Cellular senescence in age-related musculoskeletal diseases

Abstract

Aging is typically associated with decreased musculoskeletal function, leading to reduced mobility and increased frailty. As a hallmark of aging, cellular senescence plays a crucial role in various age-related musculoskeletal diseases, including osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. The detrimental effects of senescence are primarily due to impaired regenerative capacity of stem cells and the pro-inflammatory environment created by accumulated senescent cells. The secreted senescence-associated secretory phenotype (SASP) can induce senescence in neighboring cells, further amplifying senescent signals. Although the removal of senescent cells and the suppression of SASP factors have shown promise in alleviating disease progression and restoring musculoskeletal health in mouse models, clinical trials have yet to demonstrate significant efficacy. This review summarizes the mechanisms of cellular senescence in age-related musculoskeletal diseases and discusses potential therapeutic strategies targeting cellular senescence.

Keywords

cellular senescence / aging / musculoskeletal disease / degenerative diseases / senotherapy

References

[1] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell 2023; 186(2): 243–278

[2] Carosio S, Berardinelli MG, Aucello M, Musarò A. Impact of ageing on muscle cell regeneration. Ageing Res Rev 2011; 10(1): 35–42

[3] Khosla S, Farr JN, Monroe DG. Cellular senescence and the skeleton: pathophysiology and therapeutic implications. J Clin Invest 2022; 132(3): e154888

[4] 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

[5] Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, Liu J, Jiang K, Liu R, Guo Z, Deeney J, Apovian CM, Snyder-Cappione J, Hawk GS, Fleeman RM, Pihl RMF, Thompson K, Belkina AC, Cui L, Proctor EA, Kern PA, Nikolajczyk BS. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab 2020; 32(1): 44–55.e6

[6] Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF. Autophagy in healthy aging and disease. Nature Aging 2021; 1(8): 634–650

[7] Zhu Y, Liu X, Ding X, Wang F, Geng X. Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction. Biogerontology 2019; 20(1): 1–16

[8] Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab 2016; 23(2): 303–314

[9] Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 2015; 21(12): 1424–1435

[10] Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018; 15(9): 505–522

[11] Huang W, Hickson LTJ, Eirin A, Kirkland JL, Lerman LO. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol 2022; 18(10): 611–627

[12] Gao Y, Hu Y, Liu Q, Li X, Li X, Kim CY, James TD, Li J, Chen X, Guo Y. Two-dimensional design strategy to construct smart fluorescent probes for the precise tracking of senescence. Angew Chem Int Ed 2021; 60(19): 10756–10765

[13] Fukazawa R, Ikegam E, Watanabe M, Hajikano M, Kamisago M, Katsube Y, Yamauchi H, Ochi M, Ogawa S. Coronary artery aneurysm induced by Kawasaki disease in children show features typical senescence. Circ J 2007; 71(5): 709–715

[14] Markowski DN, Thies HW, Gottlieb A, Wenk H, Wischnewsky M, Bullerdiek J. HMGA2 expression in white adipose tissue linking cellular senescence with diabetes. Genes Nutr 2013; 8(5): 449–456

[15] Le Maitre CL, Freemont AJ, Hoyland JA. Accelerated cellular senescence in degenerate intervertebral discs: a possible role in the pathogenesis of intervertebral disc degeneration. Arthritis Res Ther 2007; 9(3): R45

[16] Martin JA, Brown TD, Heiner AD, Buckwalter JA. Chondrocyte senescence, joint loading and osteoarthritis. Clin Orthop Relat Res 2004; 427(Suppl): S96–S103

[17] Farr JN, Xu M, Weivoda MM, Monroe DG, Fraser DG, Onken JL, Negley BA, Sfeir JG, Ogrodnik MB, Hachfeld CM, LeBrasseur NK, Drake MT, Pignolo RJ, Pirtskhalava T, Tchkonia T, Oursler MJ, Kirkland JL, Khosla S. Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 2017; 23(9): 1072–1079

[18] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16^Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011; 479(7372): 232–236

[19] Litwic A, Edwards MH, Dennison EM, Cooper C. Epidemiology and burden of osteoarthritis. Br Med Bull 2013; 105(1): 185–199

[20] Rhinn M, Ritschka B, Keyes WM. Cellular senescence in development, regeneration and disease. Development 2019; 146(20): dev151837

[21] Mohamad Kamal NS, Safuan S, Shamsuddin S, Foroozandeh P. Aging of the cells: insight into cellular senescence and detection Methods. Eur J Cell Biol 2020; 99(6): 151108

[22] Takahashi A, Ohtani N, Yamakoshi K, Iida S, Tahara H, Nakayama K, Nakayama KI, Ide T, Saya H, Hara E. Mitogenic signalling and the p16^INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat Cell Biol 2006; 8(11): 1291–1297

[23] Watanabe S, Kawamoto S, Ohtani N, Hara E. Impact of senescence-associated secretory phenotype and its potential as a therapeutic target for senescence-associated diseases. Cancer Sci 2017; 108(4): 563–569

[24] Webley K, Bond JA, Jones CJ, Blaydes JP, Craig A, Hupp T, Wynford-Thomas D. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol Cell Biol 2000; 20(8): 2803–2808

[25] Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 2013; 14(4): 197–210

[26] Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ 2022; 29(5): 946–960

[27] Witkiewicz AK, Kumarasamy V, Sanidas I, Knudsen ES. Cancer cell cycle dystopia: heterogeneity, plasticity, and therapy. Trends Cancer 2022; 8(9): 711–725

[28] Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest 2018; 128(4): 1238–1246

[29] Yuan L, Zhai L, Qian L, Huang D, Ding Y, Xiang H, Liu X, Thompson JW, Liu J, He YH, Chen XQ, Hu J, Kong QP, Tan M, Wang XF. Switching off IMMP2L signaling drives senescence via simultaneous metabolic alteration and blockage of cell death. Cell Res 2018; 28(6): 625–643

