Abstract
Given its state of stable proliferative inhibition, cellular senescence is primarily depicted as a critical mechanism by which organisms delay the progression of carcinogenesis. Cells undergoing senescence are often associated with the alteration of a series of specific features and functions, such as metabolic shifts, stemness induction, and microenvironment remodeling. However, recent research has revealed more complexity associated with senescence, including adverse effects on both physiological and pathological processes. How organisms evade these harmful consequences and survive has become an urgent research issue. Several therapeutic strategies targeting senescence, including senolytics, senomorphics, immunotherapy, and function restoration, have achieved initial success in certain scenarios. In this review, we describe in detail the characteristic changes associated with cellular senescence and summarize currently available countermeasures.
概要
衰老的细胞通常处于一种稳定的增殖抑制状态, 因此细胞衰老最初被认为是生物体延缓癌症进展的重要机制. 细胞在衰老时通常伴随着一系列特征和功能的改变, 如代谢迁移、 干性诱导以及微环境重塑等. 然而, 近年来研究表明, 细胞衰老参与了机体一系列生理学和病理学的变化, 进一步增加了其复杂性. 生物体如何通过适应性变化来规避衰老带来的不利影响是当前研究的热点之一. 目前, 针对细胞衰老的疗法, 包括衰老细胞裂解、 衰老形态学纠正、 衰老免疫疗法以及功能恢复等, 已经在特定的情境下取得初步成果. 在这篇综述中, 我们详细描述了细胞衰老相关的特征变化, 并总结了当前衰老治疗可行的策略.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Aird KM, Zhang G, Li H, et al., 2013. Suppression of nucleotide metabolism underlies the establishment and maintenance of oncogene-induced senescence. Cell Rep, 3(4): 1252–1265. https://doi.org/10.1016/j.celrep.2013.03.004
Alspach E, Flanagan KC, Luo XM, et al., 2014. p38MAPK plays a crucial role in stromal-mediated tumorigenesis. Cancer Discov, 4(6):716–729. https://doi.org/10.1158/2159-8290.CD-13-0743
Amor C, Feucht J, Leibold J, et al., 2020. Senolytic CAR T cells reverse senescence-associated pathologies. Nature, 583(7814):127–132. https://doi.org/10.1038/s41586-020-2403-9
Arora S, Thompson PJ, Wang Y, et al., 2021. Invariant natural killer T cells coordinate removal of senescent cells. Med (N Y), 2(8):938–950. https://doi.org/10.1016/j.medj.2021.04.014
Baar MP, Brandt RMC, Putavet DA, et al., 2017. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 169(1):132–147.e16. https://doi.org/10.1016/j.cell.2017.02.031
Bai ZS, Peng YL, Ye XY, et al., 2022. Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(2):89–101. https://doi.org/10.1631/jzus.B2100804
Batlle E, Clevers H, 2017. Cancer stem cells revisited. Nat Med, 23(10):1124–1134. https://doi.org/10.1038/nm.4409
bin Imtiaz MK, Jaeger BN, Bottes S, et al., 2021. Declining lamin B1 expression mediates age-dependent decreases of hippocampal stem cell activity. Cell Stem Cell, 28(5): 967–977.e8. https://doi.org/10.1016/j.stem.2021.01.015
Blokland KEC, Pouwels SD, Schuliga M, et al., 2020. Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases. Clin Sci (Lond), 134(20):2681–2706. https://doi.org/10.1042/CS20190893
Carlsten M, Childs RW, 2015. Genetic manipulation of NK cells for cancer immunotherapy: techniques and clinical implications. Front Immunol, 6:266. https://doi.org/10.3389/fimmu.2015.00266
Chaleckis R, Murakami I, Takada J, et al., 2016. Individual variability in human blood metabolites identifies age-related differences. Proc Natl Acad Sci USA, 113(16):4252–4259. https://doi.org/10.1073/pnas.1603023113
Chambers CR, Ritchie S, Pereira BA, et al., 2021. Overcoming the senescence-associated secretory phenotype (SASP): a complex mechanism of resistance in the treatment of cancer. Mol Oncol, 15(12):3242–3255. https://doi.org/10.1002/1878-0261.13042
