{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:41:51Z","timestamp":1792795311374,"version":"4.5.0"},"reference-count":280,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T00:00:00Z","timestamp":1656547200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["P30 AG024827"],"award-info":[{"award-number":["P30 AG024827"]}]},{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine","award":["P30 AG024827"],"award-info":[{"award-number":["P30 AG024827"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Osteoarthritis (OA) is a chronic degenerative joint disease that causes pain, physical disability, and life quality impairment. The pathophysiology of OA remains largely unclear, and currently no FDA-approved disease-modifying OA drugs (DMOADs) are available. As has been acknowledged, aging is the primary independent risk factor for OA, but the mechanisms underlying such a connection are not fully understood. In this review, we first revisit the changes in OA chondrocytes from the perspective of cellular hallmarks of aging. It is concluded that OA chondrocytes share many alterations similar to cellular aging. Next, based on the findings from studies on other cell types and diseases, we propose methods that can potentially reverse osteoarthritic phenotype of chondrocytes back to a healthier state. Lastly, current challenges and future perspectives are summarized.<\/jats:p>","DOI":"10.3390\/biology11070996","type":"journal-article","created":{"date-parts":[[2022,6,30]],"date-time":"2022-06-30T20:53:02Z","timestamp":1656622382000},"page":"996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Potential Methods of Targeting Cellular Aging Hallmarks to Reverse Osteoarthritic Phenotype of Chondrocytes"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3985-7779","authenticated-orcid":false,"given":"Yuchen","family":"He","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15217, USA"},{"name":"Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha 410008, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9082-0111","authenticated-orcid":false,"given":"Katelyn E.","family":"Lipa","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15217, USA"},{"name":"Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter G.","family":"Alexander","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15217, USA"},{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4403-1477","authenticated-orcid":false,"given":"Karen L.","family":"Clark","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15217, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15217, USA"},{"name":"Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, PA 15219, USA"},{"name":"McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1697","DOI":"10.1002\/art.34453","article-title":"Osteoarthritis: A disease of the joint as an organ","volume":"64","author":"Loeser","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.rdc.2012.10.007","article-title":"Diagnosis and clinical presentation of osteoarthritis","volume":"39","author":"Abhishek","year":"2013","journal-title":"Rheum Dis Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1136\/annrheumdis-2019-216515","article-title":"Global, regional and national burden of osteoarthritis 1990-2017: A systematic analysis of the Global Burden of Disease Study 2017","volume":"79","author":"Safiri","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Lee, Y., Lee, S.H., Lim, S.M., Baek, S.H., and Ha, I.H. (2020). Mental health and quality of life of patients with osteoarthritis pain: The sixth Korea National Health and Nutrition Examination Survey (2013\u20132015). PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0242077"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/S0140-6736(14)60802-3","article-title":"Osteoarthritis","volume":"386","author":"Palmer","year":"2015","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/S0140-6736(11)60752-6","article-title":"Knee replacement","volume":"379","author":"Carr","year":"2012","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.rehab.2016.01.006","article-title":"Risk factors and burden of osteoarthritis","volume":"59","author":"Palazzo","year":"2016","journal-title":"Ann. Phys. Rehabil Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.csm.2017.02.001","article-title":"Basic science of articular cartilage","volume":"36","author":"Carballo","year":"2017","journal-title":"Clin. Sports Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.bcp.2019.02.036","article-title":"Chondrocyte dedifferentiation and osteoarthritis (OA)","volume":"165","author":"Charlier","year":"2019","journal-title":"Biochem. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.arr.2017.12.006","article-title":"Cartilage regeneration and ageing: Targeting cellular plasticity in osteoarthritis","volume":"42","author":"Loureiro","year":"2018","journal-title":"Ageing Res. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/nyas.13930","article-title":"Phenotypic instability of chondrocytes in osteoarthritis: On a path to hypertrophy","volume":"1442","author":"Singh","year":"2019","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.joca.2019.04.013","article-title":"Chondrocyte enlargement is a marker of osteoarthritis severity","volume":"27","author":"Gratal","year":"2019","journal-title":"Osteoarthr. Cartil."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Lauer, J.C., Selig, M., Hart, M.L., Kurz, B., and Rolauffs, B. (2021). Articular chondrocyte phenotype regulation through the cytoskeleton and the signaling processes that originate from or converge on the cytoskeleton: Towards a novel understanding of the intersection between actin dynamics and chondrogenic function. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22063279"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.bpj.2021.11.018","article-title":"Dedifferentiation alters chondrocyte nuclear mechanics during in vitro culture and expansion","volume":"121","author":"Ghosh","year":"2022","journal-title":"Biophys. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/bdrc.20167","article-title":"Regulation of the chondrogenic phenotype in culture","volume":"87","author":"Bobick","year":"2009","journal-title":"Birth Defects Res. C Embryo Today"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1641","DOI":"10.1093\/rheumatology\/ken341","article-title":"Morphology of the bovine chondrocyte and of its cytoskeleton in isolation and in situ: Are chondrocytes ubiquitously paired through the entire layer of articular cartilage?","volume":"47","author":"Sasazaki","year":"2008","journal-title":"Rheumatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1822","DOI":"10.1002\/jcp.25290","article-title":"Focal adhesion assembly induces phenotypic changes and dedifferentiation in chondrocytes","volume":"231","author":"Shin","year":"2016","journal-title":"J. Cell Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/0047-6374(86)90040-0","article-title":"Age-related changes in rabbit articular chondrocytes","volume":"37","author":"Dominice","year":"1986","journal-title":"Mech Ageing Dev."},{"key":"ref_19","first-page":"253","article-title":"Alteration of viscoelastic properties is associated with a change in cytoskeleton components of ageing chondrocytes from rabbit knee articular cartilage","volume":"8","author":"Duan","year":"2011","journal-title":"Mol. Cell Biomech."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s12014-015-9085-6","article-title":"Comparative proteomic analysis of hypertrophic chondrocytes in osteoarthritis","volume":"12","author":"Tsolis","year":"2015","journal-title":"Clin. Proteom."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e21410","DOI":"10.1096\/fj.202002386R","article-title":"Enhancing the potential of aged human articular chondrocytes for high-quality cartilage regeneration","volume":"35","author":"Shen","year":"2021","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41584-020-00533-7","article-title":"Mechanisms and therapeutic implications of cellular senescence in osteoarthritis","volume":"17","author":"Coryell","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41419-020-03341-9","article-title":"STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF-\u03baB signaling pathway","volume":"12","author":"Guo","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"a040907","DOI":"10.1101\/cshperspect.a040907","article-title":"Regeneration, rejuvenation, and replacement: Turning back the clock on tissue aging","volume":"13","author":"Rando","year":"2021","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.cell.2005.01.027","article-title":"Understanding the odd science of aging","volume":"120","author":"Kirkwood","year":"2005","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.berh.2009.08.006","article-title":"Why is osteoarthri.itis an age-related disease?","volume":"24","author":"Loeser","year":"2010","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1002\/art.23176","article-title":"Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II","volume":"58","author":"Lawrence","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_28","first-page":"2271","article-title":"Prevalence of knee osteoarthritis in the United States: Arthritis data from the Third National Health and Nutrition Examination Survey 1991\u201394","volume":"33","author":"Dillon","year":"2006","journal-title":"J. Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ho-Pham, L.T., Lai, T.Q., Mai, L.D., Doan, M.C., Pham, H.N., and Nguyen, T.V. (2014). Prevalence of radiographic osteoarthritis of the knee and its relationship to self-reported pain. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0094563"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1038\/nrrheum.2016.136","article-title":"Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis","volume":"12","author":"Robinson","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.1749-6632.2000.tb06651.x","article-title":"Inflamm-aging. An evolutionary perspective on immunosenescence","volume":"908","author":"Franceschi","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"166","DOI":"10.18632\/aging.100444","article-title":"Inflammaging: Disturbed interplay between autophagy and inflammasomes","volume":"4","author":"Salminen","year":"2012","journal-title":"Aging"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1002\/art.24598","article-title":"Interleukin-6 is a significant predictor of radiographic knee osteoarthritis: The Chingford Study","volume":"60","author":"Livshits","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/art.1780400419","article-title":"Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease","volume":"40","author":"Spector","year":"1997","journal-title":"Arthritis Rheum."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1136\/annrheumdis-2011-201047","article-title":"Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: A prospective cohort study","volume":"72","author":"Stannus","year":"2013","journal-title":"Ann. Rheum. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1002\/1529-0131(200106)44:6<1237::AID-ART214>3.0.CO;2-F","article-title":"Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets","volume":"44","author":"Pelletier","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1016\/j.joca.2015.01.008","article-title":"Aging-related inflammation in osteoarthritis","volume":"23","author":"Greene","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1002\/art.30137","article-title":"Synovial inflammation in patients undergoing arthroscopic meniscectomy: Molecular characterization and relationship to symptoms","volume":"63","author":"Scanzello","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/nrrheum.2010.159","article-title":"The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis","volume":"6","author":"Sellam","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1136\/ard.2011.150243","article-title":"Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: The MOST study","volume":"70","author":"Roemer","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1136\/ard.2006.067470","article-title":"Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis","volume":"66","author":"Hill","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"030501","DOI":"10.11613\/BM.2019.030501","article-title":"Hallmarks of senescence and aging","volume":"29","author":"Dodig","year":"2019","journal-title":"Biochem. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","article-title":"Hallmarks of cellular senescence","volume":"28","author":"Nehme","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1002\/1873-3468.13483","article-title":"Mechanisms of cellular rejuvenation","volume":"593","author":"Jessberger","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/s41580-019-0204-5","article-title":"The ageing epigenome and its rejuvenation","volume":"21","author":"Zhang","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1146\/annurev.bi.53.070184.001115","article-title":"The molecular structure of centromeres and telomeres","volume":"53","author":"Blackburn","year":"1984","journal-title":"Annu. Rev. Biochem."},{"key":"ref_48","first-page":"1626","article-title":"Telomere length and telomerase activity in osteoporosis and osteoarthritis","volume":"19","author":"Fragkiadaki","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1186\/gb-2008-9-9-232","article-title":"The telosome\/shelterin complex and its functions","volume":"9","author":"Xin","year":"2008","journal-title":"Genome Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3397","DOI":"10.18632\/aging.101655","article-title":"Cell cycle-dependent and -independent telomere shortening accompanies murine brain aging","volume":"10","author":"Ain","year":"2018","journal-title":"Aging"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/978-981-13-2835-0_9","article-title":"Telomeres, telomerase and ageing","volume":"90","author":"Saretzki","year":"2018","journal-title":"Subcell Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1038\/nrm3823","article-title":"Cellular senescence: From physiology to pathology","volume":"15","author":"Serrano","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1177\/1947603514537518","article-title":"Telomerase activity in articular chondrocytes is lost after puberty","volume":"5","author":"Wilson","year":"2014","journal-title":"Cartilage"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1046\/j.1474-9728.2002.00008.x","article-title":"The role of chondrocyte senescence in osteoarthritis","volume":"1","author":"Price","year":"2002","journal-title":"Aging Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"R12","DOI":"10.1186\/ar3687","article-title":"The distribution pattern of critically short telomeres in human osteoarthritic knees","volume":"14","author":"Harbo","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_56","first-page":"27","article-title":"Telomere shortening is associated with poor physical performance in knee osteoarthritis","volume":"13","author":"Manoy","year":"2020","journal-title":"Biomed. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"718890","DOI":"10.3389\/fgene.2021.718890","article-title":"Genetically predicted longer telomere length may reduce risk of hip osteoarthritis","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"B172","DOI":"10.1093\/gerona\/56.4.B172","article-title":"Telomere erosion and senescence in human articular cartilage chondrocytes","volume":"56","author":"Martin","year":"2001","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1412","DOI":"10.1016\/j.joca.2015.03.024","article-title":"Depletion of SIRT6 causes cellular senescence, DNA damage, and telomere dysfunction in human chondrocytes","volume":"23","author":"Nagai","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"125","DOI":"10.2174\/1574888X12666170817141921","article-title":"Histone Modifications in Aging: The Underlying Mechanisms and Implications","volume":"13","author":"Wang","year":"2018","journal-title":"Curr. Stem Cell Res. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e1600584","DOI":"10.1126\/sciadv.1600584","article-title":"Epigenetics and aging","volume":"2","author":"Pal","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.cell.2016.07.050","article-title":"Epigenetic Mechanisms of Longevity and Aging","volume":"166","author":"Sen","year":"2016","journal-title":"Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.gendis.2014.12.005","article-title":"Epigenetics and Osteoarthritis","volume":"2","author":"Zhang","year":"2015","journal-title":"Genes Dis."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Arias, C., and Salazar, L.A. (2021). Autophagy and polyphenols in osteoarthritis: A focus on epigenetic regulation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23010421"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1080\/03008207.2016.1208655","article-title":"Inflammation and epigenetic regulation in osteoarthritis","volume":"58","author":"Shen","year":"2017","journal-title":"Connect. Tissue Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1007\/s11926-017-0661-9","article-title":"The epigenomic landscape in osteoarthritis","volume":"19","author":"Simon","year":"2017","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.semcdb.2016.04.017","article-title":"Analysis of genetics and DNA methylation in osteoarthritis: What have we learnt about the disease?","volume":"62","author":"Reynard","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1866","DOI":"10.1002\/art.41736","article-title":"Genetic and epigenetic fine-tuning of TGFB1 expression within the human osteoarthritic joint","volume":"73","author":"Rice","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1038\/cdd.2016.31","article-title":"HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation","volume":"23","author":"Ma","year":"2016","journal-title":"Cell Death Differ."