Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration

Abstract

Emerging insights into cellular senescence highlight the relevance of senescence in musculoskeletal disorders, which represent the leading global cause of disability. Cellular senescence was initially described by Hayflick et al. in 1961 as an irreversible nondividing state in in vitro cell culture studies. We now know that cellular senescence can occur in vivo in response to various stressors as a heterogeneous and tissue-specific cell state with a secretome phenotype acquired after the initial growth arrest. In the past two decades, compelling evidence from preclinical models and human data show an accumulation of senescent cells in many components of the musculoskeletal system. Cellular senescence is therefore a defining feature of age-related musculoskeletal disorders, and targeted elimination of these cells has emerged recently as a promising therapeutic approach to ameliorate tissue damage and promote repair and regeneration of the skeleton and skeletal muscles. In this review, we summarize evidence of the role of senescent cells in the maintenance of bone homeostasis during childhood and their contribution to the pathogenesis of chronic musculoskeletal disorders, including osteoporosis, osteoarthritis, and sarcopenia. We highlight the diversity of the senescent cells in the microenvironment of bone, joint, and skeletal muscle tissue, as well as the mechanisms by which these senescent cells are involved in musculoskeletal diseases. In addition, we discuss how identifying and targeting senescent cells might positively affect pathologic progression and musculoskeletal system regeneration.

References

[1] Roberts S et al. Ageing in the musculoskeletal system. Acta Orthopaedica, 2016, 87: 15-25

[2] Goltzman D. The aging skeleton. Adv. Exp. Med. Biol., 2019, 1164: 153-160

[3] Patel J. Economic implications of osteoporotic fractures in postmenopausal women. Am. J. Manag. Care, 2020, 26: S311-S318

[4] Ma VY, Chan L, Carruthers KJ. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch. Phys. Med. Rehabil., 2014, 95: 986-995.e1

[5] von Haehling S, Morley JE, Anker SD. An overview of sarcopenia: facts and numbers on prevalence and clinical impact. J. Cachexia Sarcopenia Muscle, 2010, 1: 129-133

[6] Guo Y, Phillips BE, Atherton PJ, Piasecki M. Molecular and neural adaptations to neuromuscular electrical stimulation; Implications for ageing muscle. Mech. Ageing Dev., 2021, 193: 111402

[7] Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp. Cell Res., 1961, 25: 585-621

[8] Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res., 1965, 37: 614-636

[9] Wiley CD et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab., 2016, 23: 303-314

[10] Gorgoulis V et al. Cellular senescence: defining a path forward. Cell, 2019, 179: 813-827

[11] 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: 1424-1435

[12] Childs BG, Li H, van Deursen JM. Senescent cells: a therapeutic target for cardiovascular disease. J. Clin. Investig., 2018, 128: 1217-1228

[13] He S, Sharpless NE. Senescence in health and disease. Cell, 2017, 169: 1000-1011

[14] Ito Y, Hoare M, Narita M. Spatial and temporal control of senescence. Trends Cell Biol., 2017, 27: 820-832

[15] Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature, 1990, 345: 458-460

[16] Levy MZ, Allsopp RC, Futcher AB, Greider CW, Harley CB. Telomere end-replication problem and cell aging. J. Mol. Biol., 1992, 225: 951-960

[17] Marcand S, Gilson E, Shore D. A protein-counting mechanism for telomere length regulation in yeast. Science, 1997, 275: 986-990

[18] Bartkova J et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature, 2006, 444: 633-637

[19] Di Micco R et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature, 2006, 444: 638-642

[20] Mallette FA, Gaumont-Leclerc MF, Ferbeyre G. The DNA damage signaling pathway is a critical mediator of oncogene-induced senescence. Genes Dev., 2007, 21: 43-48

[21] Webley K et al. Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol. Cell. Biol., 2000, 20: 2803-2808

[22] Takahashi A et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nat. Cell Biol., 2006, 8: 1291-1297

[23] Imai Y et al. Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch. Cell Rep., 2014, 7: 194-207

[24] Terzi MY, Izmirli M, Gogebakan B. The cell fate: senescence or quiescence. Mol. Biol. Rep., 2016, 43: 1213-1220