[30] Cho Y, Kim YK. ROS-mediated cytoplasmic localization of CARM1 induces mitochondrial fission through DRP1 methylation. Redox Biol 2024; 73: 103212

[31] Guo Y, Guan T, Shafiq K, Yu Q, Jiao X, Na D, Li M, Zhang G, Kong J. Mitochondrial dysfunction in aging. Ageing Res Rev 2023; 88: 101955

[32] Guo Z, Wang G, Wu B, Chou WC, Cheng L, Zhou C, Lou J, Wu D, Su L, Zheng J, Ting JPY, Wan YY. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J Clin Invest 2020; 130(11): 5893–5908

[33] Zhou J, Freeman TA, Ahmad F, Shang X, Mangano E, Gao E, Farber J, Wang Y, Ma XL, Woodgett J, Vagnozzi RJ, Lal H, Force T. GSK-3α is a central regulator of age-related pathologies in mice. J Clin Invest 2013; 123(4): 1821–1832

[34] Narita M, Young ARJ, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, Hong S, Berry LS, Reichelt S, Ferreira M, Tavaré S, Inoki K, Shimizu S, Narita M. Spatial coupling of mTOR and autophagy augments secretory phenotypes. Science 2011; 332(6032): 966–970

[35] 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. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol 2013; 15(8): 978–990

[36] Takahashi A, Loo TM, Okada R, Kamachi F, Watanabe Y, Wakita M, Watanabe S, Kawamoto S, Miyata K, Barber GN, Ohtani N, Hara E. Downregulation of cytoplasmic DNases is implicated in cytoplasmic DNA accumulation and SASP in senescent cells. Nat Commun 2018; 9(1): 1249

[37] Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008; 6(12): 2853–2868

[38] Wang B, Han J, Elisseeff JH, Demaria M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat Rev Mol Cell Biol 2024; 25(12): 958–978

[39] Levi N, Papismadov N, Solomonov I, Sagi I, Krizhanovsky V. The ECM path of senescence in aging: components and modifiers. FEBS J 2020; 287(13): 2636–2646

[40] Jeon OH, Mehdipour M, Gil TH, Kang M, Aguirre NW, Robinson ZR, Kato C, Etienne J, Lee HG, Alimirah F, Walavalkar V, Desprez PY, Conboy MJ, Campisi J, Conboy IM. Systemic induction of senescence in young mice after single heterochronic blood exchange. Nat Metab 2022; 4(8): 995–1006

[41] Zhang B, Lee DE, Trapp A, Tyshkovskiy A, Lu AT, Bareja A, Kerepesi C, McKay LK, Shindyapina AV, Dmitriev SE, Baht GS, Horvath S, Gladyshev VN, White JP. Multi-omic rejuvenation and life span extension on exposure to youthful circulation. Nature Aging 2023; 3(8): 948–964

[42] 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. Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism. Nature Aging 2024; 4(6): 814–838

[43] Wiley CD, Sharma R, Davis SS, Lopez-Dominguez JA, Mitchell KP, Wiley S, Alimirah F, Kim DE, Payne T, Rosko A, Aimontche E, Deshpande SM, Neri F, Kuehnemann C, Demaria M, Ramanathan A, Campisi J. Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. Cell Metab 2021; 33(6): 1124–1136.e5

[44] Li X, Li C, Zhang W, Wang Y, Qian P, Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther 2023; 8(1): 239

[45] 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. The bystander effect contributes to the accumulation of senescent cells in vivo. Aging Cell 2019; 18(1): e12848

[46] Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 2012; 11(2): 345–349

[47] Liu X, Liu Z, Wu Z, Ren J, Fan Y, Sun L, Cao G, Niu Y, Zhang B, Ji Q, Jiang X, Wang C, Wang Q, Ji Z, Li L, Esteban CR, Yan K, Li W, Cai Y, Wang S, Zheng A, Zhang YE, Tan S, Cai Y, Song M, Lu F, Tang F, Ji W, Zhou Q, Belmonte JCI, Zhang W, Qu J, Liu GH. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell 2023; 186(2): 287–304.e26

[48] Wright NC, Looker AC, Saag KG, Curtis JR, Delzell ES, Randall S, Dawson-Hughes B. The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine. J Bone Miner Res 2014; 29(11): 2520–2526

[49] Farr JN, Fraser DG, Wang H, Jaehn K, Ogrodnik MB, Weivoda MM, Drake MT, Tchkonia T, LeBrasseur NK, Kirkland JL, Bonewald LF, Pignolo RJ, Monroe DG, Khosla S. Identification of senescent cells in the bone microenvironment. J Bone Miner Res 2016; 31(11): 1920–1929

[50] 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. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc Natl Acad Sci USA 2015; 112(46): E6301–E6310

[51] Kim HN, Chang J, Iyer S, Han L, Campisi J, Manolagas SC, Zhou D, Almeida M. Elimination of senescent osteoclast progenitors has no effect on the age-associated loss of bone mass in mice. Aging Cell 2019; 18(3): e12923

[52] Saul D, Doolittle ML, Rowsey JL, Froemming MN, Kosinsky RL, Vos SJ, Ruan M, LeBrasseur NK, Chandra A, Pignolo RJ, Passos JF, Farr JN, Monroe DG, Khosla S. Osteochondroprogenitor cells and neutrophils expressing p21 and senescence markers modulate fracture repair. J Clin Invest 2024; 134(12): e179834

[53] Sekiya I, Larson BL, Vuoristo JT, Cui JG, Prockop DJ. Adipogenic differentiation of human adult stem cells from bone marrow stroma (MSCs). J Bone Miner Res 2004; 19(2): 256–264