Chen F, Long QL, Fu D, et al., 2018. Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance. Nat Commun, 9:4315. https://doi.org/10.1038/s41467-018-06860-4
Cheng H, Xuan HW, Green CD, et al., 2018. Repression of human and mouse brain inflammaging transcriptome by broad gene-body histone hyperacetylation. Proc Natl Acad Sci USA, 115(29):7611–7616. https://doi.org/10.1073/pnas.1800656115
Cheng T, Rodrigues N, Shen H, et al., 2000. Hematopoietic stem cell quiescence maintained by p21cipl/wafl. Science, 287(5459):1804–1808. https://doi.org/10.1126/science.287.5459.1804
Chien Y, Scuoppo C, Wang XW, et al., 2011. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev, 25(20):2125–2136. https://doi.org/10.1101/gad.17276711
Contrepois K, Coudereau C, Benayoun BA, et al., 2017. Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nat Commun, 8: 14995. https://doi.org/10.1038/ncomms14995
Crespo J, Sun HY, Welling TH, et al., 2013. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol, 25(2):214–221. https://doi.org/10.1016/j.coi.2012.12.003
Crosby CM, Kronenberg M, 2018. Tissue-specific functions of invariant natural killer T cells. Nat Rev Immunol, 18(9): 559–574. https://doi.org/10.1038/s41577-018-0034-2
Cruickshanks HA, Mcbryan T, Nelson DM, et al., 2013. Senescent cells harbour features of the cancer epigenome. Nat Cell Biol, 15(12):1495–1506. https://doi.org/10.1038/ncb2879
del Gaizo Moore V, Brown JR, Certo M, et al., 2007. Chronic lymphocytic leukemia requires BCL2 to sequester pro-death BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest, 117(1):112–121. https://doi.org/10.1172/JCI28281
Delfarah A, Parrish S, Junge JA, et al., 2019. Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells. J Biol Chem, 294(27):10564–10578. https://doi.org/10.1074/jbc.RA118.005806
di Mitri D, Alimonti A, 2016. Non-cell-autonomous regulation of cellular senescence in cancer. Trends Cell Biol, 26(3): 215–226. https://doi.org/10.1016/j.tcb.2015.10.005
Dörr JR, Yu Y, Milanovic M, et al., 2013. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature, 501(7467):421–425. https://doi.org/10.1038/nature12437
Ecker BL, Kaur A, Douglass SM, et al., 2019. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov, 9(1): 82–95. https://doi.org/10.1158/2159-8290.CD-18-0168
Erbe R, Wang ZY, Wu S, et al., 2021. Evaluating the impact of age on immune checkpoint therapy biomarkers. Cell Rep, 36(8):109599. https://doi.org/10.1016/j.celrep.2021.109599
Faget DV, Ren QH, Stewart SA, 2019. Unmasking senescence: context-dependent effects of SASP in cancer. Nat Rev Cancer, 19(8):439–453. https://doi.org/10.1038/s41568-019-0156-2
Feins S, Kong WM, Williams EF, et al., 2019. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol, 94(S1):S3–S9. https://doi.org/10.1002/ajh.25418
Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al., 2017. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun, 8:422. https://doi.org/10.1038/s41467-017-00314-z
Gan KJ, Südhof TC, 2019. Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc Natl Acad Sci USA, 116(25):12524–12533. https://doi.org/10.1073/pnas.1902672116
García-Prat L, Martínez-Vicente M, Perdiguero E, et al., 2016. Autophagy maintains stemness by preventing senescence. Nature, 529(7584):37–42. https://doi.org/10.1038/nature16187
Gomes AP, Ilter D, Low V, et al., 2020. Age-induced accumulation of methylmalonic acid promotes tumour progression. Nature, 585(7824):283–287. https://doi.org/10.1038/s41586-020-2630-0
