155/2012/951574) Mitsui Y, Schneider EL (1976) Increased nuclear sizes in senescent human diploid fibroblast cultures. Exp Cell Res 100:147–152. (PMID: 127825310.1016/0014-4827(76)90336-0) Morevati M, Tavenier J, Scheibye-Knudsen M, Houlind MB, Hedayati A, Hornum M (2026) Chronic kidney disease and cellular senescence. Int J Mol Sci 27:3205. (PMID: 419773881307380010.3390/ijms27073205) Morsli S, Doherty GJ, Muñoz-Espín D (2022) Activatable senoprobes and senolytics: novel strategies to detect and target senescent cells. Mech Ageing Dev 202:111618. (PMID: 3499064710.1016/j.mad.2021.111618) Muñoz-Espín D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15:482–496. (PMID: 10.1038/nrm382324954210) Muñoz-Espín D, Canamero M, Maraver A, Gomez-Lopez G, Contreras J, Murillo-Cuesta S, Rodriguez-Baeza A, Varela-Nieto I, Ruberte J, Collado M, Serrano M (2013) Programmed cell senescence during mammalian embryonic development. Cell 155:1104–1118. (PMID: 2423896210.1016/j.cell.2013.10.019) Muthamil S, Kim HY, Jang HJ, Lyu JH, Shin UC, Go Y, Park SH, Lee HG, Park JH (2024) Biomarkers of cellular senescence and aging: current state-of-the-art challenges and future perspectives. Adv Biol 8:e2400079. (PMID: 10.1002/adbi.202400079) Nakamura AJ, Rao VA, Pommier Y, Bonner WM (2010) The complexity of phosphorylated H2AX foci formation and DNA repair assembly at DNA double-strand breaks. Cell Cycle 9:389–397. (PMID: 20046100308680310.4161/cc.9.2.10475) Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T (2012) A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11:345–349. (PMID: 22321662348829210.1111/j.1474-9726.2012.00795.x) Nikolaidou A, Spyratou E, Sandali A, Gianni T, Platoni K, Lamprogiannis L, Efstathopoulos EP (2025) Utilization of nanoparticles for treating age-related macular degeneration. Pharmaceuticals (Basel) 18:162. (PMID: 400059761185880810.3390/ph18020162) Ogrodnik M (2021) Cellular aging beyond cellular senescence: markers of senescence prior to cell cycle arrest in vitro and in vivo. Aging Cell 20:e13338. (PMID: 33711211804592710.1111/acel.13338) Ogrodnik M (2025) Aging: the wound that never starts healing. Nat Commun 16:8732. (PMID: 10.1038/s41467-025-64462-34102792612484887) Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, Day CP, Burt A, Palmer A, Anstee QM, Grellscheid SN, Hoeijmakers JHJ, Barnhoorn S, Mann DA, Bird TG, Vermeij WP, Kirkland JL, Passos JF, von Zglinicki T, Jurk D (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8:15691. (PMID: 10.1038/ncomms15691286088505474745) Ogrodnik M, Zhu Y, Langhi LGP, Tchkonia T, Krüger P, Fielder E, Victorelli S, Ruswhandi RA, Giorgadze N, Pirtskhalava T, Podgorni O, Enikolopov G, Johnson KO, Xu M, Inman C, Palmer AK, Schafer M, Weigl M, Ikeno Y, Burns TC, Passos JF, von Zglinicki T, Kirkland JL, Jurk D (2019) Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab 29:1061–1077. (PMID: 30612898650940310.1016/j.cmet.2018.12.008) Ogrodnik M, Evans SA, Fielder E, Victorelli S, Kruger P, Salmonowicz H, Weigand BM, Patel AD, Pirtskhalava T, Inman CL, Johnson KO, Dickinson SL, Rocha A, Schafer MJ, Zhu Y, Allison DB, von Zglinicki T, LeBrasseur NK, Tchkonia T, Neretti N, Passos JF, Kirkland JL, Jurk D (2021) Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20:e13296. (PMID: 33470505788404210.1111/acel.13296) Oh C, Koh D, Jeon HB, Kim KM (2022) The role of extracellular vesicles in senescence. Mol Cells 45:603–609. (PMID: 36058888944864610.14348/molcells.2022.0056) Palmer AK, Kirkland JL (2016) Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol 86:97–105. (PMID: 26924669500193310.1016/j.exger.2016.02.013) Palmer AK, Tchkonia T, LeBrasseur NK, Chini EN, Xu M, Kirkland JL (2015) Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64:2289–2298. (PMID: 26106186447735810.2337/db14-1820) Peilin W, Songsong T, Chengyu Z, Zhi C, Chunhui M, Yinxian Y, Lei Z, Min M, Zongyi W, Mengkai Y, Jing X, Tao Z, Zhuoying W, Fei Y, Chengqing Y (2019) Directed elimination of senescent