450
Views
0
CrossRef citations to date
0
Altmetric
Review

Understanding cellular senescence: pathways involved, therapeutics and longevity aiding

& ORCID Icon
Pages 2324-2345 | Received 09 Feb 2023, Accepted 06 Nov 2023, Published online: 30 Nov 2023

References

  • Campisi J, Kapahi P, Lithgow GJ, et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183.
  • McCay CM, Maynard LA, Sperling G, et al. Nutrition reviews. Volume 18 July–December, 1975. Pages 1–13. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. J Nutr. 1939;18(1):1–13. doi: 10.1093/jn/18.1.1
  • Mattison JA, Colman RJ, Beasley TM, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8 [[cited 2022 Oct 31]]. https://pubmed.ncbi.nlm.nih.gov/28094793/
  • Pifferi F, Terrien J, Marchal J, et al. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Commun Biol Internet. 2018;1 [cited 2022 Oct 31]. /pmc/articles/PMC6123706/
  • Omodei D, Fontana L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 2011;585(11):1537–1542. doi: 10.1016/j.febslet.2011.03.015
  • Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25(3):585–621. doi: 10.1016/0014-4827(61)90192-6
  • Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37(3):614–636. doi: 10.1016/0014-4827(65)90211-9
  • Shay JW, Wright WE. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol. 2000;1(1):72–76. doi: 10.1038/35036093
  • López-Otín C, Blasco MA, Partridge L, et al. The Hallmarks of ageing. Cell. 2013;153:1194–1217. doi: 10.1016/j.cell.2013.05.039
  • Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15(7):482–496. 2014; 15. doi: 10.1038/nrm3823
  • Hudgins AD, Tazearslan C, Tare A, et al. Age- and tissue-specific expression of senescence biomarkers in mice. Front Genet Internet. 2018 [[cited 2022 Nov 7]];9. doi: 10.3389/fgene.2018.00059
  • Blumenthal EJ, Mille ACK, Malkinson AM. eonine protein kinase m-dependent proteasc senescent IMR-90 fibrobla fib. Mech Ageing Dev. 1993;72:13–24. doi: 10.1016/0047-6374(93)90127-D
  • Chen Q, Ames BN. Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells (replicatlve castion/mophol/DNA damage/p53 cell cycle checkpoint). Cell Bio. 1994;91:4130–4134. doi: 10.1073/pnas.91.10.4130
  • Medrano EE, Yang F, Boissy R, et al. Terminal differentiation and senescence in the human melanocyte: repression of tyrosine-phosphorylation of the extracellular signal-regulated kinase 2 selectively defines the two phenotypes. ?Mol Biol Cell. 1994;5(4):497–509.
  • Toussaint O, Remacle J, Dierick JF, et al. From the Hayflick mosaic to the mosaics of ageing.: role of stress-induced premature senescence in human ageing. Int J Biochem Cell Biol. 2002;34(11):1415–1429.
  • Xu M, Tchkonia T, Ding H, 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. doi: 10.1073/pnas.1515386112
  • Debacq-Chainiaux F, Ben Ameur R, Bauwens E, et al. Stress-induced (premature) senescence. In: Rattan S, Hayflick L, editors. Cellular Ageing and Replicative Senescence. Vol. 4, Springer; 2016. p. 243–262.
  • Campisi J. Cellular senescence and apoptosis: how cellular responses might influence ageing phenotypes. Exp Gerontol. 2003;38:5–11. doi: 10.1016/S0531-5565(02)00152-3
  • Giaimo S, d’Adda di Fagagna F. D’Adda di Fagagna F. is cellular senescence an example of antagonistic pleiotropy? Ageing Cell. 2012;11:378–383. doi: 10.1111/j.1474-9726.2012.00807.x
  • Davidovic M, Sevo G, Svorcan P, et al. Old age as a privilege of the “selfish ones. Aging Dis. 2010;1:139.
  • Jin K. Modern biological theories of ageing. Aging Dis. 2010;1:72.
  • Rossi M, Abdelmohsen K. The emergence of senescent surface biomarkers a iss senotherapeutic targets. Cells. 2021 [[cited 2022 Nov 1]];10:1740. /pmc/articles/PMC8305747/ 10.3390/cells10071740.
  • Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in ageing skin in vivo. Proc Natl Acad Sci USA. 1995;92:9363–9367. doi: 10.1073/pnas.92.20.9363
  • Althubiti M, Lezina L, Carrera S, et al. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis 5:11 2014. 2014;5:e1528–e1528. doi: 10.1038/cddis.2014.489
  • von Zglinicki T. Telomeres: influencing the rate of ageing. Ann N Y Acad Sci. 1998;854:318–327. doi: 10.1111/j.1749-6632.1998.tb09912.x
  • Kaneko T, Tahara S, Matsuo M. Non-linear accumulation of 8-hydroxy-2’-deoxyguanosine, a marker of oxidized DNA damage, during ageing. Mutat Res DNAging Genet Instab Aging. 1996;316:277–285. doi: 10.1016/S0921-8734(96)90010-7
  • Burton DGA, Krizhanovsky V. Physiological and pathological consequences of cellular senescence. Cell Mol Life Sci. 2014;71(22):4373–4386. doi: 10.1007/s00018-014-1691-3
  • Adams PD. Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Molecular Cell. 2009;36(1):2–14. doi: 10.1016/j.molcel.2009.09.021
  • Campisi J, D’Adda Di Fagagna F. Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol. 2007;8(9):729–740. 2007; 8. doi: 10.1038/nrm2233
  • Lanigan F, Geraghty JG, Bracken AP. Transcriptional regulation of cellular senescence. Oncogene. 2011;30:2901–2911. 30:26 2011. doi: 10.1038/onc.2011.34.
  • Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2
  • Sherr CJ. Cancer cell cycles. Science. 1996;274(5293):1672–1677. doi: 10.1126/science.274.5293.1672
  • Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell. 2002;2(2):103–112. doi: 10.1016/S1535-6108(02)00102-2
  • Wagner V, Gil J. Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene. 2020;39(29):5165–5176. doi: 10.1038/s41388-020-1354-9
  • Baus F, Gire V, Fisher D, et al. Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts. EMBO J. 2003;22:3992–4002. doi: 10.1093/emboj/cdg387
  • Wiebusch L, Hagemeier C. p53- and p21-dependent premature APC/C-Cdh1 activation in G2 is part of the long-term response to genotoxic stress. Oncogene. 2010;29:3477–3489. doi: 10.1038/onc.2010.99
  • Müllers E, Silva Cascales H, Jaiswal H, et al. Nuclear translocation of cyclin B1 marks the restriction point for terminal cell cycle exit in G2 phase. Cell Cycle. 2014;13(17):2733–2743.