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1136\/annrheumdis-2018-213882","article-title":"RNA sequencing data integration reveals an miRNA interactome of osteoarthritis cartilage","volume":"78","author":"Ramos","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1111\/brv.12291","article-title":"Mitochondrial function, ornamentation, and immunocompetence","volume":"92","author":"Koch","year":"2017","journal-title":"Biol. Rev. Camb. Philos Soc."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"dev143420","DOI":"10.1242\/dev.143420","article-title":"The role of mitochondria in stem cell fate and aging","volume":"145","author":"Zhang","year":"2018","journal-title":"Development"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cmet.2016.09.017","article-title":"Mammalian mitochondria and aging: An update","volume":"25","author":"Kauppila","year":"2017","journal-title":"Cell Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1172\/JCI120842","article-title":"The role of mitochondria in aging","volume":"128","author":"Jang","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.molcel.2016.01.028","article-title":"The mitochondrial basis of aging","volume":"61","author":"Sun","year":"2016","journal-title":"Mol. Cell"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s13048-019-0529-x","article-title":"Mitochondrial dysfunction and endoplasmic reticulum stress involved in oocyte aging: An analysis using single-cell RNA-sequencing of mouse oocytes","volume":"12","author":"Zhang","year":"2019","journal-title":"J. Ovarian Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1146\/annurev-biophys-121219-081604","article-title":"Mitochondria-associated proteostasis","volume":"49","author":"Ruan","year":"2020","journal-title":"Annu. Rev. Biophys."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1146\/annurev-biochem-062917-012739","article-title":"Mitochondrial proteases: Multifaceted regulators of mitochondrial plasticity","volume":"89","author":"Deshwal","year":"2020","journal-title":"Annu. Rev. Biochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2082","DOI":"10.1080\/15548627.2020.1822097","article-title":"Mitophagy in degenerative joint diseases","volume":"17","author":"Sun","year":"2021","journal-title":"Autophagy"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1102s","DOI":"10.1177\/19476035211063858","article-title":"Role of mitochondria in physiology of chondrocytes and diseases of osteoarthritis and rheumatoid arthritis","volume":"13","author":"Kan","year":"2021","journal-title":"Cartilage"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mito.2019.07.003","article-title":"Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling","volume":"49","author":"Wu","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1126\/science.1201940","article-title":"Mitochondria and the autophagy-inflammation-cell death axis in organismal aging","volume":"333","author":"Green","year":"2011","journal-title":"Science"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41569-018-0064-2","article-title":"Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty","volume":"15","author":"Ferrucci","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e99238","DOI":"10.15252\/embj.201899238","article-title":"Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis","volume":"37","author":"Riley","year":"2018","journal-title":"Embo J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00395-017-0618-1","article-title":"Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart","volume":"112","author":"Gadicherla","year":"2017","journal-title":"Basic Res. Cardiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/s41574-021-00626-7","article-title":"Mitochondrial and metabolic dysfunction in ageing and age-related diseases","volume":"18","author":"Amorim","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"118602","DOI":"10.1016\/j.lfs.2020.118602","article-title":"Role of mitochondria in mediating chondrocyte response to mechanical stimuli","volume":"263","author":"He","year":"2020","journal-title":"Life Sci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.phrs.2018.09.026","article-title":"Fibroblast growth factor 18 exerts anti-osteoarthritic effects through PI3K-AKT signaling and mitochondrial fusion and fission","volume":"139","author":"Yao","year":"2019","journal-title":"Pharmacol. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"7504","DOI":"10.1002\/jcp.30386","article-title":"Moderate mechanical stress suppresses the IL-1\u03b2-induced chondrocyte apoptosis by regulating mitochondrial dynamics","volume":"236","author":"Zhang","year":"2021","journal-title":"J. Cell Physiol."},{"key":"ref_90","first-page":"1335","article-title":"Mitochondrial genetics and epigenetics in osteoarthritis","volume":"10","author":"Blanco","year":"2019","journal-title":"Front. Genet."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"703847","DOI":"10.3389\/fphar.2021.703847","article-title":"Urolithin A protects chondrocytes from mechanical overloading-induced injuries","volume":"12","author":"He","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"101249","DOI":"10.1016\/j.arr.2020.101249","article-title":"The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis","volume":"66","author":"Zheng","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-019-0101-y","article-title":"The proteostasis network and its decline in ageing","volume":"20","author":"Hipp","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"22173","DOI":"10.1073\/pnas.1906592116","article-title":"Proteostasis collapse is a driver of cell aging and death","volume":"116","author":"Santra","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1083\/jcb.201709072","article-title":"Pathways of cellular proteostasis in aging and disease","volume":"217","author":"Klaips","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.freeradbiomed.2018.08.037","article-title":"Impaired proteostasis during skeletal muscle aging","volume":"132","author":"Fernando","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.redox.2017.07.008","article-title":"Proteostasis, oxidative stress and aging","volume":"13","author":"Korovila","year":"2017","journal-title":"Redox Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1002\/art.40456","article-title":"Impaired proteasomal function in human osteoarthritic chondrocytes can contribute to decreased levels of SOX9 and Aggrecan","volume":"70","author":"Serrano","year":"2018","journal-title":"Arthritis Rheumatol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.14336\/AD.2019.1130","article-title":"Age-related decline in expression of molecular chaperones induces endoplasmic reticulum stress and chondrocyte apoptosis in articular cartilage","volume":"11","author":"Tan","year":"2020","journal-title":"Aging Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"6404035","DOI":"10.1155\/2019\/6404035","article-title":"4-phenylbutyric acid reduces endoplasmic reticulum stress in chondrocytes that is caused by loss of the protein disulfide isomerase ERp57","volume":"2019","author":"Rellmann","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"829","DOI":"10.3892\/mmr.2021.12469","article-title":"MAPK inhibitors protect against early-stage osteoarthritis by activating autophagy","volume":"24","author":"Lan","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1177\/1535370220929621","article-title":"Are insulin-resistance and oxidative stress cause or consequence of aging","volume":"245","author":"Wysocka","year":"2020","journal-title":"Exp. Biol. Med."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"3631","DOI":"10.1016\/j.bbadis.2018.08.036","article-title":"Mechanistic targeting of advanced glycation end-products in age-related diseases","volume":"1864","author":"Rowan","year":"2018","journal-title":"Biochim Biophys. Acta Mol. Basis Dis."