Grosse L, Wagner N, Emelyanov A, et al., 2020. Defined p16High senescent cell types are indispensable for mouse health-span. Cell Metab, 32(1):87–99.e6. https://doi.org/10.1016/j.cmet.2020.05.002
Guerrero A, Herranz N, Sun B, et al., 2019. Cardiac glycosides are broad-spectrum senolytics. Nat Metab, 1(11): 1074–1088. https://doi.org/10.1038/s42255-019-0122-z
Han L, Long QL, Li SJ, et al., 2020. Senescent stromal cells promote cancer resistance through SIRT1 loss-potentiated overproduction of small extracellular vesicles. Cancer Res, 80(16):3383–3398. https://doi.org/10.1158/0008-5472.CAN-20-0506
Haynes L, Eaton SM, Burns EM, et al., 2003. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc Natl Acad Sci USA, 100(25):15053–15058. https://doi.org/10.1073/pnas.2433717100
Henson SM, Lanna A, Riddell NE, et al., 2014. p38 signaling inhibits MTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest, 124(9):4004–4016. https://doi.org/10.1172/JCI75051
Hernandez-Segura A, Nehme J, Demaria M, 2018. Hallmarks of cellular senescence. Trends Cell Biol, 28(6):436–453. https://doi.org/10.1016/j.tcb.2018.02.001
Herranz N, Gallage S, Mellone M, et al., 2015. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol, 17(9): 1205–1217. https://doi.org/10.1038/ncb3225
Ho TT, Warr MR, Adelman ER, et al., 2017. Autophagy maintains the metabolism and function of young and old stem cells. Nature, 543(7644):205–210. https://doi.org/10.1038/nature21388
Hong MH, Clubb JD, Chen YY, 2020. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell, 38(4): 473–488. https://doi.org/10.1016/j.ccell.2020.07.005
Hwang HJ, Lee YR, Kang D, et al., 2020. Endothelial cells under therapy-induced senescence secrete CXCL11, which increases aggressiveness of breast cancer cells. Cancer Lett, 490:100–110. https://doi.org/10.1016/j.canlet.2020.06.019
Jeng MY, Hull PA, Fei MJ, et al., 2018. Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1. J Exp Med, 215(1):51–62. https://doi.org/10.1084/jem.20161066
Jeon OH, Kim C, Laberge RM, et al., 2017. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med, 23(6):775–781. https://doi.org/10.1038/nm.4324
Jin WN, Shi KB, He WY, et al., 2021. Neuroblast senescence in the aged brain augments natural killer cell cytotoxicity leading to impaired neurogenesis and cognition. Nat Neurosci, 24(1):61–73. https://doi.org/10.1038/s41593-020-00745-w
Johmura Y, Yamanaka T, Omori S, et al., 2021. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science, 371(6526):265–270. https://doi.org/10.1126/science.abb5916
Kalamakis G, Brüne D, Ravichandran S, et al., 2019. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell, 176(6): 1407–1419.e14. https://doi.org/10.1016/j.cell.2019.01.040
Kale A, Sharma A, Stolzing A, et al., 2020. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing, 17:16. https://doi.org/10.1186/s12979-020-00187-9
Kaplon J, Zheng L, Meissl K, et al., 2013. A key role for mitochondrial gatekeeper pyruvate dehydrogenase in oncogene-induced senescence. Nature, 498(7452):109–112. https://doi.org/10.1038/nature12154
Kaur A, Webster MR, Marchbank K, et al., 2016. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature, 532(7598):250–254. https://doi.org/10.1038/nature17392
Kaur A, Ecker BL, Douglass SM, et al., 2019. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov, 9(1):64–81. https://doi.org/10.1158/2159-8290.CD-18-0193
Kirkland JL, Tchkonia T, 2020. Senolytic drugs: from discovery to translation. J Intern Med, 288(5):518–536. https://doi.org/10.1111/joim.13141