  • Krenning L, Feringa FM, Shaltiel IA, et al. Transient activation of p53 in G2 phase is sufficient to induce senescence. Mol Cell. 2014;55(1):59–72.
  • Gire V, Dulic V. Senescence from G2 arrest, revisited. Cell Cycle. 2015;14(3):297–304. doi: 10.1080/15384101.2014.1000134
  • Gillis LD, Leidal AM, Hill R, et al. p21Cip1/WAF1 mediates cyclin B1 degradation in response to DNA damage. Cell Cycle. 2009;8(2):253–256.
  • Nakayama Y, Yamaguchi N. Role of cyclin B1 levels in DNA damage and DNA damage-induced senescence. Int Rev Cell Mol Biol. 2013;305:303–337.
  • Johmura Y, Shimada M, Misaki T, et al. Necessary and sufficient role for a mitosis skip in senescence induction. Mol Cell. 2014;55(1):73–84.
  • Krenning L, Medema RH. Enter the nucleus to exit the cycle. Cell Cycle. 2014;13(17):2651–2652. doi: 10.4161/15384101.2014.948783
  • Müllers E, Silva Cascales H, Burdova K, et al. Residual Cdk1/2 activity after DNA damage promotes senescence. Ageing Cell. 2017;16:575–584. doi: 10.1111/acel.12588
  • Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in ageing skin in vivo. Proc Nat Acad Sci. 1995;92:9363–9367. doi: 10.1073/pnas.92.20.9363
  • Stein GH, Beeson M, Gordon L. Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science. 1990;249(4969):666–669. doi: 10.1126/science.2166342
  • Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and ageing. Cell. 2007;130:223–233. doi: 10.1016/j.cell.2007.07.003
  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013
  • Kumari R, Jat P. Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol. 2021:485. doi: 10.3389/fcell.2021.645593
  • Zindy F, Quelle DE, Roussel MF, et al. Expression of the p16INK4a tumour suppressor versus other INK4 family members during mouse development and ageing. Oncogene. 1997;15:203–211. doi: 10.1038/sj.onc.1201178
  • Krishnamurthy J, Torrice C, Ramsey MR, et al. Ink4a/Arf expression is a biomarker of ageing. J Clin Investig. 2004;114:1299–1299. doi: 10.1172/JCI22475
  • Zeng N, Yang K-T, Bayan J-A, et al. PTEN controls β-cell regeneration in aged mice by regulating cell cycle inhibitor p16ink4a. Ageing Cell. 2013;12:1000–1011. doi: 10.1111/acel.12132
  • Min EY, Kim IH, Lee J, et al. The effects of fucodian on senescence are controlled by the p16INK4a-pRb and p14Arf-p53 pathways in hepatocellular carcinoma and hepatic cell lines. Int J Oncol. 2014;45(1):47–56. doi: 10.3892/ijo.2014.2426
  • Hobson S, Arefin S, Kublickiene K, et al. Senescent cells in early vascular ageing and bone disease of chronic kidney disease—A novel target for treatment. Toxins (Basel). 2019;11:11. InternetAvailable from: https://pubmed.ncbi.nlm.nih.gov/30717151/
  • Mijit M, Caracciolo V, Melillo A, et al. Role of p53 in the regulation of cellular senescence. Biomolecules Internet. 2020;10:420. /pmc/articles/PMC7175209/. doi: 10.3390/biom10030420.
  • Sharpless NE, Sherr CJ. Forging a signature of in vivo senescence. Nat Rev Cancer. 2015;15(7):397–408. doi: 10.1038/nrc3960
  • Debacq-Chainiaux F, Erusalimsky JD, Campisi J, et al. Protocols to detect senescence-associated beta-galactosidase (SA-βgal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc. 2009;4:1798–1806. 4:12 2009. doi: 10.1038/nprot.2009.191.
  • Severino J, Allen RG, Balin S, et al. Is β-galactosidase staining a marker of senescence in vitro and in vivo? Exp Cell Res. 2000;257(1):162–171.
  • Lee BY, Han JA, Im JS, et al. Senescence-associated β-galactosidase is lysosomal β-galactosidase. Ageing Cell. 2006;5:187–195. doi: 10.1111/j.1474-9726.2006.00199.x
  • Biran A, Zada L, Karam PA, et al. Quantitative identification of senescent cells in ageing and disease. Ageing Cell. 2017;16:661–671. doi: 10.1111/acel.12592
  • Aksenova AY, Mirkin SM. At the beginning of the end and in the middle of the beginning: structure and maintenance of telomeric DNA repeats and interstitial telomeric sequences. Genes. 2019;10:118. 2019; 10:118. doi: 10.3390/genes10020118.
  • Tomita K. How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis. Curr Genet. 2018;64:1177–1181. doi: 10.1007/s00294-018-0836-6
  • Srinivas N, Rachakonda S, Kumar R. Telomeres and telomere length: a General overview. Cancers. 2020;12:558. 2020; 12:558. doi: 10.3390/cancers12030558.
  • Oikawa S, Kawanishi S. Site-specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening. FEBS Lett. 1999;453(3):365–368. doi: 10.1016/S0014-5793(99)00748-6
  • Barnes RP, Fouquerel E, Opresko PL. The impact of oxidative DNA damage and stress on telomere homeostasis. Mech Ageing Dev. 2019;177:37–45. doi: 10.1016/j.mad.2018.03.013
  • Von Zglinicki T, Wan T, Miwa S. Senescence in post-mitotic cells: a driver of ageing? Antioxid Redox Signal. 2021;34:308–323. doi: 10.1089/ars.2020.8048
  • Bodnar AG, Ouellette M, Frolkis M, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998;279(5349):349–352.
  • Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019;20:299–309. 20:5 2019. doi: 10.1038/s41576-019-0099-1.