[54] Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284(5411): 143–147

[55] Liu F, Yuan L, Li L, Yang J, Liu J, Chen Y, Zhang J, Lu Y, Yuan Y, Cheng J. S-sulfhydration of SIRT3 combats BMSC senescence and ameliorates osteoporosis via stabilizing heterochromatic and mitochondrial homeostasis. Pharmacol Res 2023; 192: 106788

[56] Chen Q, Shou P, Zheng C, Jiang M, Cao G, Yang Q, Cao J, Xie N, Velletri T, Zhang X, Xu C, Zhang L, Yang H, Hou J, Wang Y, Shi Y. Fate decision of mesenchymal stem cells: adipocytes or osteoblasts. Cell Death Differ 2016; 23(7): 1128–1139

[57] Sun W, Qiao W, Zhou B, Hu Z, Yan Q, Wu J, Wang R, Zhang Q, Miao D. Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition. Metabolism 2018; 88: 61–71

[58] Wang Y, Xie F, He Z, Che L, Chen X, Yuan Y, Liu C. Senescence-targeted and NAD⁺-dependent SIRT1-activated nanoplatform to counteract stem cell senescence for promoting aged bone regeneration. Small 2024; 20(12): e2304433

[59] Hu M, Xing L, Zhang L, Liu F, Wang S, Xie Y, Wang J, Jiang H, Guo J, Li X, Wang J, Sui L, Li C, Liu D, Liu Z. NAP1L2 drives mesenchymal stem cell senescence and suppresses osteogenic differentiation. Aging Cell 2022; 21(2): e13551

[60] Yoshino J, Baur JA, Imai SI. NAD⁺ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 2018; 27(3): 513–528

[61] Xu R, Fu Z, Liu X, Xiao T, Zhang P, Du Y, Yuan H, Cheng J, Jiang H. Transplantation of osteoporotic bone marrow stromal cells rejuvenated by the overexpression of SATB2 prevents alveolar bone loss in ovariectomized rats. Exp Gerontol 2016; 84: 71–79

[62] Wu G, Xu R, Zhang P, Xiao T, Fu Y, Zhang Y, Du Y, Ye J, Cheng J, Jiang H. Estrogen regulates stemness and senescence of bone marrow stromal cells to prevent osteoporosis via ERβ-SATB2 pathway. J Cell Physiol 2018; 233(5): 4194–4204

[63] Chen J, Kuang S, Cen J, Zhang Y, Shen Z, Qin W, Huang Q, Wang Z, Gao X, Huang F, Lin Z. Multiomics profiling reveals VDR as a central regulator of mesenchymal stem cell senescence with a known association with osteoporosis after high-fat diet exposure. Int J Oral Sci 2024; 16(1): 41

[64] Matikainen N, Pekkarinen T, Ryhänen EM, Schalin-Jäntti C. Physiology of calcium homeostasis: an overview. Endocrinol Metab Clin North Am 2021; 50(4): 575–590

[65] Slovik DM, Adams JS, Neer RM, Holick MF, Potts JT Jr. Deficient production of 1, 25-dihydroxyvitamin D in elderly osteoporotic patients. N Engl J Med 1981; 305(7): 372–374

[66] Yang R, Chen J, Zhang J, Qin R, Wang R, Qiu Y, Mao Z, Goltzman D, Miao D. 1, 25-Dihydroxyvitamin D protects against age-related osteoporosis by a novel VDR-Ezh2-p16 signal axis. Aging Cell 2020; 19(2): e13095

[67] Yang R, Zhang J, Li J, Qin R, Chen J, Wang R, Goltzman D, Miao D. Inhibition of Nrf2 degradation alleviates age-related osteoporosis induced by 1, 25-Dihydroxyvitamin D deficiency. Free Radic Biol Med 2022; 178: 246–261

[68] Yin X, Zhou C, Li J, Liu R, Shi B, Yuan Q, Zou S. Autophagy in bone homeostasis and the onset of osteoporosis. Bone Res 2019; 7(1): 28

[69] Ma Y, Qi M, An Y, Zhang L, Yang R, Doro DH, Liu W, Jin Y. Autophagy controls mesenchymal stem cell properties and senescence during bone aging. Aging Cell 2018; 17(1): e12709

[70] Kohno K, Izumi H, Uchiumi T, Ashizuka M, Kuwano M. The pleiotropic functions of the Y-box-binding protein, YB-1. BioEssays 2003; 25(7): 691–698

[71] Xiao Y, Cai GP, Feng X, Li YJ, Guo WH, Guo Q, Huang Y, Su T, Li CJ, Luo XH, Zheng YJ, Yang M. Splicing factor YBX1 regulates bone marrow stromal cell fate during aging. EMBO J 2023; 42(9): e111762

[72] Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med 1995; 332(5): 305–311

[73] Kim HJ, Kim WJ, Shin HR, Yoon HI, Moon JI, Lee E, Lim JM, Cho YD, Lee MH, Kim HG, Ryoo HM. ROS-induced PADI2 downregulation accelerates cellular senescence via the stimulation of SASP production and NFκB activation. Cell Mol Life Sci 2022; 79(3): 155

[74] Xu P, Lin B, Deng X, Huang K, Zhang Y, Wang N. VDR activation attenuates osteoblastic ferroptosis and senescence by stimulating the Nrf2/GPX4 pathway in age-related osteoporosis. Free Radic Biol Med 2022; 193(Pt 2): 720–735

[75] Ambrosi TH, Marecic O, McArdle A, Sinha R, Gulati GS, Tong X, Wang Y, Steininger HM, Hoover MY, Koepke LS, Murphy MP, Sokol J, Seo EY, Tevlin R, Lopez M, Brewer RE, Mascharak S, Lu L, Ajanaku O, Conley SD, Seita J, Morri M, Neff NF, Sahoo D, Yang F, Weissman IL, Longaker MT, Chan CKF. Aged skeletal stem cells generate an inflammatory degenerative niche. Nature 2021; 597(7875): 256–262

