{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:50:18Z","timestamp":1791521418846,"version":"4.3.4"},"reference-count":30,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:00:00Z","timestamp":1791417600000},"content-version":"vor","delay-in-days":7,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Vitamin D deficiency has been implicated in biological processes linked to aging and organismal resilience, yet its relationship to long\u2010term systemic aging trajectories remains incompletely characterized. We analyzed longitudinal electronic health record data from two large healthcare systems: Leumit Health Services (LHS), a nationwide Israeli health organization, and TriNetX, a federated US research network. We examined more than 1.67 million serum 25\u2010hydroxyvitamin D [25(OH)D] measurements from over 468,500 adults in LHS (2009\u20132020). Longitudinal matched analyses compared severe deficiency (&lt;\u200910\u2009ng\/mL) with sufficiency (&gt;\u200930\u2009ng\/mL) in LHS and were externally validated in 223,175 propensity score\u2010matched TriNetX pairs; matched cohorts were approximately 54\u2009years old, 65%\u201367% female, and followed for up to 10\u2009years. In both populations, severe deficiency was associated with increased risks across multiple aging\u2010related outcomes. All\u2010cause mortality was higher in LHS (adjusted HR 2.57, 95% CI 2.38\u20132.79) and TriNetX (HR 1.59, 1.55\u20131.63). To assess modifiability, we modeled vitamin D supplementation longitudinally using pharmacy\u2010dispensed purchases calibrated to predict serum 25(OH)D changes over time. Supplementation was independently associated with dose\u2010dependent reductions across mortality and multiple aging\u2010related outcomes; for &gt;\u200910\u2009ng\/mL\u2010equivalent supplementation, mortality HR was 0.72 (0.68\u20130.76), while showing no corresponding association for skin malignancy. To strengthen causal interpretation, we additionally implemented inverse\u2010probability\u2010of\u2010treatment\u2010weighted marginal structural Cox models for mortality, which yielded results consistent with conventional adjusted models. Together, these findings support severe vitamin D deficiency as an important and potentially modifiable determinant of systemic aging vulnerability and age\u2010related multimorbidity in human populations.<\/jats:p>","DOI":"10.1111\/acel.70752","type":"journal-article","created":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:21:09Z","timestamp":1791519669000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vitamin D Deficiency, Supplementation, and Aging\u2010Related Morbidity and Mortality Across Two Longitudinal Population Cohorts"],"prefix":"10.1111","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4389-8896","authenticated-orcid":false,"given":"Ariel","family":"Israel","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medical &amp; Health Sciences Tel Aviv University  Tel\u2010Aviv Israel"},{"name":"Leumit Research Institute Leumit Health Services  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9765-8938","authenticated-orcid":false,"given":"Abraham","family":"Weizman","sequence":"additional","affiliation":[{"name":"Research Unit, Faculty of Medical &amp; Health Sciences, Geha Mental Health Center, Felsenstein Medical Research Center and Sagol School of Neurosciences Tel\u2010Aviv University  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5646-0071","authenticated-orcid":false,"given":"Sarah","family":"Israel","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Infectious Diseases, Hadassah Medical Center, Faculty of Medicine Hebrew University of Jerusalem  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shai","family":"Ashkenazi","sequence":"additional","affiliation":[{"name":"Adelson School of Medicine Ariel University  Ariel Israel"},{"name":"Schneider Children\u2019s Medical Center  Petah\u2010Tikva Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7862-3940","authenticated-orcid":false,"given":"Eytan","family":"Ruppin","sequence":"additional","affiliation":[{"name":"Translational Research Institute and the Department of Surgery Cedars\u2010Sinai Medical Center  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7713-423X","authenticated-orcid":false,"given":"Eli","family":"Magen","sequence":"additional","affiliation":[{"name":"Adelson School of Medicine Ariel University  Ariel Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Merzon","sequence":"additional","affiliation":[{"name":"Leumit Research Institute Leumit Health Services  Tel\u2010Aviv Israel"},{"name":"Adelson School of Medicine Ariel University  Ariel Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shlomo","family":"Vinker","sequence":"additional","affiliation":[{"name":"Leumit Research Institute Leumit Health Services  Tel\u2010Aviv Israel"},{"name":"Department of Family Medicine, Faculty of Medical &amp; Health Sciences Tel Aviv University  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,8]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1210\/jendso\/bvab124","article-title":"The Effects of Vitamin D Supplementation and 25\u2010Hydroxyvitamin D Levels on the Risk of Myocardial Infarction and Mortality","volume":"5","author":"Acharya P.","year":"2021","journal-title":"Journal of the Endocrine Society"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1373\/clinchem.2012.193003","article-title":"Low 25\u2010Hydroxyvitamin D and Risk of Type 2 Diabetes: A Prospective Cohort Study and Metaanalysis","volume":"59","author":"Afzal S.","year":"2013","journal-title":"Clinical Chemistry"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.3945\/ajcn.115.120873","article-title":"Vitamin D Deficiency in Europe: Pandemic?","volume":"103","author":"Cashman