  • Bernardes De Jesus B, Blasco MA. Ageing by telomere loss can be Reversed. Cell Stem Cell. 2011;8:3–4. doi: 10.1016/j.stem.2010.12.013
  • Prieto-Oliveira P. Telomerase activation in the treatment of ageing or degenerative diseases: a systematic review. Mol Cell Biochem. 2021;476:599–607. doi: 10.1007/s11010-020-03929-x
  • Smith-Sonneborn J. Telomerase biology associations offer keys to cancer and ageing therapeutics. Curr Aging Sci. 2019;13:11–21. doi: 10.2174/1874609812666190620124324
  • Collado M, Serrano M. Senescence in tumours: evidence from mice and humans. Nat Rev Cancer. 2010;10:51–57. 10:1 2010;. doi: 10.1038/nrc2772.
  • Chen W, Kang J, Xia J, et al. p53-related apoptosis resistance and tumour suppression activity in UVB-induced premature senescent human skin fibroblasts. Int J Mol Med. 2008;21:645–653. doi: 10.3892/ijmm.21.5.645
  • Tchkonia T, Zhu Y, Van Deursen J, et al. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Investig. 2013;123(3):966–972.
  • Childs BG, Durik M, Baker DJ, et al. Cellular senescence in ageing and age-related disease: from mechanisms to therapy. Nature Med. 2015;21:1424–1435. doi: 10.1038/nm.4000
  • Dörr JR, Yu Y, Milanovic M, et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature. 2013;501(7467):421–425.
  • Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014;31(6):722.
  • Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. 2010;12(7):676–685. doi: 10.1038/ncb2070
  • Sorrentino JA, Krishnamurthy J, Tilley S, et al. p16INK4a reporter mice reveal age-promoting effects of environmental toxicants. J Clin Investig. 2014;124:169–173. doi: 10.1172/JCI70960
  • Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan. Nature. 2016;530:184–189. doi: 10.1038/nature16932
  • Lujambio A. To clear, or not to clear (senescent cells)? That is the question. BioEssays: news and reviews in molecular, cellular and developmental biology. BioEssays. 2016;38(Suppl 1):S56–64. doi: 10.1002/bies.201670910
  • Valentine JM, Kumar S, Moumen A. A p53-independent role for the MDM2 antagonist nutlin-3 in DNA damage response initiation. BMC Cancer. 2011 [cited 2022 Feb 21];11(1). https://pubmed.ncbi.nlm.nih.gov/21338495/
  • Liu Y, Leslie PL, Zhang Y. Life and death decision-making by p53 and implications for cancer immunotherapy. Trends Cancer. 2021;7(3):226–239. doi: 10.1016/j.trecan.2020.10.005
  • Sheekey E, Narita M. p53 in senescence – it’s a marathon, not a sprint.FEBS J. 2021 [[cited 2022 Feb 18];290(5):1212–1220. https://onlinelibrary.wiley.com/doi/full/10.1111/febs.16325.
  • Xu Y, Li N, Xiang R, et al. Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends Biochem Sci. 2014;39(6):268–276. doi: 10.1016/j.tibs.2014.04.004
  • Jung SH, Hwang HJ, Kang D, et al. mTOR kinase leads to PTEN-loss-induced cellular senescence by phosphorylating p53. Oncogene. 2019;38:1639–1650. doi: 10.1038/s41388-018-0521-8
  • Spallarossa P, Altieri P, Aloi C, et al. Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2. Am J Physiol Heart Circ Physiol. 2009;297:H2169–2181. doi: 10.1152/ajpheart.00068.2009
  • Rufini A, Tucci P, Celardo I, et al. Senescence and ageing: the critical roles of p53. Oncogene. 2013;32:5129–5143. doi: 10.1038/onc.2012.640
  • Al Bitar S, Gali-Muhtasib H. The role of the cyclin dependent kinase inhibitor p21 cip1/waf1 in targeting cancer: molecular mechanisms and novel therapeutics. Cancers [Internet]. 2019;11:11. Available from: https://pubmed.ncbi.nlm.nih.gov/31575057/
  • Benson EK, Mungamuri SK, Attie O, et al. p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes. Oncogene. 2014;33:3959–3969. doi: 10.1038/onc.2013.378
  • Yosef R, Pilpel N, Papismadov N, et al. p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signalling. EMBO J. 2017;36:2280–2295. doi: 10.15252/embj.201695553
  • Zhang Y, Gao Y, Zhang G, et al. DNMT3a plays a role in switches between doxorubicin-induced senescence and apoptosis of colorectal cancer cells. Intl J Cancer. 2011;128(3):551–561.
  • Aliouat-Denis CM, Dendouga N, Van Den Wyngaert I, et al. p53-independent regulation of p21Waf1/Cip1 expression and senescence by Chk2. Mol Cancer Res. 2005;3:627–634. doi: 10.1158/1541-7786.MCR-05-0121
  • Kiyokawa H, Kineman RD, Manova-Todorova KO, et al. Enhanced growth of mice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1). Cell. 1996;85(5):721–732.
  • Nakayama K, Ishida N, Shirane M, et al. Mice lacking p27(Kip1) display increased body size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumours. Cell. 1996;85:707–720. doi: 10.1016/S0092-8674(00)81237-4
  • McKay LK, White JP. The AMPK/p27Kip1 pathway as a novel target to promote autophagy and resilience in aged cells. Cells. 2021;10(6):1430. doi: 10.3390/cells10061430
  • Pruitt SC, Freeland A, Rusiniak ME, et al. Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing. Nat Commun. 2013;4(1):2626.
  • Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the ageing process via an integrated signalling network. Ageing Res Rev. 2012;11:230–241. doi: 10.1016/j.arr.2011.12.005
  • Cuervo AM. Autophagy and ageing. Trends Genet. 2008;24:604–612. doi: 10.1016/j.tig.2008.10.002
  • Rubinsztein DC, Mariño G, Kroemer G. Autophagy and ageing. Cell. 2011;146:682–695. doi: 10.1016/j.cell.2011.07.030
  • Kang HT, Lee KB, Kim SY, et al. Autophagy Impairment Induces Premature Senescence in Primary Human Fibroblasts. PLoS One. 2011;6(8):e23367. doi: 10.1371/journal.pone.0023367
  • He C, Bassik MC, Moresi V, et al. Exercise–induced BCL2–regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481:511–515. doi: 10.1038/nature10758
  • Bernet JD, Doles JD, Hall JK, et al. P38 MAPK signalling underlies a cell autonomous loss of stem cell self-renewal in aged skeletal muscle. Nature Med. 2014;20:265. doi: 10.1038/nm.3465
  • Alway SE, Siu PM. Nuclear Apoptosis Contributes to Sarcopenia. Exer Sport Sci Rev. 2008;36(2):51. doi: 10.1097/JES.0b013e318168e9dc
  • Chakravarthy MV, Abraha TW, Schwartz RJ, et al. Insulin-like growth factor-I extends in vitro replicative life span of skeletal muscle satellite cells by enhancing G1/S cell cycle progression via the activation of phosphatidylinositol 3’-kinase/Akt signalling pathway. J Biol Chem. 2000;275:35942–35952. doi: 10.1074/jbc.M005832200
  • Machida S, Booth FW. Increased nuclear proteins in muscle satellite cells in aged animals as compared to young growing animals. Exp Gerontol. 2004;39(10):1521–1525. doi: 10.1016/j.exger.2004.08.009
  • Chakkalakal JV, Jones KM, Basson MA, et al. The aged niche disrupts muscle stem cell quiescence. Nature. 2012;490(7420):355.
  • Besson A, Dowdy SF, Roberts JM. CDK inhibitors: cell cycle regulators and beyond. Dev Cell. 2008;14(2):159–169. doi: 10.1016/j.devcel.2008.01.013
  • Chu IM, Hengst L, Slingerland JM. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer. 2008;8(4):253–267. doi: 10.1038/nrc2347
  • Wu FY, Wang SE, Sanders ME, et al. Reduction of cytosolic p27(Kip1) inhibits cancer cell motility, survival, and tumourigenicity. Cancer Res. 2006;66:2162–2172. doi: 10.1158/0008-5472.CAN-05-3304
  • Sun X, Shi B, Zheng H, et al. Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway. Cell Death Dis. 2018;9(3). https://pubmed.ncbi.nlm.nih.gov/29449532/.
  • Lopes-Paciencia S, Saint-Germain E, Rowell M-C, et al. The senescence-associated secretory phenotype and its regulation. Cytokine. 2019;117:15–22. doi: 10.1016/j.cyto.2019.01.013
  • Mohamad Kamal NS, Safuan S, Shamsuddin S, et al. Ageing of the cells: insight into cellular senescence and detection methods. Eur J Cell Biol. 2020;99:151108–151108. doi: 10.1016/j.ejcb.2020.151108
  • Waaijer MEC, Parish WE, Strongitharm BH, et al. The number of p16INK4a positive cells in human skin reflects biological age. Ageing Cell. 2012;11:722–725. doi: 10.1111/j.1474-9726.2012.00837.x
  • Herbig U, Ferreira M, Condel L, et al. Cellular senescence in ageing primates. Science. 2006;311:1257. doi: 10.1126/science.1122446
  • Xu M, Palmer AK, Ding H, et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife. 2015;4:1–19. doi: 10.7554/eLife.12997
  • Ogrodnik M, Miwa S, Tchkonia T, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun. 2017 [[cited 2022 Nov 7]];8(1): https://pubmed.ncbi.nlm.nih.gov/28608850/
  • Surks MI, DeFesi CR. Determination of the cell number of each cell type in the anterior pituitary of Euthyroid and hypothyroid rats 1. Endocrinology. 1977;101(3):946–958. doi: 10.1210/endo-101-3-946
  • Rodier F, Campisi J. Four faces of cellular senescence. J Cell Bio. 2011;192(4):547–556. doi: 10.1083/jcb.201009094
  • Minamino T, Orimo M, Shimizu I, et al. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nature Med. 2009;15(9):1082–1087. 2009; 15. doi: 10.1038/nm.2014
  • Zhang X, Zhang S, Liu X, et al. Oxidation resistance 1 is a novel senolytic target. Ageing Cell. 2018;17:12780–12780. doi: 10.1111/acel.12780
  • Coppé J-P, Desprez P-Y, Krtolica A, et al. The senescence-associated secretory phenotype: the dark side of tumour suppression. Annu Rev Pathol. 2010;5(1):99–118. 10.1146/annurev-pathol-121808-102144
  • Gorgoulis V, Adams PD, Alimonti A, et al. Cellular Senescence: Defining a Path Forward. Cell. 2019;179(4):813–827.
  • Freund A, Orjalo AV, Desprez P-Y, et al. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010;16(5):238–246.
  • Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15(8):978–990.
  • Coppé J-P, Patil CK, Rodier F, et al. Senescence-associated secretory phenotypes Reveal cell-Nonautonomous functions of oncogenic RAS and the p53 tumour suppressor. PLoS Biol. 2008;6:e301–e301. doi: 10.1371/journal.pbio.0060301
  • Coppé J-P, Rodier F, Patil CK, et al. Tumour suppressor and ageing biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem. 2011;286:36396–36403. doi: 10.1074/jbc.M111.257071
  • Maciel-Barón LA, Morales-Rosales SL, Aquino-Cruz AA, et al. Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli. Age. 2016;38:1–14. 1 2016; 38. doi: 10.1007/s11357-015-9864-z.
  • Kuilman T, Michaloglou C, Vredeveld LCW, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133(6):1019–1031.
  • Acosta JC, O’Loghlen A, Banito A, et al. Chemokine signalling via the CXCR2 receptor reinforces senescence. Cell. 2008;133:1006–1018. doi: 10.1016/j.cell.2008.03.038
  • Rodier F, Coppé J-P, Patil CK, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973–979. 11:8 2009. doi: 10.1038/ncb1909
  • Pazolli E, Alspach E, Milczarek A, et al. Chromatin remodeling underlies the senescence- associated secretory phenotype of tumour stromal fibroblasts that supports cancer progression. Cancer Res. 2012;72:2251–2261. doi: 10.1158/0008-5472.CAN-11-3386
  • Sun Y, Coppé JP, Lam EWF. Cellular senescence: the sought or the unwanted? Trends in molecular medicine. Trends Mol Med. 2018;24(10):871–885. doi: 10.1016/j.molmed.2018.08.002
  • Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30(8):1536–1548. doi: 10.1038/emboj.2011.69
  • Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–395. 2009; 460:392–5. doi: 10.1038/nature08221
  • Herranz N, Gallage S, Mellone M, et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol. 2015;17(9):1205–1217. 2015; 17. doi: 10.1038/ncb3225
  • Laberge R-M, Sun Y, Orjalo AV, et al. MTOR regulates the pro-tumourigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2014;17(8):1049–1061. 2015; 17. doi: 10.1038/ncb3195
  • Narita M, Young ARJ, Arakawa S, et al. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science. 2011;332(6032):966–970.
