{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T21:18:31Z","timestamp":1783459111761,"version":"3.55.0"},"reference-count":45,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T00:00:00Z","timestamp":1780358400000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["168937"],"award-info":[{"award-number":["168937"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["479552-BME"],"award-info":[{"award-number":["479552-BME"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"name":"du Qu\u00e9bec\u2014Sante"},{"name":"Research Institute of the McGill University Health Centre and from Mitacs"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Aging is associated with many chronic conditions that increase morbidity and mortality. These include obesity, diabetes, sarcopenia, osteoporosis, and neurodegeneration. The deubiquitinase USP19 is involved in many of these disorders suggesting that it may modulate common mechanism(s) that impact the aging process. Inactivation of USP19 is protective against muscle atrophy, obesity, and diabetes in young adult mice. Whether such protection persists in older adult mice remains unknown. In addition, the potential role of USP19 in osteoporosis remains unexplored. Here, we demonstrate that loss of USP19 is protective against loss of muscle mass and obesity in mice aged 22-24\u2009months. Glucose tolerance was also improved in these older adult USP19 KO mice, but only in females. Bone mineral content was decreased in the USP19 KO bone, more evidently in cortical bone than in trabecular bone and only in males. This was associated with a reduced work-to-failure in the KO femurs. Osteoblasts derived from USP19 KO bone marrow cells demonstrated decreased ex-vivo mineralization compared to WT cells and the KO marrow cells showed enhanced differentiation into TRAP-positive multinucleated osteoclasts. These findings identify important potential benefits as well as risks of therapeutic targeting of USP19 for the prevention or treatment of key aging related disorders.<\/jats:p>","DOI":"10.1093\/gerona\/glag138","type":"journal-article","created":{"date-parts":[[2026,5,31]],"date-time":"2026-05-31T11:34:01Z","timestamp":1780227241000},"source":"Crossref","is-referenced-by-count":0,"title":["Effect of inactivation of the USP19 deubiquitinase gene in mice on important phenotypes of aging"],"prefix":"10.1093","volume":"81","author":[{"given":"Kai","family":"Sheng","sequence":"first","affiliation":[{"name":"Department of Surgery, McGill University and McGill University Health Centre, Shriner\u2019s Hospital for Children , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin S","family":"Coyne","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University and McGill University Health Centre , Montreal, Quebec,","place":["Canada"]},{"name":"Department of Biochemistry, McGill University and McGill University Health Centre , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"B\u00e9dard","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University and McGill University Health Centre , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGill University and McGill University Health Centre, Shriner\u2019s Hospital for Children , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3421-7147","authenticated-orcid":false,"given":"David","family":"Goltzman","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University and McGill University Health Centre , Montreal, Quebec,","place":["Canada"]},{"name":"Department of Physiology, McGill University and McGill University Health Centre , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisbet","family":"Haglund","sequence":"additional","affiliation":[{"name":"Department of Surgery, McGill University and McGill University Health Centre, Shriner\u2019s Hospital for Children , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8394-7563","authenticated-orcid":false,"given":"Simon S","family":"Wing","sequence":"additional","affiliation":[{"name":"Department of Medicine, McGill University and McGill University Health Centre , Montreal, Quebec,","place":["Canada"]},{"name":"Department of Biochemistry, McGill University and McGill University Health Centre , Montreal, Quebec,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"2026070716514148100_glag138-B1","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1093\/ajcn\/76.2.473","article-title":"Longitudinal changes in body composition in older men and women: role of body weight change and physical activity","volume":"76","author":"Hughes","year":"2002","journal-title":"Am J Clin