Kowald A, Passos JF, Kirkwood TBL, 2020. On the evolution of cellular senescence. Aging Cell, 19(12):e13270. https://doi.org/10.1111/acel.13270
Krtolica A, Parrinello S, Lockett S, et al., 2001. Senescent fibro-blasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA, 98(21):12072–12077. https://doi.org/10.1073/pnas.211053698
Kuilman T, Michaloglou C, Vredeveld LCW, et al., 2008. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell, 133(6):1019–1031. https://doi.org/10.1016/j.cell.2008.03.039
Kuilman T, Michaloglou C, Mooi WJ, et al., 2010. The essence of senescence. Genes Dev, 24(22):2463–2479. https://doi.org/10.1101/gad.1971610
Lawrenson K, Grun B, Benjamin E, et al., 2010. Senescent fibro-blasts promote neoplastic transformation of partially transformed ovarian epithelial cells in a three-dimensional model of early stage ovarian cancer. Neoplasia, 12(4):317–325. https://doi.org/10.1593/neo.91948
Lee S, Schmitt CA, 2019. The dynamic nature of senescence in cancer. Nate Cell Biol, 21(1):94–101. https://doi.org/10.1038/s41556-018-0249-2
Lee S, Yu Y, Trimpert J, et al., 2021. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature, 599(7884):283–289. https://doi.org/10.1038/s41586-021-03995-1
Lei Q, Gao F, Liu T, et al., 2021. Extracellular vesicles deposit PCNA to rejuvenate aged bone marrow-derived mesenchymal stem cells and slow age-related degeneration. Sci Transl Med, 13(578):eaaz8697. https://doi.org/10.1126/scitranslmed.aaz8697
Levi N, Papismadov N, Solomonov I, et al., 2020. The ECM path of senescence in aging: components and modifiers. FEBS J, 287(13):2636–2646. https://doi.org/10.1111/febs.15282
L’Hôte V, Courbeyrette R, Pinna G, et al., 2021. Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy. Aging Cell, 20(9): e13447. https://doi.org/10.1111/acel.13447
Li FM, Huangyang P, Burrows M, et al., 2020. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat Cell Biol, 22(6):728–739. https://doi.org/10.1038/s41556-020-0511-2
Li H, Lakshmikanth T, Garofalo C, et al., 2011. Pharmacological activation of p53 triggers anticancer innate immune response through induction of ULBP2. Cell Cycle, 10(19): 3346–3358. https://doi.org/10.4161/cc.10.19.17630
Lian JY, Yue Y, Yu WN, et al., 2020. Immunosenescence: a key player in cancer development. J Hematol Oncol, 13:151. https://doi.org/10.1186/s13045-020-00986-z
Liu Y, Elf SE, Miyata Y, et al., 2009. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell, 4(1):37–48. https://doi.org/10.1016/j.stem.2008.11.006
Liu ZY, Leung D, Thrush K, et al., 2020. Underlying features of epigenetic aging clocks in vivo and in vitro. Aging Cell, 19(10):e13229. https://doi.org/10.1111/acel.13229
Lizardo DY, Lin YL, Gokcumen O, et al., 2017. Regulation of lipids is central to replicative senescence. Mol BioSyst, 13(3):498–509. https://doi.org/10.1039/c6mb00842a
Loo TM, Miyata K, Tanaka Y, et al., 2020. Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer. Cancer Sci, 111(2):304–311. https://doi.org/10.1111/cas.14266
Lujambio A, Akkari L, Simon J, et al., 2013. Non-cell-autonomous tumor suppression by p53. Cell, 153(2):449–460. https://doi.org/10.1016/j.cell.2013.03.020
Manfredi R, 2004. HIV infection and advanced age: emerging epidemiological, clinical, and management issues. Ageing Res Rev, 3(1):31–54. https://doi.org/10.1016/j.arr.2003.07.001
Mavrogonatou E, Pratsinis H, Papadopoulou A, et al., 2019. Extracellular matrix alterations in senescent cells and their significance in tissue homeostasis. Matrix Biol, 75–76: 27–42. https://doi.org/10.1016/j.matbio.2017.10.004