cells attenuates development of osteoarthritis by inhibition of c-IAP and XIAP. Biochimica Et Biophysica Acta (BBA)-Mol Basis Dis 1865:2618–2632. (PMID: 10.1016/j.bbadis.2019.05.017) Puspitasari YM, Ministrini S, Schwarz L, Karch C, Liberale L, Camici GG (2022) Modern concepts in cardiovascular disease: inflamm-aging. Front Cell Dev Biol 10:882211. (PMID: 35663390915848010.3389/fcell.2022.882211) Rattan SIS (2016) Experimental foundations of the Hayflick system. In: Rattan SIS, Hayflick L (eds) Cellular ageing and replicative senescence healthy ageing and longevity. Springer, Cham, pp 15–26. Regulski MJ (2017) Cellular senescence: what, why, and how. Wounds 29:168–174. (PMID: 28682291) Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ, CANTOS Trial Group (2017) Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 377:1119–1131. (PMID: 2884575110.1056/NEJMoa1707914) Rim C, You MJ, Nahm M, Kwon MS (2024) Emerging role of senescent microglia in brain aging-related neurodegenerative diseases. Transl Neurodegener 13:10. (PMID: 10.1186/s40035-024-00402-33837878810877780) Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192:547–556. (PMID: 21321098304412310.1083/jcb.201009094) Romero-García N, Mas-Bargues C, Huete-Acevedo J, Borrás C (2023) Extracellular vesicles and cellular ageing. Subcell Biochem 102:271–311. (PMID: 3660013710.1007/978-3-031-21410-3_11) Saccon TD, Nagpal R, Yadav H, Cavalcante MB, Nunes ADC, Schneider A, Gesing A, Hughes B, Yousefzadeh M, Tchkonia T, Kirkland JL, Niedernhofer LJ, Robbins PD, Masternak MM (2021) Senolytic combination of dasatinib and quercetin alleviates intestinal senescence and inflammation and modulates the gut microbiome in aged mice. J Gerontol A Biol Sci Med Sci 76:1895–1905. (PMID: 33406219851406410.1093/gerona/glab002) Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK (2017) Cellular senescence mediates fibrotic pulmonary disease. Nat Commun 8:14532. (PMID: 10.1038/ncomms14532282300515331226) Sikora E, Bielak-Zmijewska A, Mosieniak G (2021) A common signature of cellular senescence; does it exist? Ageing Res Rev 71:101458. (PMID: 3450004310.1016/j.arr.2021.101458) da Silva PFL, Ogrodnik M, Kucheryavenko O, Glibert J, Miwa S, Cameron K, Ishaq A, Saretzki G, Nagaraja-Grellscheid S, Nelson G, von Zglinicki T (2019) The bystander effect contributes to the accumulation of senescent cells in vivo. Aging Cell 18:e12848. (PMID: 3046235910.1111/acel.12848) Takasugi M (2018) Emerging roles of extracellular vesicles in cellular senescence and aging. Aging Cell 17:e12734. (PMID: 29392820584788210.1111/acel.12734) Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667–684. (PMID: 20701600294154510.1111/j.1474-9726.2010.00608.x) Vasto S, Candore G, Balistreri CR, Caruso M, Colonna-Romano G, Grimaldi MP, Listi F, Nuzzo D, Lio D, Caruso C (2007) Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev 128:83–91. (PMID: 1711842510.1016/j.mad.2006.11.015) Walaszczyk A, Dookun E, Redgrave R, Tual-Chalot S, Victorelli S, Spyridopoulos I, Owens A, Arthur HM, Passos JF, Richardson GD (2019) Pharmacological clearance of senescent cells improves survival and recovery in aged mice following acute myocardial infarction. Aging Cell 18:e12945. (PMID: 30920115651615110.1111/acel.12945) Wallis R, Mizen H, Bishop CL (2020) The bright and dark side of extracellular vesicles in the senescence-associated secretory phenotype. Mech Ageing Dev 189:111263. (PMID: 32461143734700510.1016/j.mad.2020.111263) Wang WJ, Cai GY, Chen XM (2017) Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease. Oncotarget 8:64520–64533. (PMID: 28969091561002310.18632/oncotarget.17327) Wang B, Han J, Elisseeff JH, Demaria M (2024a) The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol 25:958–978. (PMID: 10.1038/s41580-024-00727-x38654098) Wang Y, Kuca K, You L, Nepovimova E, Heger Z, Valko M, Adam V, Wu Q, Jomova K (2024b) The role of cellular senescence in neurodegenerative diseases. Arch Toxicol 98:2393–2408. (PMID: 