[25] 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: 563-569

[26] Bracken AP et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev., 2007, 21: 525-530

[27] Gil J, Bernard D, Martínez D, Beach D. Polycomb CBX7 has a unifying role in cellular lifespan. Nat. Cell Biol., 2004, 6: 67-72

[28] Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature, 1999, 397: 164-168

[29] Childs BG et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov., 2017, 16: 718-735

[30] Nishimura K et al. Perturbation of ribosome biogenesis drives cells into senescence through 5S RNP-mediated p53 activation. Cell Rep., 2015, 10: 1310-1323

[31] Lessard F et al. Senescence-associated ribosome biogenesis defects contributes to cell cycle arrest through the Rb pathway. Nat. Cell Biol., 2018, 20: 789-799

[32] Del Toro N et al. Ribosomal protein RPL22/eL22 regulates the cell cycle by acting as an inhibitor of the CDK4-cyclin D complex. Cell Cycle, 2019, 18: 759-770

[33] Pantazi A et al. Inhibition of the 60S ribosome biogenesis GTPase LSG1 causes endoplasmic reticular disruption and cellular senescence. Aging Cell, 2019, 18: e12981

[34] Liu X et al. Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis. Nat. Commun., 2021, 12: 1832

[35] Hernandez-Segura A, Rubingh R, Demaria M. Identification of stable senescence-associated reference genes. Aging Cell, 2019, 18: e12911

[36] Dimri GP et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA., 1995, 92: 9363-9367

[37] Hall BM et al. p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging, 2017, 9: 1867-1884

[38] Odgren PR et al. False-positive beta-galactosidase staining in osteoclasts by endogenous enzyme: studies in neonatal and month-old wild-type mice. Connect. Tissue Res., 2006, 47: 229-234

[39] Yang NC, Hu ML. The limitations and validities of senescence associated-beta-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Exp. Gerontol., 2005, 40: 813-819

[40] Alcorta DA et al. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl Acad. Sci. USA., 1996, 93: 13742-13747

[41] Veronese N et al. Pain increases the risk of developing frailty in older adults with osteoarthritis. Pain Med., 2017, 18: 414-427

[42] Farr JN et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res., 2016, 31: 1920-1929

[43] Swanson EC, Manning B, Zhang H, Lawrence JB. Higher-order unfolding of satellite heterochromatin is a consistent and early event in cell senescence. J. Cell Biol., 2013, 203: 929-942

[44] Criscione SW et al. Reorganization of chromosome architecture in replicative cellular senescence. Sci. Adv., 2016, 2: e1500882

[45] Hewitt G et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun., 2012, 3

[46] Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol., 2018, 28: 436-453

[47] Li C et al. Programmed cell senescence in skeleton during late puberty. Nat. Commun., 2017, 8

[48] Su J et al. Cellular senescence mediates the detrimental effect of prenatal dexamethasone exposure on postnatal long bone growth in mouse offspring. Stem Cell Res. Ther., 2020, 11: 270

[49] Hermann A et al. Age-dependent neuroectodermal differentiation capacity of human mesenchymal stromal cells: limitations for autologous cell replacement strategies. Cytotherapy, 2010, 12: 17-30

[50] Wang AS, Ong PF, Chojnowski A, Clavel C, Dreesen O. Loss of lamin B1 is a biomarker to quantify cellular senescence in photoaged skin. Sci. Rep., 2017, 7

[51] Davalos AR et al. p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol., 2013, 201: 613-629

[52] Zhang Y et al. Nuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation. Nat. Commun., 2018, 9

[53] Hernandez-Segura A et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol., 2017, 27: 2652-2660.e2654

[54] Basisty N et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol., 2020, 18: e3000599

[55] Kohli J et al. Algorithmic assessment of cellular senescence in experimental and clinical specimens. Nat. Protoc., 2021, 16: 2471-2498

[56] Coppe JP et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol., 2008, 6: 2853-2868

[57] Rodier F et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol., 2009, 11: 973-979

[58] Demaria M et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell, 2014, 31: 722-733

[59] Laberge RM et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol., 2015, 17: 1049-1061

[60] Wiley CD et al. Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis. Cell Metab., 2021, 33: 1124-1136.e5