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/nrrheum.2016.65","article-title":"Ageing and the pathogenesis of osteoarthritis","volume":"12","author":"Loeser","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/S1357-2725(02)00301-1","article-title":"The chondrocyte","volume":"35","author":"Archer","year":"2003","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.bbadis.2016.01.003","article-title":"ROS\/oxidative stress signaling in osteoarthritis","volume":"1862","author":"Lepetsos","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1038\/s41586-019-0920-1","article-title":"The CH25H-CYP7B1-ROR\u03b1 axis of cholesterol metabolism regulates osteoarthritis","volume":"566","author":"Choi","year":"2019","journal-title":"Nature"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/j.jbspin.2018.07.005","article-title":"Fatty acids and osteoarthritis: Different types, different effects","volume":"86","author":"Loef","year":"2019","journal-title":"Jt. Bone Spine"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1038\/s41467-020-17242-0","article-title":"LDHA-mediated ROS generation in chondrocytes is a potential therapeutic target for osteoarthritis","volume":"11","author":"Arra","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_110","first-page":"4493","article-title":"Correlation of insulin-like growth factor 1 and osteoarthritic cartilage degradation: A spontaneous osteoarthritis in guinea-pig","volume":"21","author":"Wei","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1186\/s13075-021-02662-0","article-title":"Insulin-like growth factor-1 in articular cartilage repair for osteoarthritis treatment","volume":"23","author":"Wen","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1080\/08977194.2018.1548444","article-title":"Growth factor signalling in osteoarthritis","volume":"36","author":"Huang","year":"2018","journal-title":"Growth Factors"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1759720x211006959","DOI":"10.1177\/1759720X211006959","article-title":"Promising targets for therapy of osteoarthritis: A review on the Wnt and TGF-\u03b2 signalling pathways","volume":"13","author":"Cherifi","year":"2021","journal-title":"Ther. Adv. Musculoskelet. Dis."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"R1338","DOI":"10.1186\/ar1833","article-title":"Reduced transforming growth factor-beta signaling in cartilage of old mice: Role in impaired repair capacity","volume":"7","author":"Scharstuhl","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_115","first-page":"394","article-title":"Regulation and role of TGF\u03b2 signaling pathway in aging and osteoarthritis joints","volume":"5","author":"Girard","year":"2013","journal-title":"Aging Dis."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.joca.2011.12.003","article-title":"Chondrocyte hypertrophy and osteoarthritis: Role in initiation and progression of cartilage degeneration?","volume":"20","year":"2012","journal-title":"Osteoarthr. Cartil."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1007\/s11357-012-9433-7","article-title":"Type II TGF\u03b2 receptor modulates chondrocyte phenotype","volume":"35","author":"Duval","year":"2013","journal-title":"Age"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1002\/art.38641","article-title":"Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor 1 and osteogenic protein 1","volume":"66","author":"Loeser","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1146\/annurev-physiol-030212-183715","article-title":"Genome instability and aging","volume":"75","author":"Vijg","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1146\/annurev-biochem-062917-012239","article-title":"Nuclear Genomic Instability and Aging","volume":"87","author":"Niedernhofer","year":"2018","journal-title":"Annu. Rev. Biochem."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1111\/febs.14663","article-title":"Toward understanding genomic instability, mitochondrial dysfunction and aging","volume":"286","author":"Fakouri","year":"2019","journal-title":"FEBS J."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.ajhg.2019.06.005","article-title":"DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging","volume":"105","author":"Tiwari","year":"2019","journal-title":"Am. J. Hum. Genet."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.freeradbiomed.2021.02.020","article-title":"Oxidative stress-induced DNA damage and repair in primary human osteoarthritis chondrocytes: Focus on IKK\u03b1 and the DNA Mismatch Repair System","volume":"166","author":"Neri","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"R380","DOI":"10.1186\/ar1499","article-title":"Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: Oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function","volume":"7","author":"Yudoh","year":"2005","journal-title":"Arthritis Res. Ther."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"e01774","DOI":"10.1016\/j.heliyon.2019.e01774","article-title":"Blood leukocyte LINE-1 hypomethylation and oxidative stress in knee osteoarthritis","volume":"5","author":"Teerawattanapong","year":"2019","journal-title":"Heliyon"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Jeong, S., Lee, K., Wen, X., Kim, Y., Cho, N.Y., Jang, J.J., and Kang, G.H. (2017). Tumoral LINE-1 hypomethylation is associated with poor survival of patients with intrahepatic cholangiocarcinoma. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3595-8"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1002\/art.34340","article-title":"Increased recycling of polyamines is associated with global DNA hypomethylation in rheumatoid arthritis synovial fibroblasts","volume":"64","author":"Karouzakis","year":"2012","journal-title":"Arthritis Rheum."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1002\/jor.23349","article-title":"Infrapatellar fat pad-derived mesenchymal stromal cells from osteoarthritis patients: In vitro genetic stability and replicative senescence","volume":"35","author":"Neri","year":"2017","journal-title":"J. Orthop. Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/0014-4827(61)90192-6","article-title":"The serial cultivation of human diploid cell strains","volume":"25","author":"Hayflick","year":"1961","journal-title":"Exp. Cell Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1007\/s11033-020-05341-6","article-title":"Alterations of cell cycle genes in cancer: Unmasking the role of cancer stem cells","volume":"47","author":"Caglar","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/nrc3960","article-title":"Forging a signature of in vivo senescence","volume":"15","author":"Sharpless","year":"2015","journal-title":"Nat. Rev. Cancer"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1016\/j.cub.2017.07.033","article-title":"Unmasking transcriptional heterogeneity in senescent cells","volume":"27","author":"Melov","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1111\/acel.12518","article-title":"Small molecule compounds that induce cellular senescence","volume":"15","author":"Petrova","year":"2016","journal-title":"Aging Cell"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.cmet.2015.11.011","article-title":"Mitochondrial dysfunction induces senescence with a distinct secretory phenotype","volume":"23","author":"Wiley","year":"2016","journal-title":"Cell Metab."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1038\/ncb2784","article-title":"A complex secretory program orchestrated by the inflammasome controls paracrine senescence","volume":"15","author":"Acosta","year":"2013","journal-title":"Nat. Cell Biol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"625497","DOI":"10.3389\/fcell.2021.625497","article-title":"Chondrocyte ag.ging: The molecular determinants and therapeutic opportunities","volume":"9","author":"Ramasamy","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41580-020-00314-w","article-title":"Cellular senescence in ageing: From mechanisms to therapeutic opportunities","volume":"22","author":"Krizhanovsky","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1111\/1756-185X.12096","article-title":"Correlation between senescence-associated beta-galactosidase expression in articular cartilage and disease severity of patients with knee osteoarthritis","volume":"19","author":"Gao","year":"2016","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"706","DOI":"10.3389\/fphys.2018.00706","article-title":"Role of the inflammation-autophagy-senescence integrative network in osteoarthritis","volume":"9","author":"Vinatier","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_140","first-page":"S41","article-title":"Plasma membrane microdomains in aging and disease","volume":"10","author":"Shimada","year":"2010","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"101413","DOI":"10.1016\/j.arr.2021.101413","article-title":"Cellular senescence in knee osteoarthritis: Molecular mechanisms and therapeutic implications","volume":"70","author":"Xie","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.joca.2021.11.002","article-title":"Novel role of estrogen receptor-\u03b1 on regulating chondrocyte phenotype and response to mechanical loading","volume":"30","author":"Wang","year":"2022","journal-title":"Osteoarthr. Cartil."