Meyers AK, Zhu XW, 2020. The NLRP3 inflammasome: metabolic regulation and contribution to inflammaging. Cells, 9(8):1808. https://doi.org/10.3390/cells9081808
Milanovic M, Fan DNY, Belenki D, et al., 2018a. Senescence-associated reprogramming promotes cancer stemness. Nature, 553(7686):96–100. https://doi.org/10.1038/nature25167
Milanovic M, Yu Y, Schmitt CA, 2018b. The senescence-sternness alliance-a cancer-hijacked regeneration principle. Trends Cell Biol, 28(12):1049–1061. https://doi.org/10.1016/j.tcb.2018.09.001
Minhas PS, Latif-Hernandez A, Mcreynolds MR, et al., 2021. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature, 590(7844):122–128. https://doi.org/10.1038/s41586-020-03160-0
Montes CL, Chapoval AI, Nelson J, et al., 2008. Tumor-induced senescent T cells with suppressor function: a potential form of tumor immune evasion. Cancer Res, 68(3):870–879. https://doi.org/10.1158/0008-5472.CAN-07-2282
Moyon S, Frawley R, Marechal D, et al., 2021. TET1-mediated DNA hydroxymethylation regulates adult remyelination in mice. Nat Commun, 12:3359. https://doi.org/10.1038/s41467-021-23735-3
Muñoz-Galván S, Lucena-Cacace A, Perez M, et al., 2019. Tumor cell-secreted PLD increases tumor stemness by senescence-mediated communication with microenvironment. Oncogene, 38(8):1309–1323. https://doi.org/10.1038/s41388-018-0527-2
Nacarelli T, Fukumoto T, Zundell JA, et al., 2020. NAMPT inhibition suppresses cancer stem-like cells associated with therapy-induced senescence in ovarian cancer. Cancer Res, 80(4):890–900. https://doi.org/10.1158/0008-5472.CAN-19-2830
Oltra SS, Peña-Chilet M, Flower K, et al., 2019. Acceleration in the DNA methylation age in breast cancer tumours from very young women. Sci Rep, 9(1):14991. https://doi.org/10.1038/s41598-019-51457-6
Otero-Albiol D, Carnero A, 2021. Cellular senescence or stemness: hypoxia flips the coin. J Exp Clin Cancer Res, 40:243. https://doi.org/10.1186/s13046-021-02035-0
Ozsvari B, Nuttall JR, Sotgia F, et al., 2018. Azithromycin and roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging, 10(11): 3294–3307. https://doi.org/10.18632/aging.101633
Pathan M, Fonseka P, Chitti SV, et al., 2019. Vesiclepedia 2019: a compendium of RNA, proteins, lipids and metabolites in extracellular vesicles. Nucleic Acids Res, 47(D1): D516–D519. https://doi.org/10.1093/nar/gky1029
Pawelec G, 2019. Does patient age influence anti-cancer immunity? Semin Immunopathol, 41(1): 125–131. https://doi.org/10.1007/s00281-018-0697-6
Pazolli E, Alspach E, Milczarek A, et al., 2012. Chromatin remodeling underlies the senescence-associated secretory phenotype of tumor stromal fibroblasts that supports cancer progression. Cancer Res, 72(9):2251–2261. https://doi.org/10.1158/0008-5472.CAN-11-3386
Pereira BI, Devine OP, Vukmanovic-Stejic M, et al., 2019. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat Commun, 10:2387. https://doi.org/10.1038/s41467-019-10335-5
Perrigue PM, Rakoczy M, Pawlicka KP, et al., 2020. Cancer stem cell-inducing media activates senescence reprogramming in fibroblasts. Cancers, 12(7):1745. https://doi.org/10.3390/cancers12071745
Poblocka M, Bassey AL, Smith VM, et al., 2021. Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker. Sci Rep, 11:20358. https://doi.org/10.1038/s41598-021-99852-2
Qing YJ, Li H, Zhao YZ, et al., 2021. One-two punch therapy for the treatment of T-cell malignancies involving p53-dependent cellular senescence. Oxid Med Cell Longev, 2021:5529518. https://doi.org/10.1155/2021/5529518