Nutr"},{"key":"2026070716514148100_glag138-B2","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/BF03324517","article-title":"Body composition changes in stable-weight elderly subjects: the effect of sex","volume":"15","author":"Zamboni","year":"2003","journal-title":"Aging Clin Exp Res"},{"key":"2026070716514148100_glag138-B3","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1093\/ajcn\/85.2.405","article-title":"Effects of birth cohort and age on body composition in a sample of community-based elderly","volume":"85","author":"Ding","year":"2007","journal-title":"Am J Clin Nutr"},{"key":"2026070716514148100_glag138-B4","doi-asserted-by":"publisher","first-page":"E366","DOI":"10.1152\/ajpendo.2000.279.2.E366","article-title":"Weight stability masks sarcopenia in elderly men and women","volume":"279","author":"Gallagher","year":"2000","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"2026070716514148100_glag138-B5","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1093\/epirev\/mxs006","article-title":"Adiposity, muscle mass, and muscle strength in relation to functional decline in older persons","volume":"35","author":"Schaap","year":"2013","journal-title":"Epidemiol Rev"},{"key":"2026070716514148100_glag138-B6","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cmet.2021.12.012","article-title":"Why does obesity cause diabetes?","volume":"34","author":"Klein","year":"2022","journal-title":"Cell Metab"},{"key":"2026070716514148100_glag138-B7","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9101429","article-title":"Type 2 diabetes mellitus and cancer: epidemiology, physiopathology and prevention","volume":"9","author":"Rey-Renones","year":"2021","journal-title":"Biomedicines"},{"key":"2026070716514148100_glag138-B8","doi-asserted-by":"publisher","first-page":"734","DOI":"10.2337\/dc14-1996","article-title":"Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation","volume":"38","author":"Harding","year":"2015","journal-title":"Diabetes Care"},{"key":"2026070716514148100_glag138-B9","doi-asserted-by":"publisher","first-page":"100944","DOI":"10.1016\/j.arr.2019.100944","article-title":"Diabetes mellitus and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 144 prospective studies","volume":"55","author":"Xue","year":"2019","journal-title":"Ageing Res Rev"},{"key":"2026070716514148100_glag138-B10","doi-asserted-by":"publisher","first-page":"3307594","DOI":"10.1155\/jdr\/3307594","article-title":"The prevalence and progression of microvascular complications and the interaction with ethnicity and socioeconomic status in people with type 2 diabetes: a systematic review and meta-analysis","volume":"2025","author":"Alobaid","year":"2025","journal-title":"J Diabetes Res"},{"key":"2026070716514148100_glag138-B11","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1186\/s13019-024-03157-0","article-title":"Comparison of adverse cardiovascular event endpoints between patients with diabetes and patients without diabetes based on coronary artery plaques: a systematic review and meta-analysis","volume":"19","author":"Ma","year":"2024","journal-title":"J Cardiothorac Surg"},{"key":"2026070716514148100_glag138-B12","doi-asserted-by":"publisher","first-page":"2024","DOI":"10.1093\/gerona\/glad167","article-title":"The health, aging, and body composition (Health ABC) study-ground-breaking science for 25 years and counting","volume":"78","author":"Newman","year":"2023","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"2026070716514148100_glag138-B13","doi-asserted-by":"publisher","DOI":"10.1093\/ageing\/afae286","article-title":"Association between sarcopenic obesity and risk of frailty in older adults: a systematic review and meta-analysis","volume":"54","author":"Gengxin","year":"2025","journal-title":"Age Ageing"},{"key":"2026070716514148100_glag138-B14","doi-asserted-by":"publisher","first-page":"111997","DOI":"10.1016\/j.mad.2024.111997","article-title":"Deciphering osteosarcopenia through the hallmarks of aging","volume":"222","author":"Franulic","year":"2024","journal-title":"Mech Ageing Dev."