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.18632\/aging.102635","article-title":"Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK\/mTOR","volume":"12","author":"Feng","year":"2020","journal-title":"Aging"},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.omtn.2019.10.032","article-title":"miR-140 attenuates the progression of early-stage osteoarthritis by retarding chondrocyte senescence","volume":"19","author":"Si","year":"2020","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"3673","DOI":"10.1038\/ncomms4673","article-title":"G-protein stimulatory subunit alpha and Gq\/11\u03b1 G-proteins are both required to maintain quiescent stem-like chondrocytes","volume":"5","author":"Chagin","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1038\/s41467-018-03299-5","article-title":"Paracrine cellular senescence exacerbates biliary injury and impairs regeneration","volume":"9","author":"Lu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Kalluri, R., and LeBleu, V.S. (2020). The biology, function, and biomedical applications of exosomes. Science, 367.","DOI":"10.1126\/science.aau6977"},{"key":"ref_149","first-page":"57","article-title":"Exosomes in intercellular communication and implications for osteoarthritis","volume":"59","author":"Asghar","year":"2020","journal-title":"Rheumatology"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.2217\/nnm-2018-0498","article-title":"Primary chondrocyte exosomes mediate osteoarthritis progression by regulating mitochondrion and immune reactivity","volume":"14","author":"Zheng","year":"2019","journal-title":"Nanomedicine"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/s41419-019-1739-2","article-title":"The exosome-like vesicles from osteoarthritic chondrocyte enhanced mature IL-1\u03b2 production of macrophages and aggravated synovitis in osteoarthritis","volume":"10","author":"Ni","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1080\/15384101.2018.1526603","article-title":"MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1\/miR-206\/GIT1 axis in osteoarthritis","volume":"17","author":"Liu","year":"2018","journal-title":"Cell Cycle"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.freeradbiomed.2018.08.038","article-title":"Reactive oxygen species, aging and articular cartilage homeostasis","volume":"132","author":"Bolduc","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"13046","DOI":"10.1111\/jcmm.15905","article-title":"Activating Nrf2 signalling alleviates osteoarthritis development by inhibiting inflammasome activation","volume":"24","author":"Yan","year":"2020","journal-title":"J. Cell Mol. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1016\/j.bbcan.2017.07.002","article-title":"Nuclear localization of metabolic enzymes in immunity and metastasis","volume":"1868","author":"He","year":"2017","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.cell.2013.06.016","article-title":"The NAD(+)\/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling","volume":"154","author":"Mouchiroud","year":"2013","journal-title":"Cell"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"2337","DOI":"10.1681\/ASN.2016040385","article-title":"Nicotinamide Mononucleotide, an NAD(+) Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner","volume":"28","author":"Guan","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"E1876","DOI":"10.1073\/pnas.1718819115","article-title":"NAD(+) supplementation normalizes key Alzheimer\u2019s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency","volume":"115","author":"Hou","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"12948","DOI":"10.1038\/ncomms12948","article-title":"Nicotinamide riboside is uniquely and orally bioavailable in mice and humans","volume":"7","author":"Trammell","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41514-017-0016-9","article-title":"Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD(+) levels in humans safely and sustainably: A randomized, double-blind, placebo-controlled study","volume":"3","author":"Dellinger","year":"2017","journal-title":"NPJ Aging Mech. Dis."},{"key":"ref_161","first-page":"873","article-title":"Nuclear p53-mediated repression of autophagy involves PINK1 transcriptional down-regulation","volume":"25","author":"Goiran","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.cell.2014.03.026","article-title":"Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)\/SIRT1 reduction","volume":"157","author":"Fang","year":"2014","journal-title":"Cell"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"5304","DOI":"10.1038\/s41467-019-13321-z","article-title":"ZFP161 regulates replication fork stability and maintenance of genomic stability by recruiting the ATR\/ATRIP complex","volume":"10","author":"Kim","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.cbi.2017.06.025","article-title":"Wogonin, a natural flavonoid, intercalates with genomic DNA and exhibits protective effects in IL-1\u03b2 stimulated osteoarthritis chondrocytes","volume":"274","author":"Khan","year":"2017","journal-title":"Chem. Biol. Interact."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1038\/s41580-019-0152-0","article-title":"DNA double-strand break repair-pathway choice in somatic mammalian cells","volume":"20","author":"Scully","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_166","doi-asserted-by":"crossref","unstructured":"J\u00e4ger, K., and Walter, M. (2016). Therapeutic Targeting of Telomerase. Genes, 7.","DOI":"10.3390\/genes7070039"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1089\/rej.2012.1359","article-title":"Ectopic expression of telomerase safely increases health span and life span","volume":"15","author":"Mendelsohn","year":"2012","journal-title":"Rejuvenation Res."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1089\/rej.2010.1085","article-title":"A natural product telomerase activator as part of a health maintenance program","volume":"14","author":"Harley","year":"2011","journal-title":"Rejuvenation Res."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1111\/j.1474-9726.2011.00700.x","article-title":"The telomerase activator TA-65 elongates short telomeres and increases health span of adult\/old mice without increasing cancer incidence","volume":"10","author":"Schneeberger","year":"2011","journal-title":"Aging Cell"},{"key":"ref_170","first-page":"382","article-title":"Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence","volume":"2","author":"Dock","year":"2011","journal-title":"Aging Dis."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"243","DOI":"10.2147\/OPTH.S100042","article-title":"Evaluation of an oral telomerase activator for early age-related macular degeneration-a pilot study","volume":"10","author":"Dow","year":"2016","journal-title":"Clin. Ophthalmol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1582-4934.2011.01460.x","article-title":"Pharmaceutical regulation of telomerase and its clinical potential","volume":"16","author":"Sprouse","year":"2012","journal-title":"J. Cell Mol. Med."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/emmm.201200212","article-title":"Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis","volume":"4","author":"Eitan","year":"2012","journal-title":"EMBO Mol. Med."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1161\/01.RES.0000121104.05977.F3","article-title":"Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells","volume":"94","author":"Haendeler","year":"2004","journal-title":"Circ. Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1002\/jcb.21322","article-title":"Age-dependent telomere-shortening is repressed by phosphorylated alpha-tocopherol together with cellular longevity and intracellular oxidative-stress reduction in human brain microvascular endotheliocytes","volume":"102","author":"Tanaka","year":"2007","journal-title":"J. Cell Biochem."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1097\/FJC.0b013e31802ef519","article-title":"Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity","volume":"49","author":"Dong","year":"2007","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1007\/s10059-013-0260-1","article-title":"Novel in vitro culture condition improves the stemness of human dermal stem\/progenitor cells","volume":"36","author":"Shim","year":"2013","journal-title":"Mol. Cells"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1038\/ng.3781","article-title":"Systematic analysis of telomere length and somatic alterations in 31 cancer types","volume":"49","author":"Barthel","year":"2017","journal-title":"Nat. Genet."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"e01314-17","DOI":"10.1128\/mBio.01314-17","article-title":"Long Telomeres Do Not Affect Cellular Fitness in Yeast","volume":"8","author":"Harari","year":"2017","journal-title":"MBio"},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"S17","DOI":"10.1093\/gerona\/glu042","article-title":"Epigenetics of aging and aging-related disease","volume":"69","author":"Brunet","year":"2014","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"111215","DOI":"10.1016\/j.mad.2020.111215","article-title":"SIRT1 and aging related signaling pathways","volume":"187","author":"Chen","year":"2020","journal-title":"Mech. Ageing Dev."