[61] Kuilman T et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell, 2008, 133: 1019-1031

[62] Acosta JC et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol., 2013, 15: 978-990

[63] Liu X, Wan M. A tale of the good and bad: cell senescence in bone homeostasis and disease. Int. Rev. Cell Mol. Biol., 2019, 346: 97-128

[64] Munoz-Espin D et al. Programmed cell senescence during mammalian embryonic development. Cell, 2013, 155: 1104-1118

[65] Storer M et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell, 2013, 155: 1119-1130

[66] Xue W et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 2007, 445: 656-660

[67] Iannello A, Thompson TW, Ardolino M, Lowe SW, Raulet DH. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med., 2013, 210: 2057-2069

[68] Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA., 2001, 98: 12072-12077

[69] Kirkland JL, Tchkonia T. Cellular senescence: a translational perspective. EBioMedicine, 2017, 21: 21-28

[70] Song S, Lam EW, Tchkonia T, Kirkland JL, Sun Y. Senescent cells: emerging targets for human aging and age-related diseases. Trends Biochem. Sci., 2020, 45: 578-592

[71] Borodkina AV, Deryabin PI, Giukova AA, Nikolsky NN. “Social life” of senescent cells: what is SASP and why study it? Acta Nat., 2018, 10: 4-14

[72] Kumari R, Jat P. Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front. Cell Dev. Biol., 2021, 9: 645593

[73] Cuollo L, Antonangeli F, Santoni A, Soriani A. The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology, 2020, 9: 485

[74] Birch J, Gil J. Senescence and the SASP: many therapeutic avenues. Genes Dev., 2020, 34: 1565-1576

[75] Payea MJ, Anerillas C, Tharakan R, Gorospe M. Translational control during cellular senescence. Mol. Cell. Biol., 2021, 41: e00512-e00520

[76] Tanaka Y, Takahashi A. Senescence-associated extracellular vesicle (SA-EV) release plays a role in senescence-associated secretory phenotype (SASP) in age-associated diseases. J. Biochem., 2021, 169: 147-153

[77] Rauch F. The dynamics of bone structure development during pubertal growth. J. Musculoskelet. Neuronal Interact., 2012, 12: 1-6

[78] Yakar S, Isaksson O. Regulation of skeletal growth and mineral acquisition by the GH/IGF-1 axis: lessons from mouse models. Growth Horm. IGF Res., 2016, 28: 26-42

[79] Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol., 2014, 15: 482-496

[80] Fuchs Y, Steller H. Programmed cell death in animal development and disease. Cell, 2011, 147: 742-758

[81] Triana-Martinez F, Pedraza-Vazquez G, Maciel-Baron LA, Konigsberg M. Reflections on the role of senescence during development and aging. Arch. Biochem. Biophys., 2016, 598: 40-49

[82] Marrani E, Giani T, Simonini G, Cimaz R. Pediatric osteoporosis: diagnosis and treatment considerations. Drugs, 2017, 77: 679-695

[83] Nellans KW, Kowalski E, Chung KC. The epidemiology of distal radius fractures. Hand Clin., 2012, 28: 113-125

[84] Huber AM et al. Prevalent vertebral fractures among children initiating glucocorticoid therapy for the treatment of rheumatic disorders. Arthritis Care Res., 2010, 62: 516-526

[85] Berger C et al. Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents. CMAJ, 2008, 178: 1660-1668

[86] Glatt V, Canalis E, Stadmeyer L, Bouxsein ML. Age-related changes in trabecular architecture differ in female and male C57BL/6J mice. J. Bone Miner. Res., 2007, 22: 1197-1207

[87] Ding M, Hvid I. Quantification of age-related changes in the structure model type and trabecular thickness of human tibial cancellous bone. Bone, 2000, 26: 291-295

[88] Javaheri B, Pitsillides AA. Aging and mechanoadaptive responsiveness of bone. Curr. Osteoporos. Rep., 2019, 17: 560-569

[89] Piemontese M et al. Old age causes de novo intracortical bone remodeling and porosity in mice. JCI Insight, 2017, 2: e93771

[90] Pignolo RJ, Samsonraj RM, Law SF, Wang H, Chandra A. Targeting cell senescence for the treatment of age-related bone loss. Curr. Osteoporos. Rep., 2019, 17: 70-85