},{"key":"2026070716514148100_glag138-B15","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.jamda.2023.09.027","article-title":"Associations between osteosarcopenia and falls, fractures, and frailty in older adults: results from the Canadian longitudinal study on aging (CLSA)","volume":"25","author":"Lee","year":"2024","journal-title":"J Am Med Dir Assoc"},{"key":"2026070716514148100_glag138-B16","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1007\/s40520-024-02785-9","article-title":"Osteosarcopenia increases the risk of mortality: a systematic review and meta-analysis of prospective observational studies","volume":"36","author":"Veronese","year":"2024","journal-title":"Aging Clin Exp Res"},{"key":"2026070716514148100_glag138-B17","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":"Lopez-Otin","year":"2023","journal-title":"Cell"},{"key":"2026070716514148100_glag138-B18","doi-asserted-by":"publisher","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":"2026070716514148100_glag138-B19","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cell.2018.09.048","article-title":"Biological functions of autophagy genes: a disease perspective","volume":"176","author":"Levine","year":"2019","journal-title":"Cell"},{"key":"2026070716514148100_glag138-B20","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1146\/annurev-biochem-060310-170328","article-title":"The ubiquitin code","volume":"81","author":"Komander","year":"2012","journal-title":"Annu Rev Biochem"},{"key":"2026070716514148100_glag138-B21","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1152\/physrev.00002.2013","article-title":"Deubiquitylases from genes to organism","volume":"93","author":"Clague","year":"2013","journal-title":"Physiol Rev"},{"key":"2026070716514148100_glag138-B22","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nrm2731","article-title":"Breaking the chains: structure and function of the deubiquitinases","volume":"10","author":"Komander","year":"2009","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026070716514148100_glag138-B23","doi-asserted-by":"publisher","DOI":"10.3390\/biom12050703","article-title":"On the study of deubiquitinases: using the right tools for the job","volume":"12","author":"Caba","year":"2022","journal-title":"Biomolecules"},{"key":"2026070716514148100_glag138-B24","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.molcel.2021.10.027","article-title":"Deubiquitinases: from mechanisms to their inhibition by small molecules","volume":"82","author":"Lange","year":"2022","journal-title":"Mol Cell"},{"key":"2026070716514148100_glag138-B25","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1007\/s00125-018-4754-4","article-title":"The deubiquitinating enzyme USP19 modulates adipogenesis and potentiates high fat diet induced obesity and glucose intolerance","volume":"62","author":"Coyne","year":"2019","journal-title":"Diabetologia"},{"key":"2026070716514148100_glag138-B26","doi-asserted-by":"publisher","first-page":"2966","DOI":"10.1210\/en.2018-00290","article-title":"Knockout of USP19 deubiquitinating enzyme prevents muscle wasting by modulating insulin and glucocorticoid signaling","volume":"159","author":"Coyne","year":"2018","journal-title":"Endocrinology"},{"key":"2026070716514148100_glag138-B27","doi-asserted-by":"publisher","first-page":"3889","DOI":"10.1096\/fj.15-270579","article-title":"Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting","volume":"29","author":"Bedard","year":"2015","journal-title":"Faseb J"},{"key":"2026070716514148100_glag138-B28","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1359\/jbmr.080318","article-title":"Exogenous PTH and endogenous 1,25-dihydroxyvitamin D are complementary in inducing an anabolic effect on bone","volume":"23","author":"Samadfam","year":"2008","journal-title":"J Bone Miner Res"},{"key":"2026070716514148100_glag138-B29","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/s0169-6009(08)80187-0","article-title":"A rapid, quantitative assay for measuring alkaline phosphatase activity in osteoblastic cells in vitro","volume":"27","author":"Sabokbar","year":"1994","journal-title":"Bone Miner"},{"key":"2026070716514148100_glag138-B30","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1359\/jbmr.060915","article-title":"Co-treatment of PTH with osteoprotegerin or alendronate increases its anabolic effect on the skeleton of oophorectomized mice","volume":"22","author":"Samadfam","year":"2007","journal-title":"J Bone Miner Res"},{"key":"2026070716514148100_glag138-B31","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1530\/JOE-15-0128","article-title":"Female-specific regulation of skeletal muscle mass by USP19 in young mice","volume":"225","author":"Ogawa","year":"2015","journal-title":"J Endocrinol"},{"key":"2026070716514148100_glag138-B32","doi-asserted-by":"crossref","first-page":"41455","DOI":"10.1074\/jbc.M111.276824","article-title":"17beta-estradiol represses myogenic differentiation by increasing ubiquitin-specific peptidase 19 through estrogen receptor alpha","volume":"286","author":"Ogawa","year":"2011","journal-title":"J Biol Chem"},{"key":"2026070716514148100_glag138-B33","doi-asserted-by":"publisher","first-page":"259","DOI":"10.4049\/jimmunol.1900083","article-title":"USP19 