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"24","DOI":"10.5483\/BMBRep.2019.52.1.290","article-title":"Sirtuin signaling in cellular senescence and aging","volume":"52","author":"Lee","year":"2019","journal-title":"BMB Rep."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1111\/acel.12685","article-title":"Sirtuins at the crossroads of stemness, aging, and cancer","volume":"16","author":"Vassilopoulos","year":"2017","journal-title":"Aging Cell"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"e1800092","DOI":"10.1002\/mnfr.201800092","article-title":"Dietary Intervention Modifies DNA Methylation Age Assessed by the Epigenetic Clock","volume":"62","author":"Corsi","year":"2018","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.cmet.2018.01.014","article-title":"Caloric Restriction Engages Hepatic RNA Processing Mechanisms in Rhesus Monkeys","volume":"27","author":"Rhoads","year":"2018","journal-title":"Cell Metab."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1186\/s13059-017-1187-1","article-title":"Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism","volume":"18","author":"Hahn","year":"2017","journal-title":"Genome Biol."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1517\/14712598.2016.1124084","article-title":"Gene therapy for human osteoarthritis: Principles and clinical translation","volume":"16","author":"Madry","year":"2016","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1038\/s41584-020-00523-9","article-title":"Non-surgical management of knee osteoarthritis: Comparison of ESCEO and OARSI 2019 guidelines","volume":"17","author":"Arden","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.molmed.2022.01.005","article-title":"Bringing gene therapy to where it\u2019s needed","volume":"28","author":"Radtke","year":"2022","journal-title":"Trends Mol. Med."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1002\/jor.23228","article-title":"rAAV-mediated combined gene transfer and overexpression of TGF-\u03b2 and SOX9 remodels human osteoarthritic articular cartilage","volume":"34","author":"Tao","year":"2016","journal-title":"J. Orthop. Res."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"e2008451","DOI":"10.1002\/adma.202008451","article-title":"Hydrogel-guided, rAAV-mediated IGF-I overexpression enables long-term cartilage repair and protection against perifocal osteoarthritis in a large-animal full-thickness chondral defect model at one year in vivo","volume":"33","author":"Madry","year":"2021","journal-title":"Adv. Mater."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1177\/03635465211049414","article-title":"rAAV-mediated sox9 overexpression improves the repair of osteochondral defects in a clinically relevant large animal model over time in vivo and reduces perifocal osteoarthritic changes","volume":"49","author":"Lange","year":"2021","journal-title":"Am. J. Sports Med."},{"key":"ref_193","doi-asserted-by":"crossref","unstructured":"Urich, J., Cucchiarini, M., and Rey-Rico, A. (2020). Therapeutic delivery of rAAV sox9 via polymeric micelles counteracts the effects of osteoarthritis-associated inflammatory cytokines in human articular chondrocytes. Nanomaterials, 10.","DOI":"10.3390\/nano10061238"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"6985","DOI":"10.2147\/IJN.S144579","article-title":"rAAV-mediated overexpression of TGF-\u03b2 via vector delivery in polymeric micelles stimulates the biological and reparative activities of human articular chondrocytes in vitro and in a human osteochondral defect model","volume":"12","author":"Venkatesan","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_195","doi-asserted-by":"crossref","unstructured":"Chen, D., Shen, J., and Hui, T. (2015). Epigenetic and microRNA regulation during osteoarthritis development. F1000Research, 4.","DOI":"10.12688\/f1000research.6548.1"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.bbacli.2014.11.009","article-title":"MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis","volume":"3","author":"Song","year":"2015","journal-title":"BBA Clin."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"BSR20191908","DOI":"10.1042\/BSR20191908","article-title":"miR-122\/SIRT1 axis regulates chondrocyte extracellular matrix degradation in osteoarthritis","volume":"40","author":"Bai","year":"2020","journal-title":"Biosci. Rep."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"1987","DOI":"10.1016\/j.joca.2013.09.008","article-title":"Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1\u03b2 signaling in osteoarthritis fibroblast-like synoviocytes","volume":"21","author":"Wang","year":"2013","journal-title":"Osteoarthr. Cartil."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1111\/acel.12368","article-title":"Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging","volume":"14","author":"Burstein","year":"2015","journal-title":"Aging Cell"},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"e12773","DOI":"10.1111\/acel.12773","article-title":"Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice","volume":"17","author":"Foote","year":"2018","journal-title":"Aging Cell"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"650","DOI":"10.18632\/aging.102647","article-title":"Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function","volume":"12","author":"Wang","year":"2020","journal-title":"Aging"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/nrd.2018.174","article-title":"Mitochondria as a therapeutic target for common pathologies","volume":"17","author":"Murphy","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"28423","DOI":"10.1038\/srep28423","article-title":"Trehalose, sucrose and raffinose are novel activators of autophagy in human keratinocytes through an mTOR-independent pathway","volume":"6","author":"Chen","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.phrs.2016.06.024","article-title":"mTOR-independent autophagy inducer trehalose rescues against insulin resistance-induced myocardial contractile anomalies: Role of p38 MAPK and Foxo1","volume":"111","author":"Wang","year":"2016","journal-title":"Pharmacol. Res."},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"e3081","DOI":"10.1038\/cddis.2017.453","article-title":"Trehalose ameliorates oxidative stress-mediated mitochondrial dysfunction and ER stress via selective autophagy stimulation and autophagic flux restoration in osteoarthritis development","volume":"8","author":"Tang","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"3729","DOI":"10.1007\/s00018-020-03497-9","article-title":"The role of SIRT3-mediated mitochondrial homeostasis in osteoarthritis","volume":"77","author":"He","year":"2020","journal-title":"Cell Mol. Life Sci."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1016\/j.joca.2018.07.004","article-title":"Activation of AMPK-SIRT3 signaling is chondroprotective by preserving mitochondrial DNA integrity and function","volume":"26","author":"Chen","year":"2018","journal-title":"Osteoarthr. Cartil."},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"5027","DOI":"10.1096\/fj.201902459R","article-title":"Adenosine A2A receptor (A2AR) stimulation enhances mitochondrial metabolism and mitigates reactive oxygen species-mediated mitochondrial injury","volume":"34","author":"Castro","year":"2020","journal-title":"FASEB J."},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41419-020-2680-0","article-title":"Stabilization of HIF-1\u03b1 alleviates osteoarthritis via enhancing mitophagy","volume":"11","author":"Hu","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_210","doi-asserted-by":"crossref","first-page":"jcs247353","DOI":"10.1242\/jcs.247353","article-title":"Mitochondrial dysfunction triggers a catabolic response in chondrocytes via ROS-mediated activation of the JNK\/AP1 pathway","volume":"133","author":"Ansari","year":"2020","journal-title":"J. Cell Sci."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"e1700108","DOI":"10.1002\/pmic.201700108","article-title":"Protein turnover in aging and longevity","volume":"18","author":"Basisty","year":"2018","journal-title":"Proteomics"},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.neurobiolaging.2007.01.010","article-title":"Aging of the brain, neurotrophin signaling, and Alzheimer\u2019s disease: Is IGF1-R the common culprit?","volume":"29","author":"Puglielli","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_213","doi-asserted-by":"crossref","first-page":"4269","DOI":"10.18632\/aging.101721","article-title":"Protein synthesis and quality control in aging","volume":"10","author":"Anisimova","year":"2018","journal-title":"Aging"},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1016\/j.celrep.2017.10.038","article-title":"Mitochondrial stress restores the heat shock response and prevents proteostasis collapse during aging","volume":"21","author":"Labbadia","year":"2017","journal-title":"Cell Rep."