  • Young ARJ, Narita M, Narita M. Cell senescence as both a dynamic and a Static phenotype. Methods Mol Biol. 2013;965:1–13.
  • Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Investig. 2018;128(4):1238–1246. doi: 10.1172/JCI95148
  • Krtolica A, Parrinello S, Lockett S, et al. Senescent fibroblasts promote epithelial cell growth and tumourigenesis: a link between cancer and ageing. Proc Natl Acad Sci, USA. 2001;98(21):12072–12077. doi: 10.1073/pnas.211053698
  • Coppe JP, Kauser K, Campisi J, et al. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem. 2006;281(40):29568–29574.
  • Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101.
  • Di Mitri D, Toso A, Chen JJ, et al. Tumour-infiltrating gr-1+ myeloid cells antagonize senescence in cancer. Nature. 2014;515(7525):134–137.
  • Eggert T, Wolter K, Ji J, et al. Distinct functions of senescence-associated immune responses in liver tumour surveillance and tumour progression. Cancer Cell. 2016;30:533–547. doi: 10.1016/j.ccell.2016.09.003
  • Demaria M, O’Leary MN, Chang J, et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discovery. 2017;7(2):165–176.
  • Kim YH, Choi YW, Lee J, et al. Senescent tumour cells lead the collective invasion in thyroid cancer. Nat Commun. 2017;8(1). [[cited 2022 Feb 21]]. https://pubmed.ncbi.nlm.nih.gov/28489070/
  • Chen F, Long Q, Fu D, et al. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat Commun. 2018 [[cited 2022 Feb 21]];9(1): https://pubmed.ncbi.nlm.nih.gov/30333494/
  • Gilbert LA, Hemann MT. Chemotherapeutic resistance: surviving stressful situations. Cancer Res. 2011;71(15):5062–5066. doi: 10.1158/0008-5472.CAN-11-0277
  • Gilbert LA, Hemann MT. DNA damage-mediated induction of a chemoresistant niche. Cell. 2010;143(3):355–366. doi: 10.1016/j.cell.2010.09.043
  • Bent EH, Gilbert LA, Hemann MT. A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 2016;30(16):1811–1821. doi: 10.1101/gad.284851.116
  • Anerillas C, Abdelmohsen K, Gorospe M. Regulation of senescence traits by MAPKs. Geroscience. 2020;42(2):397–408. doi: 10.1007/s11357-020-00183-3
  • van Deursen JM. The role of senescent cells in ageing. Nature. 2014;509:439–446. doi: 10.1038/nature13193
  • McHugh D, Gil J. Senescence and ageing: Causes, consequences, and therapeutic avenues. J Cell Bio. 2018;217:65–77. doi: 10.1083/jcb.201708092
  • Gong X, Liu A, Ming X, et al. UV-induced interaction between p38 MAPK and p53 serves as a molecular switch in determining cell fate. FEBS Lett. 2010;584(23):4711–4716.
  • Dhillon AS, Hagan S, Rath O, et al. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–3290.
  • Pimienta G, Pascual J. Canonical and alternative MAPK signalling. Cell Cycle. 2007;6:2628–2632. doi: 10.4161/cc.6.21.4930
  • Alimbetov D, Davis T, Brook AJC, et al. Suppression of the senescence-associated secretory phenotype (SASP) in human fibroblasts using small molecule inhibitors of p38 MAP kinase and MK2. Biogerontology. 2016;17(2):305–315. doi: 10.1007/s10522-015-9610-z
  • Vermeulen L, De Wilde G, Van Damme P, et al. Transcriptional activation of the NF-kappaB p65 subunit by mitogen- and stress-activated protein kinase-1 (MSK1). EMBO J. 2003;22:1313–1324. doi: 10.1093/emboj/cdg139
  • Reber L, Vermeulen L, Haegeman G, et al. Ser276 phosphorylation of NF-kB p65 by MSK1 controls SCF expression in inflammation. PLoS One. 2009;4(2):e4393. doi: 10.1371/journal.pone.0004393
  • Catanzaro JM, Sheshadri N, Pan J-A, et al. Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4. Nat Commun. 2014;5(1):3729.
  • Hydbring P, Bahram F, Su Y, et al. Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation. Proc Natl Acad Sci, USA. 2010;107(1):58–63.
  • MacIà A, Vaquero M, Gou-Fàbregas M, et al. Sprouty1 induces a senescence-associated secretory phenotype by regulating NFκB activity: implications for tumourigenesis. Cell Death Diff. 2014;21:333–343. doi: 10.1038/cdd.2013.161
  • Wang W, Martindale JL, Yang X, et al. Increased stability of the p16 mRNA with replicative senescence. EMBO Reports. 2005;6(2):158–164. doi: 10.1038/sj.embor.7400346
  • Wang H, Han L, Zhao G, et al. hnRNP A1 antagonizes cellular senescence and senescence-associated secretory phenotype via regulation of SIRT1 mRNA stability. Ageing Cell. 2016;15:1063–1073. doi: 10.1111/acel.12511
  • Ziaei S, Shimada N, Kucharavy H, et al. MNK1 expression increases during cellular senescence and modulates the subcellular localization of hnRNP A1. Exp Cell Res. 2012;318(5):500–508.