[91] Farr JN, Khosla S. Cellular senescence in bone. Bone, 2019, 121: 121-133

[92] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell, 2013, 153: 1194-1217

[93] Manolagas SC. The quest for osteoporosis mechanisms and rational therapies: how far we’ve come, how much further we need to go. J. Bone Miner. Res., 2018, 33: 371-385

[94] Kim HN et al. DNA damage and senescence in osteoprogenitors expressing Osx1 may cause their decrease with age. Aging Cell, 2017, 16: 693-703

[95] Chen Q et al. DNA damage drives accelerated bone aging via an NF-κB-dependent mechanism. J. Bone Miner. Res., 2013, 28: 1214-1228

[96] Kim HN et al. Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence. JCI Insight, 2020, 5: e138815

[97] Farr JN et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med., 2017, 23: 1072-1079

[98] Kim HN et al. Elimination of senescent osteoclast progenitors has no effect on the age-associated loss of bone mass in mice. Aging Cell, 2019, 18: e12923

[99] Tyagi AM et al. Premature T cell senescence in Ovx mice is inhibited by repletion of estrogen and medicarpin: a possible mechanism for alleviating bone loss. Osteoporos. Int., 2012, 23: 1151-1161

[100] Farr JN et al. Independent roles of estrogen deficiency and cellular senescence in the pathogenesis of osteoporosis: evidence in young adult mice and older humans. J. Bone Miner. Res., 2019, 34: 1407-1418

[101] Costantini S, Conte C. Bone health in diabetes and prediabetes. World J. Diabetes, 2019, 10: 421-445

[102] Valderrábano RJ, Linares MI. Diabetes mellitus and bone health: epidemiology, etiology and implications for fracture risk stratification. Clin. Diabetes Endocrinol., 2018, 4

[103] Eckhardt BA et al. Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes. JCI Insight, 2020, 5: e135236

[104] Khosla S, Farr JN, Tchkonia T, Kirkland JL. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol., 2020, 16: 263-275

[105] Almeida M et al. Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice. Aging Cell, 2020, 19: e13247

[106] Cleveland RJ, Callahan LF. Can osteoarthritis predict mortality? North Carol. Med. J., 2017, 78: 322-325

[107] Misra D et al. Knee osteoarthritis and frailty: findings from the Multicenter Osteoarthritis Study and Osteoarthritis Initiative. J. Gerontol. Ser. A Biol. Sci. Med. Sci., 2015, 70: 339-344

[108] Jeon OH et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med., 2017, 23: 775-781

[109] Jeon OH, David N, Campisi J, Elisseeff JH. Senescent cells and osteoarthritis: a painful connection. J. Clin. Investig., 2018, 128: 1229-1237

[110] Faust HJ et al. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. J. Clin. Investig., 2020, 130: 5493-5507

[111] Jeon OH et al. Senescence cell-associated extracellular vesicles serve as osteoarthritis disease and therapeutic markers. JCI Insight, 2019, 4: e125019

[112] van Deursen JM. The role of senescent cells in ageing. Nature, 2014, 509: 439-446

[113] Martin, J. A., Brown, T. D., Heiner, A. D. & Buckwalter, J. A. Chondrocyte senescence, joint loading and osteoarthritis. Clin. Orthop. Rel. Res. S96–S103 (2004).

[114] Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res. Ther., 2009, 11: 224

[115] Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat. Rev. Rheumatol., 2011, 7: 33-42

[116] Yu SM, Kim SJ. Thymoquinone-induced reactive oxygen species causes apoptosis of chondrocytes via PI3K/Akt and p38kinase pathway. Exp. Biol. Med., 2013, 238: 811-820

[117] Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue inflammation in early and late osteoarthritis. Ann. Rheum. Dis., 2005, 64: 1263-1267

[118] Blom AB et al. Synovial lining macrophages mediate osteophyte formation during experimental osteoarthritis. Osteoarthritis Cartilage, 2004, 12: 627-635

[119] van Lent PL et al. Crucial role of synovial lining macrophages in the promotion of transforming growth factor beta-mediated osteophyte formation. Arthritis Rheum., 2004, 50: 103-111