[76] Liu X, Gu Y, Kumar S, Amin S, Guo Q, Wang J, Fang CL, Cao X, Wan M. Oxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow. Cell Metab 2023; 35(4): 667–684.e6

[77] Xie L, Cheng Y, Hu B, Chen X, An Y, Xia Z, Cai G, Li C, Peng H. PCLAF induces bone marrow adipocyte senescence and contributes to skeletal aging. Bone Res 2024; 12(1): 38

[78] Cheng W, Fu Y, Lin Z, Huang M, Chen Y, Hu Y, Lin Q, Yu B, Liu G. Lipoteichoic acid restrains macrophage senescence via β-catenin/FOXO1/REDD1 pathway in age-related osteoporosis. Aging Cell 2024; 23(3): e14072

[79] Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E, Brioschi S, Shchukina I, Kerndl M, Bambouskova M, Yao Z, Laha A, Zaitsev K, Burdess S, Gillfilan S, Stewart SA, Colonna M, Artyomov MN. Comprehensive profiling of an aging immune system reveals clonal GZMK⁺ CD8⁺ T cells as conserved hallmark of inflammaging. Immunity 2021; 54(1): 99–115.e12

[80] Lagnado A, Leslie J, Ruchaud-Sparagano MH, Victorelli S, Hirsova P, Ogrodnik M, Collins AL, Vizioli MG, Habiballa L, Saretzki G, Evans SA, Salmonowicz H, Hruby A, Geh D, Pavelko KD, Dolan D, Reeves HL, Grellscheid S, Wilson CH, Pandanaboyana S, Doolittle M, von Zglinicki T, Oakley F, Gallage S, Wilson CL, Birch J, Carroll B, Chapman J, Heikenwalder M, Neretti N, Khosla S, Masuda CA, Tchkonia T, Kirkland JL, Jurk D, Mann DA, Passos JF. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J 2021; 40(9): e106048

[81] Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-hora M, Feng JQ, Bonewald LF, Kodama T, Wutz A, Wagner EF, Penninger JM, Takayanagi H. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med 2011; 17(10): 1231–1234

[82] Johnson VL, Hunter DJ. The epidemiology of osteoarthritis. Best Pract Res Clin Rheumatol 2014; 28(1): 5–15

[83] Loeser RF, Collins JA, Diekman BO. Ageing and the pathogenesis of osteoarthritis. Nat Rev Rheumatol 2016; 12(7): 412–420

[84] Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet 2019; 393(10182): 1745–1759

[85] Swahn H, Li K, Duffy T, Olmer M, D’Lima DD, Mondala TS, Natarajan P, Head SR, Lotz MK. Senescent cell population with ZEB1 transcription factor as its main regulator promotes osteoarthritis in cartilage and meniscus. Ann Rheum Dis 2023; 82(3): 403–415

[86] 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. 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

[87] Ni W, Zhang H, Mei Z, Hongyi Z, Wu Y, Xu W, Ma Y, Yang W, Liang Y, Gu T, Su Y, Fan S, Shen S, Hu Z. An inducible long noncoding RNA, LncZFHX2, facilitates DNA repair to mediate osteoarthritis pathology. Redox Biol 2023; 66: 102858

[88] Hu S, Zhang C, Ni L, Huang C, Chen D, Shi K, Jin H, Zhang K, Li Y, Xie L, Fang M, Xiang G, Wang X, Xiao J. Stabilization of HIF-1α alleviates osteoarthritis via enhancing mitophagy. Cell Death Dis 2020; 11(6): 481

[89] Duarte JH. Osteoarthritis: SIRT6 prevents chondrocyte senescence and DNA damage. Nat Rev Rheumatol 2015; 11(5): 260

[90] Nagai K, Matsushita T, Matsuzaki T, Takayama K, Matsumoto T, Kuroda R, Kurosaka M. Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes. Osteoarthr Cartilage 2015; 23(8): 1412–1420

[91] Ji ML, Jiang H, Li Z, Geng R, Hu JZ, Lin YC, Lu J. Sirt6 attenuates chondrocyte senescence and osteoarthritis progression. Nat Commun 2022; 13(1): 7658

[92] Loeser RF. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 2009; 17(8): 971–979

[93] Hui W, Young DA, Rowan AD, Xu X, Cawston TE, Proctor CJ. Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage. Ann Rheum Dis 2016; 75(2): 449–458

[94] Cho Y, Kim H, Yook G, Yong S, Kim S, Lee N, Kim YJ, Kim JH, Kim TW, Chang MJ, Lee KM, Chang CB, Kang SB, Kim JH. Predisposal of interferon regulatory factor 1 deficiency to accumulate DNA damage and promote osteoarthritis development in cartilage. Arthritis Rheumatol 2024; 76(6): 882–893

[95] Lin S, Wu B, Hu X, Lu H. Sirtuin 4 (Sirt4) downregulation contributes to chondrocyte senescence and osteoarthritis via mediating mitochondrial dysfunction. Int J Biol Sci 2024; 20(4): 1256–1278

[96] Kang D, Lee J, Jung J, Carlson BA, Chang MJ, Chang CB, Kang SB, Lee BC, Gladyshev VN, Hatfield DL, Lee BJ, Kim JH. Selenophosphate synthetase 1 deficiency exacerbates osteoarthritis by dysregulating redox homeostasis. Nat Commun 2022; 13(1): 779

[97] Kang D, Shin J, Cho Y, Kim HS, Gu YR, Kim H, You KT, Chang MJ, Chang CB, Kang SB, Kim JS, Kim VN, Kim JH. Stress-activated miR-204 governs senescent phenotypes of chondrocytes to promote osteoarthritis development. Sci Transl Med 2019; 11(486): eaar6659