  • Alspach E, Flanagan KC, Luo X, et al. p38MAPK plays a crucial role in stromal-mediated tumourigenesis. Cancer Discovery. 2014;4:716–729. doi: 10.1158/2159-8290.CD-13-0743
  • Wiley CD, Campisi J. From ancient pathways to ageing cells-connecting metabolism and cellular senescence. Cell Metab. 2016;23:1013–1021. doi: 10.1016/j.cmet.2016.05.010
  • Georgilis A, Klotz S, Hanley CJ, et al. PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumourigenic effects of senescent cells. Cancer Cell. 2018;34:85–102.e9. doi: 10.1016/j.ccell.2018.06.007
  • Noh JH, Kim KM, Laura Idda M, et al. GRSF1 suppresses cell senescence. Ageing. 2018;10:1856–1866. doi: 10.18632/aging.101516
  • Noh JH, Kim KM, Pandey PR, et al. Loss of RNA-binding protein GRSF1 activates mTOR to elicit a proinflammatory transcriptional program. Nucleic Acids Res. 2019;47(5):2472–2486.
  • Roux PP, Topisirovic I. Signalling pathways involved in the regulation of mRNA translation. Mol Cell Biol [Internet]. 2018;38 [[cited 2021 Nov 26]]. https://pubmed.ncbi.nlm.nih.gov/29610153/
  • Sun X, Shi B, Zheng H, et al. Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway. Cell Death Dis [Internet]. 2018 [cited 2021 Nov 25]; 9(3). https://pubmed.ncbi.nlm.nih.gov//29449532/
  • Tomimatsu K, Narita M. Translating the effects of mTOR on secretory senescence. Nat Cell Biol. 2015;17(10):1230–1232. doi: 10.1038/ncb3244
  • Sadasivam S, DeCaprio JA. The DREAM complex: master coordinator of cell cycle dependent gene expression. Nat Rev Cancer. 2013;13:585. doi: 10.1038/nrc3556
  • Litovchick L, Sadasivam S, Florens L, et al. Evolutionarily conserved multisubunit RBL2/p130 and E2F4 protein complex represses human cell cycle-dependent genes in quiescence. Molecular Cell. 2007;26(4):539–551.
  • Schmich J, Kraus Y, De Vito D, et al. Induction of reverse development in two marine hydrozoans. Int J Dev Biol. 2007;51(1):45–56.
  • Sadasivam S, Duan S, DeCaprio JA. The MuvB complex sequentially recruits B-Myb and FoxM1 to promote mitotic gene expression. Genes Dev. 2012;26(5):474–489. doi: 10.1101/gad.181933.111
  • Schmit F, Cremer S, Gaubatz S. LIN54 is an essential core subunit of the DREAM/LINC complex that binds to the cdc2 promoter in a sequence-specific manner. FEBS J. 2009;276(19):5703–5716. doi: 10.1111/j.1742-4658.2009.07261.x
  • Müller GA, Engeland K. The central role of CDE/CHR promoter elements in the regulation of cell cycle-dependent gene transcription. FEBS J. 2010;277(4):877–893. doi: 10.1111/j.1742-4658.2009.07508.x
  • Müller GA, Quaas M, Schümann M, et al. The CHR promoter element controls cell cycle-dependent gene transcription and binds the DREAM and MMB complexes. Nucleic Acids Res. 2012;40(4):1561–1578.
  • Guiley KZ, Liban TJ, Felthousen JG, et al. Structural mechanisms of DREAM complex assembly and regulation. Genes Dev. 2015;29(9):961–974.
  • Fischer M, Müller GA. Cell cycle transcription control: DREAM/MuvB and RB-E2F complexes. Crit Rev Biochem Mol Biol. 2017;52:638–662. doi: 10.1080/1040923820171360836
  • Litovchick L, Florens LA, Swanson SK, et al. DYRK1A protein kinase promotes quiescence and senescence through DREAM complex assembly. Genes Dev. 2011;25(8):801–813.
  • Iness AN, Felthousen J, Ananthapadmanabhan V, et al. The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb. Oncogene. 2018;38:1080–1092. 38:7 2018. doi: 10.1038/s41388-018-0490-y.
  • Quaas M, Müller GA, Engeland K. p53 can repress transcription of cell cycle genes through a p21(WAF1/CIP1)-dependent switch from MMB to DREAM protein complex binding at CHR promoter elements. Cell Cycle (Georgetown, Tex). 2012;11:4661–4672. doi: 10.4161/cc.22917
  • Horn HF, Vousden KH. Coping with stress: multiple ways to activate p53. Oncogene. 2007;26(9):1306–1316. doi: 10.1038/sj.onc.1210263
  • Fernandez-Rebollo E, Franzen J, Goetzke R, et al. Senescence-associated metabolomic phenotype in primary and iPSC-Derived mesenchymal stromal cells. Stem Cell Rep. 2020;14(2):201–209. doi: 10.1016/j.stemcr.2019.12.012
  • He S, Sharpless NE. Senescence in health and disease. Cell. 2017;169:1000–1000. doi: 10.1016/j.cell.2017.05.015
  • Borghesan M, Fafián-Labora J, Eleftheriadou O, 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(13):3956–3971.e6.
  • Song S, Tchkonia T, Jiang J, et al. Targeting senescent cells for a healthier ageing: challenges and opportunities. Adv Sci. 2020;7:2002611. doi: 10.1002/advs.202002611
  • Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232–236.
  • Jeon OH, Kim C, Laberge R-M, et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med. 2017;23(6):775–781.
  • Palmer AK, Xu M, Zhu Y, et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Ageing Cell. 2019;18:e12950. doi: 10.1111/acel.12950
  • Wang L, Wang B, Gasek NS, et al. Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity. Cell Metab. 2022;34(1):75–89.e8.
  • Sun Y, Li Q, Kirkland JL. Targeting senescent cells for a healthier longevity: the roadmap for an era of global ageing. Life Med. 2022;1:103–119. doi: 10.1093/lifemedi/lnac030
  • Cai Y, Zhou H, Zhu Y, et al. Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell Res. 2020;30(7):574.
  • Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nature Med. 2018;24(8):1246–1256.
  • Krishnamurthy J, Torrice C, Ramsey MR, et al. Ink4a/Arf expression is a biomarker of ageing. J Clin Investig. 2004;114:1299–1307. doi: 10.1172/JCI22475
  • Gasek NS, Kuchel GA, Kirkland JL, et al. Strategies for targeting senescent cells in human disease. Nature Ageing. 2021;1:870–879. 1:10 2021. doi: 10.1038/s43587-021-00121-8.