},{"key":"ref_215","doi-asserted-by":"crossref","unstructured":"Pellegrino, M.W., and Haynes, C.M. (2015). Mitophagy and the mitochondrial unfolded protein response in neurodegeneration and bacterial infection. BMC Biol., 13.","DOI":"10.1186\/s12915-015-0129-1"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"5396","DOI":"10.1074\/jbc.TM117.000893","article-title":"Mitochondrial proteostasis in the context of cellular and organismal health and aging","volume":"294","author":"Moehle","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"5648","DOI":"10.1038\/s41467-019-13540-4","article-title":"The autophagy receptor p62\/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy","volume":"10","author":"Kumsta","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1111\/j.1749-6632.2000.tb06646.x","article-title":"Calorie restriction and age-related ox.xidative stress","volume":"908","author":"Merry","year":"2000","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1186\/s13075-019-1925-8","article-title":"Calorie restriction with regular chow, but not a high-fat diet, delays onset of spontaneous osteoarthritis in the Hartley guinea pig model","volume":"21","author":"Radakovich","year":"2019","journal-title":"Arthritis Res. Ther."},{"key":"ref_220","doi-asserted-by":"crossref","unstructured":"Gaband\u00e9-Rodr\u00edguez, E., G\u00f3mez de Las Heras, M.M., and Mittelbrunn, M. (2019). Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria. Cells, 9.","DOI":"10.3390\/cells9010082"},{"key":"ref_221","doi-asserted-by":"crossref","unstructured":"Hwangbo, D.S., Lee, H.Y., Abozaid, L.S., and Min, K.J. (2020). Mechanisms of lifespan regulation by calorie restriction and intermittent fasting in model organisms. Nutrients, 12.","DOI":"10.3390\/nu12041194"},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.cmet.2013.12.008","article-title":"Fasting: Molecular mechanisms and clinical applications","volume":"19","author":"Longo","year":"2014","journal-title":"Cell Metab."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1017\/S0007114518002593","article-title":"Mediterranean diet and its components in relation to all-cause mortality: Meta-analysis","volume":"120","author":"Eleftheriou","year":"2018","journal-title":"Br. J. Nutr."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1080\/14728222.2017.1294684","article-title":"Nutrient sensing pathways as therapeutic targets for healthy ageing","volume":"21","author":"Aiello","year":"2017","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_225","doi-asserted-by":"crossref","first-page":"165612","DOI":"10.1016\/j.bbadis.2019.165612","article-title":"Current nutritional and pharmacological anti-aging interventions","volume":"1866","author":"Ros","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cmet.2016.05.011","article-title":"Metformin as a tool to target aging","volume":"23","author":"Barzilai","year":"2016","journal-title":"Cell Metab."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s10522-016-9660-x","article-title":"Repurposing FDA-approved drugs for anti-aging therapies","volume":"17","author":"Snell","year":"2016","journal-title":"Biogerontology"},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s10522-017-9724-6","article-title":"Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing","volume":"18","author":"Bettedi","year":"2017","journal-title":"Biogerontology"},{"key":"ref_229","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1083\/jcb.201707168","article-title":"Regulation of reproduction and longevity by nutrient-sensing pathways","volume":"217","author":"Templeman","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_230","doi-asserted-by":"crossref","unstructured":"Schell, J., Scofield, R.H., Barrett, J.R., Kurien, B.T., Betts, N., Lyons, T.J., Zhao, Y.D., and Basu, A. (2017). Strawberries improve pain and inflammation in obese adults with radiographic evidence of knee osteoarthritis. Nutrients, 9.","DOI":"10.3390\/nu9090949"},{"key":"ref_231","doi-asserted-by":"crossref","unstructured":"Du, C., Smith, A., Avalos, M., South, S., Crabtree, K., Wang, W., Kwon, Y.H., Vijayagopal, P., and Juma, S. (2019). Blueberries improve pain, gait performance, and inflammation in individuals with symptomatic knee osteoarthritis. Nutrients, 11.","DOI":"10.3390\/nu11020290"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1080\/17453674.2016.1235087","article-title":"Cellular senescence in aging and osteoarthritis","volume":"87","author":"Toh","year":"2016","journal-title":"Acta Orthop."},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1083\/jcb.201708092","article-title":"Senescence and aging: Causes, consequences, and therapeutic avenues","volume":"217","author":"McHugh","year":"2018","journal-title":"J. Cell Biol."},{"key":"ref_234","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/nrd.2017.116","article-title":"Senescent cells: An emerging target for diseases of ageing","volume":"16","author":"Childs","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1038\/nm.4010","article-title":"Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice","volume":"22","author":"Chang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.cell.2017.02.031","article-title":"Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging","volume":"169","author":"Baar","year":"2017","journal-title":"Cell"},{"key":"ref_237","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.drudis.2017.01.004","article-title":"Therapeutic interventions for aging: The case of cellular senescence","volume":"22","author":"Demaria","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.ebiom.2019.08.069","article-title":"Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease","volume":"47","author":"Hickson","year":"2019","journal-title":"EBioMedicine"},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1136\/annrheumdis-2020-217072","article-title":"Serum NT\/CT SIRT1 ratio reflects early osteoarthritis and chondrosenescence","volume":"79","author":"Batshon","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1038\/nm.4324","article-title":"Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment","volume":"23","author":"Jeon","year":"2017","journal-title":"Nat. Med."},{"key":"ref_241","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ebiom.2018.09.015","article-title":"Fisetin is a senotherapeutic that extends health and lifespan","volume":"36","author":"Yousefzadeh","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.joca.2020.11.006","article-title":"Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2\/NF-\u03baB axis","volume":"29","author":"Shao","year":"2021","journal-title":"Osteoarthr. Cartil."},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.freeradbiomed.2021.05.003","article-title":"Senolytics and senomorphics: Natural and synthetic therapeutics in the treatment of aging and chronic diseases","volume":"171","author":"Lagoumtzi","year":"2021","journal-title":"Free Radic. Biol. Med."},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.mce.2016.08.049","article-title":"Targeting metabolism in cellular senescence, a role for intervention","volume":"455","author":"Nacarelli","year":"2017","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_245","doi-asserted-by":"crossref","unstructured":"Kritsilis, M., Rizou, S.V., Koutsoudaki, P.N., Evangelou, K., Gorgoulis, V.G., and Papadopoulos, D. (2018). Ageing, cellular senescence and neurodegenerative disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102937"},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1016\/j.cell.2016.11.052","article-title":"In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming","volume":"167","author":"Ocampo","year":"2016","journal-title":"Cell"},{"key":"ref_247","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1007\/s11357-020-00185-1","article-title":"Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues","volume":"42","author":"Yousefzadeh","year":"2020","journal-title":"Geroscience"},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1038\/s43587-021-00143-2","article-title":"Regulation of aged skeletal muscle regeneration by circulating extracellular vesicles","volume":"1","author":"Sahu","year":"2021","journal-title":"Nat. Aging"},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"575057","DOI":"10.3389\/fbioe.2020.575057","article-title":"Immunomodulation of MSCs and MSC-Derived Extracellular Vesicles in Osteoarthritis","volume":"8","author":"Zhao","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_250","doi-asserted-by":"crossref","unstructured":"Mas-Bargues, C., Sanz-Ros, J., Rom\u00e1n-Dom\u00ednguez, A., Gimeno-Mallench, L., Ingl\u00e9s, M., Vi\u00f1a, J., and Borr\u00e1s, C. (2020). Extracellular vesicles from healthy cells improves cell function and stemness in premature senescent stem cells by miR-302b and HIF-1\u03b1 activation. Biomolecules, 10.","DOI":"10.3390\/biom10060957"},{"key":"ref_251","doi-asserted-by":"crossref","first-page":"626755","DOI":"10.3389\/fimmu.2021.626755","article-title":"MSCs and inflammatory cells crosstalk in regenerative medicine: Concerted actions for cptimized resolution driven by energy metabolism","volume":"12","author":"Varin","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_252","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1146\/annurev-biochem-013118-111902","article-title":"Exosomes","volume":"88","author":"Pegtel","year":"2019","journal-title":"Annu. Rev. Biochem."