[98] Rahmati M, Nalesso G, Mobasheri A, Mozafari M. Aging and osteoarthritis: central role of the extracellular matrix. Ageing Res Rev 2017; 40: 20–30

[99] Iijima H, Gilmer G, Wang K, Bean AC, He Y, Lin H, Tang WY, Lamont D, Tai C, Ito A, Jones JJ, Evans C, Ambrosio F. Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity. Nat Commun 2023; 14(1): 18

[100] Fu B, Shen J, Zou X, Sun N, Zhang Z, Liu Z, Zeng C, Liu H, Huang W. Matrix stiffening promotes chondrocyte senescence and the osteoarthritis development through downregulating HDAC3. Bone Res 2024; 12(1): 32

[101] Varela-Eirín M, Varela-Vázquez A, Guitián-Caamaño A, Paíno CL, Mato V, Largo R, Aasen T, Tabernero A, Fonseca E, Kandouz M, Caeiro JR, Blanco A, Mayán MD. Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis. Cell Death Dis 2018; 9(12): 1166

[102] Ismail HM, Yamamoto K, Vincent TL, Nagase H, Troeberg L, Saklatvala J. Interleukin-1 acts via the JNK-2 signaling pathway to induce aggrecan degradation by human chondrocytes. Arthritis Rheumatol 2015; 67(7): 1826–1836

[103] Han Z, Boyle DL, Chang L, Bennett B, Karin M, Yang L, Manning AM, Firestein GS. c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 2001; 108(1): 73–81

[104] Clancy R, Rediske J, Koehne C, Stoyanovsky D, Amin A, Attur M, Iyama K, Abramson SB. Activation of stress-activated protein kinase in osteoarthritic cartilage: evidence for nitric oxide dependence. Osteoarthr Cartilage 2001; 9(4): 294–299

[105] Loeser RF, Kelley KL, Armstrong A, Collins JA, Diekman BO, Carlson CS. Deletion of JNK enhances senescence in joint tissues and increases the severity of age-related osteoarthritis in mice. Arthritis Rheumatol 2020; 72(10): 1679–1688

[106] Arra M, Swarnkar G, Alippe Y, Mbalaviele G, Abu-Amer Y. IκB-ζ signaling promotes chondrocyte inflammatory phenotype, senescence, and erosive joint pathology. Bone Res 2022; 10(1): 12

[107] Roh K, Noh J, Kim Y, Jang Y, Kim J, Choi H, Lee Y, Ji M, Kang D, Kim MS, Paik MJ, Chung J, Kim JH, Kang C. Lysosomal control of senescence and inflammation through cholesterol partitioning. Nat Metab 2023; 5(3): 398–413

[108] McHugh D, Gil J. Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol 2018; 217(1): 65–77

[109] Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell 2017; 168(6): 960–976

[110] Liu GY, Sabatini DM. mTOR at the nexus of nutrition, growth, ageing and disease. Nat Rev Mol Cell Biol 2020; 21(4): 183–203

[111] Cao Y, Ruan J, Kang J, Nie X, Lan W, Ruan G, Li J, Zhu Z, Han W, Tang S, Ding C. Extracellular vesicles in infrapatellar fat pad from osteoarthritis patients impair cartilage metabolism and induce senescence. Adv Sci (Weinh) 2024; 11(3): e2303614

[112] Chen X, Gong W, Shao X, Shi T, Zhang L, Dong J, Shi Y, Shen S, Qin J, Jiang Q, Guo B. METTL3-mediated m⁶A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression. Ann Rheum Dis 2022; 81(1): 87–99

[113] Faust HJ, Zhang H, Han J, Wolf MT, Jeon OH, Sadtler K, Peña AN, Chung L, Maestas DR Jr, Tam AJ, Pardoll DM, Campisi J, Housseau F, Zhou D, Bingham CO III, Elisseeff JH. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. J Clin Invest 2020; 130(10): 5493–5507

[114] Dowdell J, Erwin M, Choma T, Vaccaro A, Iatridis J, Cho SK. Intervertebral disk degeneration and repair. Neurosurgery 2017; 80(3S): S46–S54

[115] Adam M, Deyl Z. Degenerated annulus fibrosus of the intervertebral disc contains collagen type II. Ann Rheum Dis 1984; 43(2): 258–263

[116] Yee A, Lam MPY, Tam V, Chan WCW, Chu IK, Cheah KSE, Cheung KMC, Chan D. Fibrotic-like changes in degenerate human intervertebral discs revealed by quantitative proteomic analysis. Osteoarthritis Cartilage 2016; 24(3): 503–513

[117] Lundon K, Bolton K. Structure and function of the lumbar intervertebral disk in health, aging, and pathologic conditions. J Orthop Sports Phys Ther 2001; 31(6): 291–306

[118] Zehra U, Tryfonidou M, Iatridis JC, Illien-Jünger S, Mwale F, Samartzis D. Mechanisms and clinical implications of intervertebral disc calcification. Nat Rev Rheumatol 2022; 18(6): 352–362

[119] Chen S, Lei L, Li Z, Chen F, Huang Y, Jiang G, Guo X, Zhao Z, Liu H, Wang H, Liu C, Zheng Z, Wang J. Grem1 accelerates nucleus pulposus cell apoptosis and intervertebral disc degeneration by inhibiting TGF-β-mediated Smad2/3 phosphorylation. Exp Mol Med 2022; 54(4): 518–530

[120] Yang F, Liu W, Huang Y, Yang S, Shao Z, Cai X, Xiong L. Regulated cell death: implications for intervertebral disc degeneration and therapy. J Orthop Translat 2022; 37: 163–172

[121] Kang L, Zhang H, Jia C, Zhang R, Shen C. Epigenetic modifications of inflammation in intervertebral disc degeneration. Ageing Res Rev 2023; 87: 101902