[120] Campisi J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol., 2013, 75: 685-705

[121] Coryell PR, Diekman BO, Loeser RF. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol., 2021, 17: 47-57

[122] Heijink A et al. Biomechanical considerations in the pathogenesis of osteoarthritis of the knee. Knee Surg. Sports Traumatol., 2012, 20: 423-435

[123] Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Clin. Geriatr. Med., 2010, 26: 355-369

[124] Brown TD, Johnston RC, Saltzman CL, Marsh JL, Buckwalter JA. Posttraumatic osteoarthritis: a first estimate of incidence, prevalence, and burden of disease. J. Orthop. Trauma, 2006, 20: 739-744

[125] Zhuo Q, Yang W, Chen J, Wang Y. Metabolic syndrome meets osteoarthritis. Nat. Rev. Rheumatol., 2012, 8: 729-737

[126] Philbin EF et al. Osteoarthritis as a determinant of an adverse coronary heart disease risk profile. J. Cardiovascular Risk, 1996, 3: 529-533

[127] Cerhan JR, Wallace RB, el-Khoury GY, Moore TE, Long CR. Decreased survival with increasing prevalence of full-body, radiographically defined osteoarthritis in women. Am. J. Epidemiol., 1995, 141: 225-234

[128] Haara MM et al. Osteoarthritis of finger joints in Finns aged 30 or over: prevalence, determinants, and association with mortality. Ann. Rheum. Dis., 2003, 62: 151-158

[129] Saleh AS et al. Arterial stiffness and hand osteoarthritis: a novel relationship? Osteoarthr. Cartil., 2007, 15: 357-361

[130] Francisco V et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: when the levee breaks. J. Orthop. Res., 2018, 36: 594-604

[131] Piva SR et al. Links between osteoarthritis and diabetes: implications for management from a physical activity perspective. Clin. Geriatr. Med., 2015, 31: 67-87, viii

[132] Baudart P, Louati K, Marcelli C, Berenbaum F, Sellam J. Association between osteoarthritis and dyslipidaemia: a systematic literature review and meta-analysis. RMD Open, 2017, 3: e000442

[133] Vinatier C, Dominguez E, Guicheux J, Carames B. Role of the inflammation-autophagy-senescence integrative network in osteoarthritis. Front. Physiol., 2018, 9: 706

[134] Puenpatom RA, Victor TW. Increased prevalence of metabolic syndrome in individuals with osteoarthritis: an analysis of NHANES III data. Postgrad. Med., 2009, 121: 9-20

[135] Chadha R. Revealed aspect of metabolic osteoarthritis. J. Orthop., 2016, 13: 347-351

[136] Courties A, Sellam J, Berenbaum F. Metabolic syndrome-associated osteoarthritis. Curr. Opin. Rheumatol., 2017, 29: 214-222

[137] Farnaghi S, Crawford R, Xiao Y, Prasadam I. Cholesterol metabolism in pathogenesis of osteoarthritis disease. Int. J. Rheum. Dis., 2017, 20: 131-140

[138] Kang C. Senolytics and senostatics: a two-pronged approach to target cellular senescence for delaying aging and age-related diseases. Mol. Cells, 2019, 42: 821-827

[139] Baker DJ et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature, 2016, 530: 184-189

[140] Baker DJ et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 2011, 479: 232-236

[141] Chang J et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med., 2016, 22: 78-83

[142] Chung L et al. Interleukin 17 and senescent cells regulate the foreign body response to synthetic material implants in mice and humans. Sci. Transl. Med., 2020, 12: eaax3799

[143] Sessions GA et al. Controlled induction and targeted elimination of p16(INK4a)-expressing chondrocytes in cartilage explant culture. FASEB J., 2019, 33: 12364-12373

[144] Zhu Y et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 2015, 14: 644-658

[145] Hickson LJ et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine, 2019, 47: 446-456

[146] Xu M et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med., 2018, 24: 1246-1256

[147] Matsuzaki T et al. Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice. Ann. Rheum. Dis., 2014, 73: 1397-1404

[148] Batshon G et al. Serum NT/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence. Ann. Rheum. Dis., 2020, 79: 1370-1380

[149] Yousefzadeh MJ et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine, 2018, 36: 18-28

