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Ageing skeletal muscle undergoes profound morphological and physiological changes associated with loss of strength, mass, and function, a condition known as sarcopenia. The aetiology of sarcopenia is complex and whilst research in this area is growing rapidly, there is a relative paucity of human studies, particularly in older women. Here, we evaluate how the nine classic hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication contribute to skeletal muscle ageing and the pathophysiology of sarcopenia. We also highlight five novel hallmarks of particular significance to skeletal muscle ageing: inflammation, neural dysfunction, extracellular matrix dysfunction, reduced vascular perfusion, and ionic dyshomeostasis, and discuss how the classic and novel hallmarks are interconnected. Their clinical relevance and translational potential are also considered.<\/jats:p>","DOI":"10.1042\/cs20230319","type":"journal-article","created":{"date-parts":[[2023,11,21]],"date-time":"2023-11-21T02:01:55Z","timestamp":1700532115000},"page":"1721-1751","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":121,"title":["Hallmarks of ageing in human skeletal muscle and implications for understanding the pathophysiology of sarcopenia in women and men"],"prefix":"10.1042","volume":"137","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9247-899X","authenticated-orcid":false,"given":"Antoneta","family":"Granic","sequence":"first","affiliation":[{"name":"1AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, U.K."},{"name":"2NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Suetterlin","sequence":"additional","affiliation":[{"name":"1AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, U.K."},{"name":"2NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, U.K."},{"name":"3John Walton Muscular Dystrophy Research Centre, Institute of Genetic Medicine, Newcastle University, Centre for Life, Newcastle upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tea","family":"Shavlakadze","sequence":"additional","affiliation":[{"name":"4Regeneron Pharmaceuticals Inc., Tarrytown, New York, NY, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda\u00a0D.","family":"Grounds","sequence":"additional","affiliation":[{"name":"5Department of Anatomy, Physiology and Human Biology, School of Human Sciences, the University of Western Australia, Perth, WA 6009, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avan\u00a0A.","family":"Sayer","sequence":"additional","affiliation":[{"name":"1AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, U.K."},{"name":"2NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2023,11,21]]},"reference":[{"key":"2023112107011636400_B1","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"L\u00f3pez-Ot\u00edn","year":"2013","journal-title":"Cell"},{"key":"2023112107011636400_B2","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"L\u00f3pez-Ot\u00edn","year":"2023","journal-title":"Cell"},{"key":"2023112107011636400_B3","doi-asserted-by":"publisher","first-page":"6829","DOI":"10.18632\/aging.204248","article-title":"New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary","volume":"14","author":"Schmauck-Medina","year":"2022","journal-title":"Aging"},{"key":"2023112107011636400_B4","doi-asserted-by":"publisher","first-page":"e13524","DOI":"10.1111\/acel.13524","article-title":"Biological mechanisms of aging predict age-related disease co-occurrence in patients","volume":"21","author":"Fraser","year":"2022","journal-title":"Aging Cell"},{"key":"2023112107011636400_B5","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: the next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"2023112107011636400_B6","doi-asserted-by":"publisher","first-page":"e49874","DOI":"10.7554\/eLife.49874","article-title":"Discovery proteomics in aging human skeletal muscle finds change in spliceosome, immunity, proteostasis and mitochondria","volume":"8","author":"Ubaida-Mohien","year":"2019","journal-title":"eLife"},{"key":"2023112107011636400_B7","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.cmet.2018.05.011","article-title":"Hallmarks of brain aging: adaptive and pathological modification by metabolic states","volume":"27","author":"Mattson","year":"2018","journal-title":"Cell Metab."},{"key":"2023112107011636400_B8","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1183\/09031936.00186914","article-title":"Hallmarks of the ageing lung","volume":"45","author":"Meiners","year":"2015","journal-title":"Eur. 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