},{"key":"ref_253","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1186\/s13018-019-1529-7","article-title":"Exosomes derived from platelet-rich plasma present a novel potential in alleviating knee osteoarthritis by promoting proliferation and inhibiting apoptosis of chondrocyte via Wnt\/\u03b2-catenin signaling pathway","volume":"14","author":"Liu","year":"2019","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/s41413-020-0100-9","article-title":"Exosomes: Roles and therapeutic potential in osteoarthritis","volume":"8","author":"Ni","year":"2020","journal-title":"Bone Res."},{"key":"ref_255","doi-asserted-by":"crossref","unstructured":"Fan, Y., Li, Z., and He, Y. (2022). Exosomes in the pathogenesis, progression, and treatment of osteoarthritis. Bioengineering, 9.","DOI":"10.3390\/bioengineering9030099"},{"key":"ref_256","first-page":"48","article-title":"Danger signals and inflammaging in osteoarthritis","volume":"37","author":"Millerand","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_257","doi-asserted-by":"crossref","unstructured":"Rezu\u0219, E., Cardoneanu, A., Burlui, A., Luca, A., Codreanu, C., Tamba, B.I., Stanciu, G.-D., Dima, N., B\u0103descu, C., and Rezu\u0219, C. (2019). The link between inflammaging and degenerative joint diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030614"},{"key":"ref_258","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.joca.2014.02.002","article-title":"Biochemical evidence for gap junctions and Cx43 expression in immortalized human chondrocyte cell line: A potential model in the study of cell communication in human chondrocytes","volume":"22","author":"Goldring","year":"2014","journal-title":"Osteoarthr. Cartil."},{"key":"ref_259","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1136\/annrheumdis-2013-204244","article-title":"Articular chondrocyte network mediated by gap junctions: Role in metabolic cartilage homeostasis","volume":"74","author":"Mayan","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1016\/j.bbamem.2018.09.009","article-title":"Intercellular communication via gap junction channels between chondrocytes and bone cells","volume":"1860","author":"Wang","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_261","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1097\/01.blo.0000129346.29945.3b","article-title":"Increased intercellular communication through gap junctions may contribute to progression of osteoarthritis","volume":"422","author":"Marino","year":"2004","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_262","doi-asserted-by":"crossref","unstructured":"Gupta, A., Niger, C., Buo, A.M., Eidelman, E.R., Chen, R.J., and Stains, J.P. (2014). Connexin43 enhances the expression of osteoarthritis-associated genes in synovial fibroblasts in culture. BMC Musculoskelet. Disord., 15.","DOI":"10.1186\/1471-2474-15-425"},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.1016\/j.ajpath.2012.12.018","article-title":"Human articular chondrocytes express multiple gap junction proteins: Differential expression of connexins in normal and osteoarthritic cartilage","volume":"182","author":"Mayan","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_264","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1038\/s41419-018-1225-2","article-title":"Targeting of chondrocyte plasticity via connexin43 modulation attenuates cellular senescence and fosters a pro-regenerative environment in osteoarthritis","volume":"9","author":"Mato","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1074\/mcp.M115.050211","article-title":"Proteomic analysis of connexin 43 reveals novel interactors related to osteoarthritis","volume":"14","author":"Megias","year":"2015","journal-title":"Mol. Cell Proteom."},{"key":"ref_266","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.joca.2005.02.011","article-title":"Vulnerability to ROS-induced cell death in ageing articular cartilage: The role of antioxidant enzyme activity","volume":"13","author":"Jallali","year":"2005","journal-title":"Osteoarthr. Cartil."},{"key":"ref_267","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S0945-053X(02)00028-8","article-title":"Response of young, aged and osteoarthritic human articular chondrocytes to inflammatory cytokines: Molecular and cellular aspects","volume":"21","author":"Dozin","year":"2002","journal-title":"Matrix Biol."},{"key":"ref_268","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.maturitas.2014.12.003","article-title":"Chondrosenescence: Definition, hallmarks and potential role in the pathogenesis of osteoarthritis","volume":"80","author":"Mobasheri","year":"2015","journal-title":"Maturitas"},{"key":"ref_269","doi-asserted-by":"crossref","first-page":"677576","DOI":"10.3389\/fbioe.2021.677576","article-title":"Senolytic peptide FOXO4-DRI selectively removes senescent cells from in vitro expanded human chondrocytes","volume":"9","author":"Huang","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_270","doi-asserted-by":"crossref","unstructured":"Rim, Y.A., Nam, Y., and Ju, J.H. (2020). The role of chondrocyte hypertrophy and senescence in osteoarthritis initiation and progression. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21072358"},{"key":"ref_271","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1097\/BOR.0b013e3283494005","article-title":"Aging and osteoarthritis","volume":"23","author":"Loeser","year":"2011","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_272","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.mad.2016.12.012","article-title":"Cellular aging towards osteoarthritis","volume":"162","author":"Li","year":"2017","journal-title":"Mech. Ageing Dev."},{"key":"ref_273","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1097\/BOR.0000000000000456","article-title":"Targeting aging for disease modification in osteoarthritis","volume":"30","author":"Collins","year":"2018","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_274","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.rehab.2019.04.006","article-title":"Efficacy and potential determinants of exercise therapy in knee and hip osteoarthritis: A systematic review and meta-analysis","volume":"62","author":"Goh","year":"2019","journal-title":"Ann. Phys. Rehabil. Med."},{"key":"ref_275","first-page":"127","article-title":"Non-surgical treatment of knee osteoarthritis","volume":"25","author":"Kan","year":"2019","journal-title":"Hong Kong Med. J."},{"key":"ref_276","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s11427-021-1933-7","article-title":"Engineering osteoarthritic cartilage model through differentiating senescent human mesenchymal stem cells for testing disease-modifying drugs","volume":"65","author":"Wang","year":"2022","journal-title":"Sci. China Life Sci."},{"key":"ref_277","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1016\/j.hoc.2017.06.007","article-title":"Nonintegrating gene therapy vectors","volume":"31","author":"Athanasopoulos","year":"2017","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_278","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1038\/s41467-018-05059-x","article-title":"AAVvector-mediated in vivo reprogramming into pluripotency","volume":"9","author":"Mosteiro","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_279","doi-asserted-by":"crossref","unstructured":"Alle, Q., Le Borgne, E., Milhavet, O., and Lemaitre, J.M. (2021). Reprogramming: Emerging strategies to rejuvenate aging cells and tissues. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22083990"},{"key":"ref_280","doi-asserted-by":"crossref","first-page":"411","DOI":"10.3389\/fbioe.2019.00411","article-title":"Osteochondral tissue chip derived from iPSCs: Modeling OA pathologies and testing drugs","volume":"7","author":"Lin","year":"2019","journal-title":"Front. Bioeng. Biotechnol."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/7\/996\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:41:13Z","timestamp":1760139673000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/11\/7\/996"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,30]]},"references-count":280,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["biology11070996"],"URL":"https:\/\/doi.org\/10.3390\/biology11070996","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,30]]}}}