  • Xu M, Tchkonia T, Kirkland JL. Perspective: targeting the JAK/STAT pathway to fight age-related dysfunction. Pharmacol Res. 2016;111:152–154. doi: 10.1016/j.phrs.2016.05.015
  • Childs BG, Baker DJ, Kirkland JL, et al. Senescence and apoptosis: dueling or complementary cell fates? EMBO Reports. 2014;15:1139. doi: 10.15252/embr.201439245
  • Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017;16(10):718.
  • Zhang X, Zhang S, Liu X, et al. Oxidation resistance 1 is a novel senolytic target. Ageing Cell. 2018;17:12780. doi: 10.1111/acel.12780
  • Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Med. 2016;22(1):78.
  • Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016 [[cited 2021 Nov 30]];7. /pmc/articles/PMC4823827/. doi: 10.1038/ncomms11190
  • Yang H, Chen C, Chen H, et al. Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis. Ageing. 2020;12:12750–12770. doi: 10.18632/aging.103177
  • Ritschka B, Knauer-Meyer T, Gonçalves DS, et al. The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice. Genes Dev. 2020;34(7–8):489–494.
  • Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18. doi: 10.1016/j.ebiom.2018.09.015
  • Lilja S, Oldenburg J, Pointner A, et al. Epigallocatechin gallate effectively affects senescence and anti-SASP via SIRT3 in 3T3-L1 preadipocytes in comparison with other bioactive substances. Oxid Med Cell Longevity. 2020;2020:1–13. doi: 10.1155/2020/4793125
  • Kumar R, Sharma A, Kumari A, et al. Epigallocatechin gallate suppresses premature senescence of preadipocytes by inhibition of PI3K/Akt/mTOR pathway and induces senescent cell death by regulation of Bax/Bcl-2 pathway. Biogerontology. 2018;20:171–189. 20:2 2018. doi: 10.1007/s10522-018-9785-1.
  • Shin JH, Jeon HJ, Park J, et al. Epigallocatechin-3-gallate prevents oxidative stress-induced cellular senescence in human mesenchymal stem cells via Nrf2. Int J Mol Med. 2016;38(4):1075–1082. doi: 10.3892/ijmm.2016.2694
  • Liao VHC, Yu CW, Chu YJ, et al. Curcumin-mediated lifespan extension in caenorhabditis elegans. Mech Ageing Dev. 2011;132(10):480–487. doi: 10.1016/j.mad.2011.07.008
  • Lee KS, Lee BS, Semnani S, et al. Curcumin extends life span, improves health span, and modulates the expression of age-associated aging genes in drosophila melanogaster. Rejuvenation Res. 2010;13:561–570. https://home.liebertpub.com/rej
  • Pluta R, Ułamek-Kozioł M, Czuczwar SJ. Neuroprotective and neurological/cognitive enhancement effects of curcumin after brain ischemia injury with alzheimer’s disease phenotype. Int J Mol Sci. 2018;19(12):4002. doi: 10.3390/ijms19124002
  • Ray Hamidie RD, Yamada T, Ishizawa R, et al. Curcumin treatment enhances the effect of exercise on mitochondrial biogenesis in skeletal muscle by increasing cAMP levels. Metabolism. 2015;64(10):1334–1347.
  • Miao J, Liu J, Niu J, et al. Wnt/β-catenin/RAS signalling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction. Ageing Cell. 2019;18:e13004. doi: 10.1111/acel.13004
  • Luo C, Zhou S, Zhou Z, et al. Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells. J Am Soc Nephrol. 2018;29(4):1238–1256.
  • Davis T, Brook AJC, Rokicki MJ, et al. Evaluating the role of p38 MAPK in the accelerated cell senescence of werner syndrome fibroblasts. Pharmaceuticals. 2016;9(2):23. doi: 10.3390/ph9020023
  • Pakala R, Stabile E, Jang GJ, et al. Rapamycin attenuates atherosclerotic plaque progression in apolipoprotein E knockout mice: inhibitory effect on monocyte chemotaxis. J Cardiovasc Pharmacol. 2005;46(4):481–486. doi: 10.1097/01.fjc.0000177985.14305.15
  • Testai L, Piragine E, Piano I, et al. The citrus flavonoid naringenin protects the myocardium from ageing-dependent dysfunction: potential role of SIRT1. Oxid Med Cell Longevity. 2020;2020: doi: 10.1155/2020/4650207
  • Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Ageing Cell. 2015;14:644–658. doi: 10.1111/acel.12344
  • Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Ageing Cell. 2016;15:428–435. doi: 10.1111/acel.12445
  • Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017;16(10):718–735.
  • Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to Chemotoxicity and aging. Cell. 2017;169(1):132–147.e16.
  • Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Ageing (Albany NY). 2017;9:955. doi: 10.18632/aging.101202
  • Debacq-Chainiaux F, Erusalimsky JD, Campisi J, 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;4:1798–1806. doi: 10.1038/nprot.2009.191
  • Childs BG, Durik M, Baker DJ, et al. Cellular senescence in ageing and age-related disease: from mechanisms to therapy. Nature Med. 2015;21:1424. doi: 10.1038/nm.4000
  • Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28(6):436–453. doi: 10.1016/j.tcb.2018.02.001
  • Moysan E, Bastiat G, Benoit JP. Gemcitabine versus Modified Gemcitabine: a review of several promising chemical modifications. Mol Pharmaceut. 2013;10(2):430–444. doi: 10.1021/mp300370t
  • Mini E, Nobili S, Caciagli B, et al. Cellular pharmacology of gemcitabine. Annals Oncol Official J European Society Med Oncol. 2006 [cited 2022 Feb 16];17(Suppl 5). https://pubmed.ncbi.nlm.nih.gov/16807468/
  • Plunkett W, Huang P, Gandhi V. Preclinical characteristics of gemcitabine. Anticancer Drugs. 1995;6(Supplement 6):7–13. doi: 10.1097/00001813-199512006-00002
  • Sarkar AK, Fritz TA, Taylor WH, et al. Disaccharide uptake and priming in animal cells: inhibition of sialyl Lewis X by acetylated gal beta 1–>4GlcNAc beta-O-naphthalenemethanol. Proc Natl Acad Sci USA. 1995;92:3323–3327. doi: 10.1073/pnas.92.8.3323
  • Tilstra JS, Robinson AR, Wang J, et al. NF-κB inhibition delays DNA damage-induced senescence and ageing in mice. J Clin Investig. 2012;122:2601–2612. doi: 10.1172/JCI45785
  • Kang HT, Park JT, Choi K, et al. Chemical screening identifies ATM as a target for alleviating senescence. Nat Chem Biol. 2017;13:616–623. doi: 10.1038/nchembio.2342
  • Lee SJ, Jung YS, Yoon MH, et al. Interruption of progerin-lamin A/C binding ameliorates hutchinson-gilford progeria syndrome phenotype. J Clin Investig. 2016;126:3879–3893. doi: 10.1172/JCI84164
  • Yang HH, Hwangbo K, Zheng MS, et al. Inhibitory effects of juglanin on cellular senescence in human dermal fibroblasts. J Nat Med. 2014;68:473–480. doi: 10.1007/s11418-014-0817-0
  • Yang HH, Hwangbo K, Zheng MS, et al. Quercetin-3-O-β-D-glucuronide isolated from Polygonum aviculare inhibits cellular senescence in human primary cells. Arch Pharm Res. 2014;37:1219–1233. doi: 10.1007/s12272-014-0344-2
  • Yang HH, Hwangbo K, Zheng MS, et al. Inhibitory effects of (-)-loliolide on cellular senescence in human dermal fibroblasts. Arch Pharm Res. 2015;38:876–884. doi: 10.1007/s12272-014-0435-0
  • Yang HH, Zhang H, Son JK, et al. Inhibitory effects of quercetagetin 3,4’-dimethyl ether purified from Inula japonica on cellular senescence in human umbilical vein endothelial cells. Arch Pharm Res. 2015;38:1857–1864. doi: 10.1007/s12272-015-0577-8
  • Bae YU, Choi JH, Nagy A, et al. Antisenescence effect of mouse embryonic stem cell conditioned medium through a PDGF/FGF pathway. FASEB J. 2016;30:1276–1286. doi: 10.1096/fj.15-278846
  • Bae YU, Son Y, Kim CH, et al. Embryonic stem cell-Derived mmu-miR-291a-3p inhibits cellular senescence in human dermal fibroblasts through the TGF-β receptor 2 pathway. J Gerontol Ser A. 2019;74:1359–1367. doi: 10.1093/gerona/gly208
  • Kim EC, Kim JR. Senotherapeutics: emerging strategy for healthy ageing and age-related disease. BMB Rep. 2019;52:47. doi: 10.5483/BMBRep.2019.52.1.293
  • Liu P, Zhao H, Luo Y. Anti-ageing implications of astragalus membranaceus (Huangqi): a well-known Chinese tonic. Aging Dis. 2017;8:868–886. doi: 10.14336/AD.2017.0816
  • Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for ageing, diabetes, cancer, and cardiovascular disease. Sci Transl Med. 2017 [[cited 2022 Nov 29]];9. Available from: https://pubmed.ncbi.nlm.nih.gov/28202779/
  • Lamming DW, Ye L, Sabatini DM, et al. Rapalogs and mTOR inhibitors as anti-ageing therapeutics. J Clin Investig. 2013;123:980–989. doi: 10.1172/JCI64099
  • Si H, Liu D. Dietary antiageing phytochemicals and mechanisms associated with prolonged survival. J Nutr Biochem. 2014;25:581–591. doi: 10.1016/j.jnutbio.2014.02.001
  • Soto-Gamez A, Demaria M. Therapeutic interventions for ageing: the case of cellular senescence. Drug Discovery Today. 2017;22:786–795. doi: 10.1016/j.drudis.2017.01.004
  • Nakamura S, Yoshimori T. Autophagy and longevity. Mol Cells. 2018;41(1):65–72. doi: 10.14348/molcells.2018.2333
  • Schafer MJ, Miller JD, LeBrasseur NK. Cellular senescence: Implications for metabolic disease. Mol Cell Endocrinol. 2017;455:93–102. doi: 10.1016/j.mce.2016.08.047
  • Wiley CD, Brumwell AN, Davis SS, et al. Secretion of leukotrienes by senescent lung fibroblasts promotes pulmonary fibrosis. JCI Insight. 2019;4(24):4.
  • Di Leonardo A, Linke SP, Clarkin K, et al. DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev. 1994;8(21):2540–2551.
  • Calcinotto A, Kohli J, Zagato E, et al. Cellular senescence: Ageing, cancer, and injury. Physiol Rev. 2019;99:1047–1078. doi: 10.1152/physrev.00020.2018
  • Sharpless NE, DePinho RA. Cancer: crime and punishment. Nature. 2005;436(7051):636–637. doi: 10.1038/436636a
  • Baker DJ, Sedivy JM. Probing the depths of cellular senescence. J Cell Bio. 2013;202(1):11–13. doi: 10.1083/jcb.201305155
  • Cheung TH, Rando TA. Molecular regulation of stem cell quiescence. Nat Rev Mol Cell Biol. 2013;14(6):329–340. doi: 10.1038/nrm3591
  • Anders L, Ke N, Hydbring P, et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell. 2011;20(5):620–634.
  • Nogueira V, Park Y, Chen CC, et al. Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell. 2008;14(6):458–470.
  • Miyauchi H, Minamino T, Tateno K, et al. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J. 2004;23(1):212–220.
  • Imai Y, Takahashi A, Hanyu A, et al. Crosstalk between the Rb pathway and AKT signalling forms a quiescence-senescence switch. Cell Rep. 2014;7:194–207. doi: 10.1016/j.celrep.2014.03.006
  • Demidenko ZN, Korotchkina LG, Gudkov AV, et al. Paradoxical suppression of cellular senescence by p53. Proc Natl Acad Sci USA. 2010;107:9660–9664. doi: 10.1073/pnas.1002298107
  • Korotchkina LG, Leontieva OV, Bukreeva EI, et al. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Ageing. 2010;2:344–352. doi: 10.18632/aging.100160
  • McCay CM, Crowell MF, Maynard LA. The effect of retarded growth upon the length of life span and upon the ultimate body SizeOne Figure. J Nutr. 1935;10(1):63–79. doi: 10.1093/jn/10.1.63

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.