[150] Zheng W et al. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. Int. Immunopharmacol., 2017, 45: 135-147

[151] Shiomi T, Lemaître V, D’Armiento J, Okada Y. Matrix metalloproteinases, a disintegrin and metalloproteinases, and a disintegrin and metalloproteinases with thrombospondin motifs in non-neoplastic diseases. Pathol. Int., 2010, 60: 477-496

[152] Roach HI et al. Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis Rheum., 2005, 52: 3110-3124

[153] Neuhold LA et al. Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J. Clin. Investig., 2001, 107: 35-44

[154] Wang M et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res. Ther., 2013, 15: R5

[155] Fleischmann RM et al. A phase II trial of lutikizumab, an anti-interleukin-1α/β dual variable domain immunoglobulin, in knee osteoarthritis patients with synovitis. Arthritis Rheumatol., 2019, 71: 1056-1069

[156] Kloppenburg M et al. Etanercept in patients with inflammatory hand osteoarthritis (EHOA): a multicentre, randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis., 2018, 77: 1757-1764

[157] Schieker M et al. Effects of interleukin-1β inhibition on incident hip and knee replacement: exploratory analyses from a randomized, double-blind, placebo-controlled trial. Ann. Intern. Med., 2020, 173: 509-515

[158] de Hooge AS et al. Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging. Osteoarthr. Cartil., 2005, 13: 66-73

[159] Baskin KK, Winders BR, Olson EN. Muscle as a “mediator” of systemic metabolism. Cell Metab., 2015, 21: 237-248

[160] Manickam R, Duszka K, Wahli W. PPARs and microbiota in skeletal muscle health and wasting. Int. J. Mol. Sci., 2020, 21: 8056

[161] Periasamy M, Herrera JL, Reis FCG. Skeletal muscle thermogenesis and its role in whole body energy metabolism. Diabetes Metab. J., 2017, 41: 327-336

[162] Sartori R, Romanello V, Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat. Commun., 2021, 12

[163] Yamakawa H, Kusumoto D, Hashimoto H, Yuasa S. Stem cell aging in skeletal muscle regeneration and disease. Int. J. Mol. Sci., 2020, 21: 1830

[164] Oikawa SY, Holloway TM, Phillips SM. The impact of step reduction on muscle health in aging: protein and exercise as countermeasures. Front. Nutr., 2019, 6: 75

[165] Romanello V. The interplay between mitochondrial morphology and myomitokines in aging sarcopenia. Int. J. Mol. Sci., 2020, 22: 91

[166] Morley JE, Anker SD, von Haehling S. Prevalence, incidence, and clinical impact of sarcopenia: facts, numbers, and epidemiology-update 2014. J. Cachexia Sarcopenia Muscle, 2014, 5: 253-259

[167] da Silva PFL et al. The bystander effect contributes to the accumulation of senescent cells in vivo. Aging Cell, 2019, 18: e12848

[168] Chen QN et al. Effect of sarcolipin-mediated cell transdifferentiation in sarcopenia-associated skeletal muscle fibrosis. Exp. Cell Res., 2020, 389: 111890

[169] Alcalde-Estévez E et al. Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia. Aging, 2020, 12: 11200-11223

[170] Kudryashova E, Kramerova I, Spencer MJ. Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H. J. Clin. Investig., 2012, 122: 1764-1776

[171] Zhou J et al. GSK-3α is a central regulator of age-related pathologies in mice. J. Clin. Investig., 2013, 123: 1821-1832

[172] Cosgrove BD et al. Rejuvenation of the muscle stem cell population restores strength to injured aged muscles. Nat. Med., 2014, 20: 255-264

[173] Zhu P et al. The transcription factor Slug represses p16(Ink4a) and regulates murine muscle stem cell aging. Nat. Commun., 2019, 10

[174] Du J et al. Aging increases CCN1 expression leading to muscle senescence. Am. J. Physiol. Cell Physiol., 2014, 306: C28-C36

[175] Sousa-Victor P et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature, 2014, 506: 316-321

[176] García-Prat L et al. Autophagy maintains stemness by preventing senescence. Nature, 2016, 529: 37-42