10.1007/s00204-024-03768-53874470911272704) Wiley CD, Campisi J (2021) The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab 3:1290–1301. (PMID: 10.1038/s42255-021-00483-8346639748889622) Williams G (1957) Pleiotropy, natural selection, and the evolution of senescence. Evolution 11:398–411. (PMID: 10.1111/j.1558-5646.1957.tb02911.x) Xu M, Tchkonia T, Ding H, Ogrodnik M, Lubbers ER, Pirtskhalava T, White TA, Johnson KO, Stout MB, Mezera V, Giorgadze N, Jensen MD, LeBrasseur NK, Kirkland JL (2015) JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci U S A 112:E6301–E6310. (PMID: 26578790465558010.1073/pnas.1515386112) Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, Onken JL, Johnson KO, Verzosa GC, Langhi LGP, Weigl M, Giorgadze N, LeBrasseur NK, Miller JD, Jurk D, Singh RJ, Allison DB, Ejima K, Hubbard GB, Ikeno Y, Cubro H, Garovic VD, Hou X, Weroha SJ, Robbins PD, Niedernhofer LJ, Khosla S, Tchkonia T, Kirkland JL (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246–1256. (PMID: 10.1038/s41591-018-0092-9299881306082705) Xu C, Qiu Z, Guo Q, Huang Y, Zhao Y, Zhao R (2025) The role of cellular senescence in cardiovascular disease. Cell Death Discov 11:431. (PMID: 10.1038/s41420-025-02720-54105305812501035) Yang NC, Hu ML (2005) The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp Gerontol 40:813–819. (PMID: 1615430610.1016/j.exger.2005.07.011) Yang J, Liu M, Hong D, Zeng M, Zhang X (2021) The paradoxical role of cellular senescence in cancer. Front Cell Dev Biol 9:722205. (PMID: 34458273838884210.3389/fcell.2021.722205) Yang J, Su J, Sun Z, Song Y, Zhang Y, Zhang Z, Wei J, Shi X, Jiang N, Ge X (2024) Youthful small extracellular vesicles restore the function and reparative capacity of inflammatory-impaired periodontal ligament stem cells via delivering protein biglycan for bone regeneration. J Nanobiotechnol 22:508. (PMID: 10.1186/s12951-024-02752-6) Yousefzadeh MJ, Zhu Y, McGowan SJ, Angelini L, Fuhrmann-Stroissnigg H, Xu M, Ling YY, Melos KI, Pirtskhalava T, Inman CL, McGuckian C, Wade EA, Kato JI, Grassi D, Wentworth M, Burd CE, Arriaga EA, Ladiges WL, Tchkonia T, Kirkland JL, Robbins PD, Niedernhofer LJ (2018) Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36:18–28. (PMID: 30279143619765210.1016/j.ebiom.2018.09.015) Zaman V, Shields DC, Shams R, Drasites KP, Matzelle D, Haque A, Banik NL (2021) Cellular and molecular pathophysiology in the progression of Parkinson’s disease. Metab Brain Dis 36:815–827. (PMID: 10.1007/s11011-021-00689-5335999458170715) Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP (2019) Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22:719–728. (PMID: 10.1038/s41593-019-0372-9309365586605052) Zhu F, Li Y, Zhang J, Piao C, Liu T, Li HH, Du J (2013) Senescent cardiac fibroblast is critical for cardiac fibrosis after myocardial infarction. PLoS ONE 8:e74535. (PMID: 24040275377054910.1371/journal.pone.0074535) Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, Pirtskhalava T, Giorgadze N, Johnson KO, Giles CB, Wren JD, Niedernhofer LJ, Robbins PD, Kirkland JL (2016) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15:428–435. (PMID: 26711051485492310.1111/acel.12445) Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, CANTOS Trial Group, 2018 Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, CANTOS Trial Group (2018) Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 391:319–328. |
| Contributed Indexing: | Keywords: Biomarkers of senescence; Cellular senescence; Geroscience; Inflammageing; Senescence-associated secretory phenotype (SASP); Senolytics; Senotherapeutics |
| Substance Nomenclature: | 0 (Senotherapeutics) |
| Entry Date(s): | Date Created: 20260723 Date Completed: 20260723 Latest Revision: 20260726 |
| Update Code: | 20260726 |
| PubMed Central ID: | PMC13396041 |
| DOI: | 10.1007/s10522-026-10477-2 |
| PMID: | 42489778 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1573-6768 |
|---|---|
| DOI: | 10.1007/s10522-026-10477-2 |