[122] Kelsey R. Targeting NP cell senescence in IVDD. Nat Rev Rheumatol 2024; 20(4): 197

[123] Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 2008; 27(2): 433–446

[124] Sun K, Jing X, Guo J, Yao X, Guo F. Mitophagy in degenerative joint diseases. Autophagy 2021; 17(9): 2082–2092

[125] Zhuang Y, Liu L, Liu M, Fu J, Ai X, Long D, Leng X, Zhang Y, Gong X, Shang X, Li C, Huang B, Zhou Y, Ning X, Dong S, Feng C. The sonic hedgehog pathway suppresses oxidative stress and senescence in nucleus pulposus cells to alleviate intervertebral disc degeneration via GPX4. Biochim Biophys Acta Mol Basis Dis 2024; 1870(2): 166961

[126] Liu L, Zhang Y, Fu J, Ai X, Long D, Leng X, Zhang Y, Huang B, Li C, Zhou Y, Feng C. Gli1 depletion induces oxidative stress and apoptosis of nucleus pulposus cells via Fos in intervertebral disc degeneration. J Orthop Translat 2023; 40: 116–131

[127] Wu ZL, Wang K, Chen Y, Song W, Liu Y, Zhou KS, Mao P, Ma Z, Zhang H. Knocking down EGR1 inhibits nucleus pulposus cell senescence and mitochondrial damage through activation of PINK1-Parkin dependent mitophagy, thereby delaying intervertebral disc degeneration. Free Radic Biol Med 2024; 224: 9–22

[128] Wang Y, Wang H, Zhuo Y, Hu Y, Zhang Z, Ye J, Liu L, Luo L, Zhao C, Zhou Q, Li P. SIRT1 alleviates high-magnitude compression-induced senescence in nucleus pulposus cells via PINK1-dependent mitophagy. Aging (Albany NY) 2020; 12(16): 16126–16141

[129] Huang D, Peng Y, Li Z, Chen S, Deng X, Shao Z, Ma K. Compression-induced senescence of nucleus pulposus cells by promoting mitophagy activation via the PINK1/PARKIN pathway. J Cell Mol Med 2020; 24(10): 5850–5864

[130] Song Y, Liang H, Li G, Ma L, Zhu D, Zhang W, Tong B, Li S, Gao Y, Wu X, Zhang Y, Feng X, Wang K, Yang C. The NLRX1–SLC39A7 complex orchestrates mitochondrial dynamics and mitophagy to rejuvenate intervertebral disc by modulating mitochondrial Zn²⁺ trafficking. Autophagy 2024; 20(4): 809–829

[131] Patil P, Dong Q, Wang D, Chang J, Wiley C, Demaria M, Lee J, Kang J, Niedernhofer LJ, Robbins PD, Sowa G, Campisi J, Zhou D, Vo N. Systemic clearance of p16INK4a -positive senescent cells mitigates age-associated intervertebral disc degeneration. Aging Cell 2019; 18(3): e12927

[132] Zhang W, Li G, Zhou X, Liang H, Tong B, Wu D, Yang K, Song Y, Wang B, Liao Z, Ma L, Ke W, Zhang X, Lei J, Lei C, Feng X, Wang K, Zhao K, Yang C. Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration. J Clin Invest 2024; 134(6): e165140

[133] Guo Q, Zhu D, Wang Y, Miao Z, Chen Z, Lin Z, Lin J, Huang C, Pan L, Wang L, Zeng S, Wang J, Zheng X, Lin Y, Zhang X, Wu Y. Targeting STING attenuates ROS induced intervertebral disc degeneration. Osteoarthritis Cartilage 2021; 29(8): 1213–1224

[134] Guo Q, Chen X, Chen J, Zheng G, Xie C, Wu H, Miao Z, Lin Y, Wang X, Gao W, Zheng X, Pan Z, Zhou Y, Wu Y, Zhang X. STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF-κB signaling pathway. Cell Death Dis 2021; 12(1): 13

[135] Wu J, Chen Y, Liao Z, Liu H, Zhang S, Zhong D, Qiu X, Chen T, Su D, Ke X, Wan Y, Zhou T, Su P. Self-amplifying loop of NF-κB and periostin initiated by PIEZO1 accelerates mechano-induced senescence of nucleus pulposus cells and intervertebral disc degeneration. Mol Ther 2022; 30(10): 3241–3256

[136] Fan C, Wang W, Yu Z, Wang J, Xu W, Ji Z, He W, Hua D, Wang W, Yao L, Deng Y, Geng D, Wu X, Mao H. M1 macrophage-derived exosomes promote intervertebral disc degeneration by enhancing nucleus pulposus cell senescence through LCN2/NF-κB signaling axis. J Nanobiotechnology 2024; 22(1): 301

[137] Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet 2019; 393(10191): 2636–2646

[138] Zhang X, Habiballa L, Aversa Z, Ng YE, Sakamoto AE, Englund DA, Pearsall VM, White TA, Robinson MM, Rivas DA, Dasari S, Hruby AJ, Lagnado AB, Jachim SK, Granic A, Sayer AA, Jurk D, Lanza IR, Khosla S, Fielding RA, Nair KS, Schafer MJ, Passos JF, LeBrasseur NK. Characterization of cellular senescence in aging skeletal muscle. Nature Aging 2022; 2(7): 601–615

[139] Wosczyna MN, Konishi CT, Perez Carbajal EE, Wang TT, Walsh RA, Gan Q, Wagner MW, Rando TA. Mesenchymal stromal cells are required for regeneration and homeostatic maintenance of skeletal muscle. Cell Rep 2019; 27(7): 2029–2035.e5

[140] Joe AWB, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA, Rossi FMV. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol 2010; 12(2): 153–163

[141] Englund DA, Zhang X, Aversa Z, LeBrasseur NK. Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions. Mech Ageing Dev 2021; 200: 111595