Rajendran P, Alzahrani AM, Hanieh HN, et al., 2019. Autophagy and senescence: a new insight in selected human diseases. J Cell Physiol, 234(12):21485–21492. https://doi.org/10.1002/jcp.28895
Rezvani K, Rouce R, Liu EL, et al., 2017. Engineering natural killer cells for cancer immunotherapy. Mol Ther, 25(8): 1769–1781. https://doi.org/10.1016/j.ymthe.2017.06.012
Ritschka B, Storer M, Mas A, et al., 2017. The senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration. Genes Dev, 31(2):172–183. https://doi.org/10.1101/gad.290635.116
Ruggeri L, Capanni M, Urbani E, et al., 2002. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science, 295(5562):2097–2100. https://doi.org/10.1126/science.1068440
Sahu A, Mamiya H, Shinde SN, et al., 2018. Age-related declines in a-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration. Nat Commun, 9:4859. https://doi.org/10.1038/s41467-018-07253-3
Salazar G, Cullen A, Huang JW, et al., 2020. SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence. Autophagy, 16(6): 1092–1110. https://doi.org/10.1080/15548627.2019.1659612
Schafer MJ, White TA, Iijima K, et al., 2017. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun, 8:14532. https://doi.org/10.1038/ncomms14532
Schmitt CA, 2018. UnSASPing senescence: unmasking tumor suppression? Cancer Cell, 34(1):6–8. https://doi.org/10.1016/j.ccell.2018.06.009
Sebastian T, Malik R, Thomas S, et al., 2005. C/EBPβ cooperates with RB: E2F to implement RasV12-induced cellular senescence. EMBO J, 24(18):3301–3312. https://doi.org/10.1038/sj.emboj.7600789
Segel M, Neumann B, Hill MFE, et al., 2019. Niche stiffness underlies the ageing of central nervous system progenitor cells. Nature, 573(7772):130–134. https://doi.org/10.1038/s41586-019-1484-9
Serrano M, 2017. Ageing: tools to eliminate senescent cells. Nature, 545(7654):294–295. https://doi.org/10.1038/nature22493
Shah Y, Verma A, Marderstein AR, et al., 2021. Pan-cancer analysis reveals molecular patterns associated with age. Cell Rep, 37(10):110100. https://doi.org/10.1016/j.celrep.2021.110100
Sharma A, Almasan A, 2021. Autophagy and PTEN in DNA damage-induced senescence. Adv Cancer Res, 150:249–284. https://doi.org/10.1016/bs.acr.2021.01.006
Shi HZ, Zeng JC, Shi SH, et al., 2021. Extracellular vesicles of GMSCs alleviate aging-related cell senescence. J Dent Res, 100(3):283–292. https://doi.org/10.1177/0022034520962463
Storer M, Mas A, Robert-Moreno A, et al., 2013. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell, 155(5):1119–1130. https://doi.org/10.1016/j.cell.2013.10.041
Sturmlechner I, Zhang C, Sine CC, et al., 2021. p21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science, 374(6567):eabb3420. https://doi.org/10.1126/science.abb3420
Suda M, Shimizu I, Katsuumi G, et al., 2021. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat Aging, 1(12):1117–1126. https://doi.org/10.1038/s43587-021-00151-2
Sugrue VJ, Zoller JA, Narayan P, et al., 2021. Castration delays epigenetic aging and feminizes DNA methylation at androgen-regulated loci. eLife, 10:e64932. https://doi.org/10.7554/eLife.64932
Takahashi A, Okada R, Nagao K, et al., 2017. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat Commun, 8:15287. https://doi.org/10.1038/ncomms15287
Thompson PJ, Shah A, Ntranos V, et al., 2019. Targeted elimination of senescent beta cells prevents type 1 diabetes. Cell Metab, 29(5):1045–1060.e10. https://doi.org/10.1016/j.cmet.2019.01.021