[177] Sosa P et al. Hyperphosphatemia promotes senescence of myoblasts by impairing autophagy through Ilk overexpression, a possible mechanism involved in sarcopenia. Aging Dis., 2018, 9: 769-784

[178] Wang Y et al. Aging of the immune system causes reductions in muscle stem cell populations, promotes their shift to a fibrogenic phenotype, and modulates sarcopenia. FASEB J., 2019, 33: 1415-1427

[179] Wang Y, Wehling-Henricks M, Samengo G, Tidball JG. Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide. Aging Cell, 2015, 14: 678-688

[180] Ratnayake D et al. Macrophages provide a transient muscle stem cell niche via NAMPT secretion. Nature, 2021, 591: 281-287

[181] Ming GF, Wu K, Hu K, Chen Y, Xiao J. NAMPT regulates senescence, proliferation, and migration of endothelial progenitor cells through the SIRT1 AS lncRNA/miR-22/SIRT1 pathway. Biochem. Biophys. Res. Commun., 2016, 478: 1382-1388

[182] Baraibar M et al. Impaired metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes. Free Radic. Biol. Med., 2014, 75: S23

[183] Baraibar MA et al. Impaired energy metabolism of senescent muscle satellite cells is associated with oxidative modifications of glycolytic enzymes. Aging, 2016, 8: 3375-3389

[184] Dennison EM, Sayer AA, Cooper C. Epidemiology of sarcopenia and insight into possible therapeutic targets. Nat. Rev. Rheumatol., 2017, 13: 340-347

[185] Alsharidah M et al. Primary human muscle precursor cells obtained from young and old donors produce similar proliferative, differentiation and senescent profiles in culture. Aging cell, 2013, 12: 333-344

[186] Sugihara H, Teramoto N, Yamanouchi K, Matsuwaki T, Nishihara M. Oxidative stress-mediated senescence in mesenchymal progenitor cells causes the loss of their fibro/adipogenic potential and abrogates myoblast fusion. Aging, 2018, 10: 747-763

[187] Pacifici F et al. Prdx6 plays a main role in the crosstalk between aging and metabolic sarcopenia. Antioxidants (Basel), 2020, 9: 329

[188] Zhu S et al. Aging- and obesity-related peri-muscular adipose tissue accelerates muscle atrophy. PLoS One, 2019, 14: e0221366

[189] Tezze C et al. Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab., 2017, 25: 1374-1389.e1376

[190] von Kobbe C. Targeting senescent cells: approaches, opportunities, challenges. Aging, 2019, 11: 12844-12861

[191] Baar MP et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell, 2017, 169: 132-147.e116

[192] O’Sullivan Coyne G, Burotto M. MABp1 for the treatment of colorectal cancer. Expert Opin. Biol. Ther., 2017, 17: 1155-1161

[193] Khor SC, Wan Ngah WZ, Mohd Yusof YA, Abdul Karim N, Makpol S. Tocotrienol-rich fraction ameliorates antioxidant defense mechanisms and improves replicative senescence-associated oxidative stress in human myoblasts. Oxid. Med. Cell. Longev., 2017, 2017: 3868305

[194] Lim JJ, Ngah WZ, Mouly V, Abdul Karim N. Reversal of myoblast aging by tocotrienol rich fraction posttreatment. Oxid. Med. Cell. Longev., 2013, 2013: 978101

[195] Lim JJ, Wan Zurinah WN, Mouly V, Norwahidah AK. Tocotrienol-rich fraction (TRF) treatment promotes proliferation capacity of stress-induced premature senescence myoblasts and modulates the renewal of satellite cells: microarray analysis. Oxid. Med. Cell. Longev., 2019, 2019: 9141343

[196] Hu Z et al. MicroRNA-29 induces cellular senescence in aging muscle through multiple signaling pathways. Aging, 2014, 6: 160-175

[197] Soriano-Arroquia A, McCormick R, Molloy AP, McArdle A, Goljanek-Whysall K. Age-related changes in miR-143-3p:Igfbp5 interactions affect muscle regeneration. Aging Cell, 2016, 15: 361-369

[198] Zheng Y, Kong J, Li Q, Wang Y, Li J. Role of miRNAs in skeletal muscle aging. Clin. Interv. Aging, 2018, 13: 2407-2419