[142] Zhu P, Zhang C, Gao Y, Wu F, Zhou Y, Wu WS. The transcription factor Slug represses p16^Ink4a and regulates murine muscle stem cell aging. Nat Commun 2019; 10(1): 2568

[143] Chakkalakal JV, Jones KM, Basson MA, Brack AS. The aged niche disrupts muscle stem cell quiescence. Nature 2012; 490(7420): 355–360

[144] Moiseeva V, Cisneros A, Sica V, Deryagin O, Lai Y, Jung S, Andrés E, An J, Segalés J, Ortet L, Lukesova V, Volpe G, Benguria A, Dopazo A, Benitah SA, Urano Y, del Sol A, Esteban MA, Ohkawa Y, Serrano AL, Perdiguero E, Muñoz-Cánoves P. Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration. Nature 2023; 613(7942): 169–178

[145] König J, Grune T, Ott C. Assessing autophagy in murine skeletal muscle: current findings to modulate and quantify the autophagic flux. Curr Opin Clin Nutr Metab Care 2019; 22(5): 355–362

[146] Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M. Autophagy is required to maintain muscle mass. Cell Metab 2009; 10(6): 507–515

[147] Kim JH, Park I, Shin HR, Rhee J, Seo JY, Jo YW, Yoo K, Hann SH, Kang JS, Park J, Kim YL, Moon JY, Choi MH, Kong YY. The hypothalamic-pituitary-gonadal axis controls muscle stem cell senescence through autophagosome clearance. J Cachexia Sarcopenia Muscle 2021; 12(1): 177–191

[148] Rajabian N, Choudhury D, Ikhapoh I, Saha S, Kalyankar AS, Mehrotra P, Shahini A, Breed K, Andreadis ST. Reversine ameliorates hallmarks of cellular senescence in human skeletal myoblasts via reactivation of autophagy. Aging Cell 2023; 22(3): e13764

[149] Folmes CDL, Dzeja PP, Nelson TJ, Terzic A. Metabolic plasticity in stem cell homeostasis and differentiation. Cell Stem Cell 2012; 11(5): 596–606

[150] Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D’Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 2016; 352(6292): 1436–1443

[151] Zeng W, Zhang W, Tse EHY, Liu J, Dong A, Lam KSW, Luan S, Kung WH, Chan TC, Cheung TH. Restoration of CPEB4 prevents muscle stem cell senescence during aging. Dev Cell 2023; 58(15): 1383–1398.e6

[152] García-Prat L, Martínez-Vicente M, Perdiguero E, Ortet L, Rodríguez-Ubreva J, Rebollo E, Ruiz-Bonilla V, Gutarra S, Ballestar E, Serrano AL, Sandri M, Muñoz-Cánoves P. Autophagy maintains stemness by preventing senescence. Nature 2016; 529(7584): 37–42

[153] Shahini A, Rajabian N, Choudhury D, Shahini S, Vydiam K, Nguyen T, Kulczyk J, Santarelli T, Ikhapoh I, Zhang Y, Wang J, Liu S, Stablewski A, Thiyagarajan R, Seldeen K, Troen BR, Peirick J, Lei P, Andreadis ST. Ameliorating the hallmarks of cellular senescence in skeletal muscle myogenic progenitors in vitro and in vivo. Sci Adv 2021; 7(36): eabe5671

[154] Rajabian N, Ikhapoh I, Shahini S, Choudhury D, Thiyagarajan R, Shahini A, Kulczyk J, Breed K, Saha S, Mohamed MA, Udin SB, Stablewski A, Seldeen K, Troen BR, Personius K, Andreadis ST. Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle. Nat Commun 2023; 14(1): 886

[155] Peng Y, Du J, Günther S, Guo X, Wang S, Schneider A, Zhu L, Braun T. Mechano-signaling via Piezo1 prevents activation and p53-mediated senescence of muscle stem cells. Redox Biol 2022; 52: 102309

[156] Schwörer S, Becker F, Feller C, Baig AH, Köber U, Henze H, Kraus JM, Xin B, Lechel A, Lipka DB, Varghese CS, Schmidt M, Rohs R, Aebersold R, Medina KL, Kestler HA, Neri F, von Maltzahn J, Tümpel S, Rudolph KL. Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals. Nature 2016; 540(7633): 428–432

[157] Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J. Saltness R, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD, van Deursen JM. Naturally occurring p16^Ink4a-positive cells shorten healthy lifespan. Nature 2016; 530(7589): 184–189

[158] Childs BG, Baker DJ, Wijshake T, Conover CA, Campisi J, van Deursen JM. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 2016; 354(6311): 472–477

[159] Peng Y, Chen X, Liu S, Wu W, Shu H, Tian S, Xiao Y, Li K, Wang B, Lin H, Qing X, Shao Z. Extracellular vesicle-conjugated functional matrix hydrogels prevent senescence by exosomal mir-3594-5p-targeted HIPK2/p53 pathway for disc regeneration. Small 2023; 19(37): e2206888

[160] Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005; 55(3): 178–194

[161] Kim DHD, Xu W, Ma C, Liu X, Siminovitch K, Messner HA, Lipton JH. Genetic variants in the candidate genes of the apoptosis pathway and susceptibility to chronic myeloid leukemia. Blood 2009; 113(11): 2517–2525

[162] Huang Y, Che X, Wang PW, Qu X. p53/MDM2 signaling pathway in aging, senescence and tumorigenesis. Semin Cancer Biol 2024; 101: 44–57

[163] Novais EJ, Tran VA, Johnston SN, Darris KR, Roupas AJ, Sessions GA, Shapiro IM, Diekman BO, Risbud MV. Long-term treatment with senolytic drugs dasatinib and quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat Commun 2021; 12(1): 5213