Toso A, Revandkar A, di Mitri D, et al., 2014. Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity. Cell Rep, 9(1):75–89. https://doi.org/10.1016/j.celrep.2014.08.044
van Niel G, D’Angelo G, Raposo G, 2018. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol, 19(4):213–228. https://doi.org/10.1038/nrm.2017.125
Venkei ZG, Yamashita YM, 2018. Emerging mechanisms of asymmetric stem cell division. J Cell Biol, 217(11):3785–3795. https://doi.org/10.1083/jcb.201807037
Wang C, Vegna S, Jin HJ, et al., 2019. Inducing and exploiting vulnerabilities for the treatment of liver cancer. Nature, 574(7777):268–272. https://doi.org/10.1038/s41586-019-1607-3
Wang RW, Viganô S, Ben-David U, et al., 2021. Aneuploid senescent cells activate NF-kB to promote their immune clearance by NK cells. EMBO Rep, 22(8):e52032. https://doi.org/10.15252/embr.202052032
Weber R, Groth C, Lasser S, et al., 2021. IL-6 as a major regulator of MDSC activity and possible target for cancer immunotherapy. Cell Immunol, 359:104254. https://doi.org/10.1016/j.cellimm.2020.104254
Wiley CD, Campisi J, 2021. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab, 3(10):1290–1301. https://doi.org/10.1038/s42255-021-00483-8
Xu QX, Long QL, Zhu DX, et al., 2019. Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression. Aging Cell, 18(6):e13027. https://doi.org/10.1111/acel.13027
Xue W, Zender L, Miething C, et al., 2007. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445(7128):656–660. https://doi.org/10.1038/nature05529
Yager EJ, Ahmed M, Lanzer K, et al., 2008. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med, 205(3):711–723. https://doi.org/10.1084/jem.20071140
Yosef R, Pilpel N, Tokarsky-Amiel R, et al., 2016. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun, 7:11190. https://doi.org/10.1038/ncomms11190
Yoshida S, Nakagami H, Hayashi H, et al., 2020. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat Commun, 11:2482. https://doi.org/10.1038/s41467-020-16347-w
Zhang BY, Fu D, Xu QX, et al., 2018. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat Commun, 9:1723. https://doi.org/10.1038/s41467-018-04010-4
Zhu HY, Li QQ, Liao TP, et al., 2021. Metabolomic profiling of single enlarged lysosomes. Nat Methods, 18(7):788–798. https://doi.org/10.1038/s41592-021-01182-8
Zhu Y, Tchkonia T, Pirtskhalava T, et al., 2015. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 14(4):644–658. https://doi.org/10.1111/acel.12344
Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, et al., 2016. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell, 15(3):428–435. https://doi.org/10.1111/acel.12445
Author information
Authors and Affiliations
Contributions
Yunzi ZHAO analyzed the literature and prepared the first draft of the manuscript. Hui LI contributed to the writing and design of the manuscript. Hui HUI and Qinglong GUO revised, edited, and checked the final version. All authors have read and approved the final manuscript.
Corresponding author
Ethics declarations
Yunzi ZHAO, Hui LI, Qinglong GUO, and Hui HUI declare that they have no conflict of interests.
This review does not contain any studies with human or animal subjects performed by any of the authors.
Rights and permissions
About this article
Cite this article
Zhao, Y., Li, H., Guo, Q. et al. Multiple characteristic alterations and available therapeutic strategies of cellular senescence. J. Zhejiang Univ. Sci. B 24, 101–114 (2023). https://doi.org/10.1631/jzus.B2200178
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1631/jzus.B2200178