Inhibits TNF\u03b1- and IL-1\u03b2 triggered NF-kB Activation by Deubiquitinating TAK1","volume":"203","author":"Lei","year":"2019","journal-title":"J Immunol"},{"key":"2026070716514148100_glag138-B34","doi-asserted-by":"publisher","first-page":"12","DOI":"10.4068\/cmj.2016.52.1.12","article-title":"Signaling pathways in osteoclast differentiation","volume":"52","author":"Kim","year":"2016","journal-title":"Chonnam Med J"},{"key":"2026070716514148100_glag138-B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.bbrc.2008.10.146","article-title":"NF-kappaB functions in osteoclasts","volume":"378","author":"Soysa","year":"2009","journal-title":"Biochem Biophys Res Commun"},{"key":"2026070716514148100_glag138-B36","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1016\/s1534-5807(02)00369-6","article-title":"Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts","volume":"3","author":"Takayanagi","year":"2002","journal-title":"Dev Cell"},{"key":"2026070716514148100_glag138-B37","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1038\/sj.cdd.4401882","article-title":"Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-kappaB transactivation by RANKL","volume":"13","author":"Huang","year":"2006","journal-title":"Cell Death Differ"},{"key":"2026070716514148100_glag138-B38","doi-asserted-by":"publisher","first-page":"107","DOI":"10.4248\/BR201302001","article-title":"Endogenous glucocorticoids and bone","volume":"1","author":"Zhou","year":"2013","journal-title":"Bone Res"},{"key":"2026070716514148100_glag138-B39","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1302\/2046-3758.512.BJR-2016-0073.R1","article-title":"Identification of candidate genes in osteoporosis by integrated microarray analysis","volume":"5","author":"Li","year":"2016","journal-title":"Bone Joint Res"},{"key":"2026070716514148100_glag138-B40","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1172\/JCI17246","article-title":"A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice","volume":"111","author":"Sims","year":"2003","journal-title":"J Clin Invest"},{"key":"2026070716514148100_glag138-B41","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1056\/NEJM199410203311604","article-title":"Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man","volume":"331","author":"Smith","year":"1994","journal-title":"N Engl J Med"},{"key":"2026070716514148100_glag138-B42","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1158\/1538-7445.AM2017-1181","article-title":"Discovery and development of novel highly potent and selective inhibitors of USP19 using UbiPlex","volume":"77","author":"Gavory","year":"2017","journal-title":"Cancer Res"},{"key":"2026070716514148100_glag138-B43","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/s41531-023-00601-1","article-title":"USP19 deubiquitinase inactivation regulates alpha-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice","volume":"9","author":"Schorova","year":"2023","journal-title":"NPJ Parkinsons Dis"},{"key":"2026070716514148100_glag138-B44","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41421-018-0012-7","article-title":"DNAJC5 facilitates USP19-dependent unconventional secretion of misfolded cytosolic proteins","volume":"4","author":"Xu","year":"2018","journal-title":"Cell Discov"},{"key":"2026070716514148100_glag138-B45","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1007\/s00018-025-05589-w","article-title":"Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin specific peptidase USP19","volume":"82","author":"Picard","year":"2025","journal-title":"Cell Mol Life Sci"}],"container-title":["The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/advance-article-pdf\/doi\/10.1093\/gerona\/glag138\/68445988\/glag138.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article-pdf\/81\/8\/glag138\/68445988\/glag138.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article-pdf\/81\/8\/glag138\/68445988\/glag138.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T20:51:48Z","timestamp":1783457508000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/biomedgerontology\/article\/doi\/10.1093\/gerona\/glag138\/8699597"}},"subtitle":[],"editor":[{"given":"Fabrisia","family":"Ambrosio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":45,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,7,1]]}},"URL":"https:\/\/doi.org\/10.1093\/gerona\/glag138","relation":{},"ISSN":["1079-5006","1758-535X"],"issn-type":[{"value":"1079-5006","type":"print"},{"value":"1758-535X","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,8]]},"published":{"date-parts":[[2026,6,1]]},"article-number":"glag138"}}