[164] Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine 2019; 47: 446–456

[165] Farr JN, Atkinson EJ, Achenbach SJ, Volkman TL, Tweed AJ, Vos SJ, Ruan M, Sfeir J, Drake MT, Saul D, Doolittle ML, Bancos I, Yu K, Tchkonia T, LeBrasseur NK, Kirkland JL, Monroe DG, Khosla S. Effects of intermittent senolytic therapy on bone metabolism in postmenopausal women: a phase 2 randomized controlled trial. Nat Med 2024; 30(9): 2605–2612

[166] 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. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 2016; 15(3): 428–435

[167] 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. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 2016; 22(1): 78–83

[168] Sharma AK, Roberts RL, Benson RD Jr, Pierce JL, Yu K, Hamrick MW, McGee-Lawrence ME. The senolytic drug navitoclax (ABT-263) causes trabecular bone loss and impaired osteoprogenitor function in aged mice. Front Cell Dev Biol 2020; 8: 354

[169] Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 2017; 169(1): 132–147.e16

[170] Herman AB, Anerillas C, Harris SC, Munk R, Martindale JL, Yang X, Mazan-Mamczarz K, Zhang Y, Heckenbach IJ, Scheibye-Knudsen M, De S, Sen P, Abdelmohsen K, Gorospe M. Reduction of lamin B receptor levels by miR-340–5p disrupts chromatin, promotes cell senescence and enhances senolysis. Nucleic Acids Res 2021; 49(13): 7389–7405

[171] Cai Y, Zhou H, Zhu Y, Sun Q, Ji Y, Xue A, Wang Y, Chen W, Yu X, Wang L, Chen H, Li C, Luo T, Deng H. Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice. Cell Res 2020; 30(7): 574–589

[172] Amor C, Fernández-Maestre I, Chowdhury S, Ho YJ, Nadella S, Graham C, Carrasco SE, Nnuji-John E, Feucht J, Hinterleitner C, Barthet VJA, Boyer JA, Mezzadra R, Wereski MG, Tuveson DA, Levine RL, Jones LW, Sadelain M, Lowe SW. Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction. Nature Aging 2024; 4(3): 336–349

[173] 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. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 2020; 583(7814): 127–132

[174] Yang D, Sun B, Li S, Wei W, Liu X, Cui X, Zhang X, Liu N, Yan L, Deng Y, Zhao X. NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates. Sci Transl Med 2023; 15(709): eadd1951

[175] Helman A, Klochendler A, Azazmeh N, Gabai Y, Horwitz E, Anzi S, Swisa A, Condiotti R, Granit RZ, Nevo Y, Fixler Y, Shreibman D, Zamir A, Tornovsky-Babeay S, Dai C, Glaser B, Powers AC, Shapiro AMJ, Magnuson MA, Dor Y, Ben-Porath I. p16^Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion. Nat Med 2016; 22(4): 412–420

[176] Reyes NS, Krasilnikov M, Allen NC, Lee JY, Hyams B, Zhou M, Ravishankar S, Cassandras M, Wang C, Khan I, Matatia P, Johmura Y, Molofsky A, Matthay M, Nakanishi M, Sheppard D, Campisi J, Peng T. Sentinel p16^INK4a+ cells in the basement membrane form a reparative niche in the lung. Science 2022; 378(6616): 192–201

[177] Grosse L, Wagner N, Emelyanov A, Molina C, Lacas-Gervais S, Wagner KD, Bulavin DV. Defined p16^high senescent cell types are indispensable for mouse healthspan. Cell Metab 2020; 32(1): 87–99.e6

[178] Jeon OH, David N, Campisi J, Elisseeff JH. Senescent cells and osteoarthritis: a painful connection. J Clin Invest 2018; 128(4): 1229–1237

[179] Neuhold LA, Killar L, Zhao W, Sung MLA, Warner L, Kulik J, Turner J, Wu W, Billinghurst C, Meijers T, Poole AR, Babij P, DeGennaro LJ. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 2001; 107(1): 35–44

[180] Wang M, Sampson ER, Jin H, Li J, Ke QH, Im HJ, Chen D. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 2013; 15(1): R5

[181] Feng K, Chen Z, Pengcheng L, Zhang S, Wang X. Quercetin attenuates oxidative stress-induced apoptosis via SIRT1/AMPK-mediated inhibition of ER stress in rat chondrocytes and prevents the progression of osteoarthritis in a rat model. J Cell Physiol 2019; 234(10): 18192–18205

[182] Piao S, Du W, Wei Y, Yang Y, Feng X, Bai L. Protectin DX attenuates IL-1β-induced inflammation via the AMPK/NF-κB pathway in chondrocytes and ameliorates osteoarthritis progression in a rat model. Int Immunopharmacol 2020; 78: 106043

[183] Anerillas C, Mazan-Mamczarz K, Herman AB, Munk R, Lam KWG, Calvo-Rubio M, Garrido A, Tsitsipatis D, Martindale JL, Altés G, Rossi M, Piao Y, Fan J, Cui CY, De S, Abdelmohsen K, de Cabo R, Gorospe M. The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress. Nature Aging 2023; 3(10): 1237–1250

[184] Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular senescence: aging, cancer, and injury. Physiol Rev 2019; 99(2): 1047–1078

[185] Adams PD. Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol Cell 2009; 36(1): 2–14

[186] Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, Curran SC, Davalos AR, Wilson-Edell KA, Liu S, Limbad C, Demaria M, Li P, Hubbard GB, Ikeno Y, Javors M, Desprez PY, Benz CC, Kapahi P, Nelson PS, Campisi J. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol 2015; 17(8): 1049–1061

[187] Chien Y, Scuoppo C, Wang X, Fang X, Balgley B, Bolden JE, Premsrirut P, Luo W, Chicas A, Lee CS, Kogan SC, Lowe SW. Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev 2011; 25(20): 2125–2136

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