K. D.","year":"2016","journal-title":"American Journal of Clinical Nutrition"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","DOI":"10.1080\/0886022X.2024.2431632","article-title":"Vitamin D Supplementation Can Improve the 28\u2010Day Mortality Rate in Patients With Sepsis\u2010Associated Acute Kidney Injury","volume":"46","author":"Chen L.","year":"2024","journal-title":"Renal Failure"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"260","DOI":"10.2337\/dc12-1204","article-title":"High\u2010Dose Vitamin D Supplementation in People With Prediabetes and Hypovitaminosis D","volume":"36","author":"Davidson M. B.","year":"2013","journal-title":"Diabetes Care"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"2916","DOI":"10.2337\/dc20-1765","article-title":"Intratrial Exposure to Vitamin D and New\u2010Onset Diabetes Among Adults With Prediabetes: A Secondary Analysis From the Vitamin D and Type 2 Diabetes (D2d) Study","volume":"43","author":"Dawson\u2010Hughes B.","year":"2020","journal-title":"Diabetes Care"},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1093\/eurjhf\/hfr175","article-title":"Vitamin D Deficiency Is a Predictor of Reduced Survival in Patients With Heart Failure; Vitamin D Supplementation Improves Outcome","volume":"14","author":"Gotsman I.","year":"2012","journal-title":"European Journal of Heart Failure"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","DOI":"10.3390\/nu17020277","article-title":"Vitamin D: Evidence\u2010Based Health Benefits and Recommendations for Population Guidelines","volume":"17","author":"Grant W.","year":"2025","journal-title":"Nutrients"},{"key":"e_1_2_10_10_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1017\/S0007114513001840","article-title":"A Systematic Review of Vitamin D Status in Populations Worldwide","volume":"111","author":"Hilger J.","year":"2014","journal-title":"British Journal of Nutrition"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra070553"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s11739-021-02902-w","article-title":"Vitamin D Deficiency Is Associated With Higher Risks for SARS\u2010CoV\u20102 Infection and COVID\u201019 Severity: A Retrospective Case\u2013Control Study","volume":"17","author":"Israel A.","year":"2022","journal-title":"Internal and Emergency Medicine"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","DOI":"10.3390\/microorganisms14081757","article-title":"Delayed Pathogenicity in Toxoplasma Gondii as an Evolutionary Framework for Late\u2010Life Disease and Mortality","volume":"14","author":"Israel A.","year":"2026","journal-title":"Microorganisms"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1007\/s43440-023-00520-1","article-title":"Modulatory Role of Vitamins A, B3, C, D, and E on Skin Health, Immunity, Microbiome, and Diseases","volume":"75","author":"Joshi M.","year":"2023","journal-title":"Pharmacological Reports"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1097\/MAJ.0b013e3181aaee91","article-title":"Vitamin D Deficiency and Risk for Cardiovascular Disease","volume":"338","author":"Judd S. E.","year":"2009","journal-title":"American Journal of the Medical Sciences"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.mce.2011.04.015","article-title":"Vitamin D Metabolism and Innate Immunity","volume":"347","author":"Lagishetty V.","year":"2011","journal-title":"Molecular and Cellular Endocrinology"},{"key":"e_1_2_10_17_1","doi-asserted-by":"crossref","DOI":"10.3389\/fnut.2024.1454779","article-title":"The Role of Vitamin D in Diabetic Foot Ulcer; an Umbrella Review of Meta\u2010Analyses","volume":"11","author":"Liu L.","year":"2024","journal-title":"Frontiers in Nutrition"},{"key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1093\/eurjhf\/hfr032","article-title":"Vitamin D Status and Outcomes in Heart Failure Patients","volume":"13","author":"Liu L. C. Y.","year":"2011","journal-title":"European Journal of Heart Failure"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15495"},{"key":"e_1_2_10_20_1","volume-title":"OECD Reviews of Health Care Quality: Israel, Raising Standards","author":"OECD Reviews of Health Care Quality","year":"2012"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.cdnut.2026.107687","article-title":"Population\u2010Level Changes in Folate, Iodine, and Vitamin D Status Over More Than 20\u2009Years: Biomarker Data From the Cross\u2010Sectional National Health and Nutrition Examination Survey (NHANES 1999\u20132000 Through August 2021\u2013August 2023)","volume":"10","author":"Pfeiffer C. M.","year":"2026","journal-title":"Current Developments in Nutrition"},{"key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1210\/jc.2007-0298","article-title":"The Role of Vitamin D and Calcium in Type 2 Diabetes. A Systematic Review and Meta\u2010Analysis","volume":"92","author":"Pittas A. G.","year":"2007","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1002\/mnfr.201000174","article-title":"A Review of the Critical Role of Vitamin D in the Functioning of the Immune System and the Clinical Implications of Vitamin D Deficiency","volume":"55","author":"Schwalfenberg G. K.","year":"2011","journal-title":"Molecular Nutrition & Food Research"},{"key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/0168-8227(95)01040-K","article-title":"Serum 25\u2010Hydroxyvitamin D3 Levels Decreased in Impaired Glucose Tolerance and Diabetes Mellitus","volume":"27","author":"Scragg R.","year":"1995","journal-title":"Diabetes Research and Clinical Practice"},{"key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"21641","DOI":"10.1038\/s41598-020-77806-4","article-title":"The Potential Role of Vitamin D Supplementation as a Gut Microbiota Modifier in Healthy Individuals","volume":"10","author":"Singh P.","year":"2020","journal-title":"Scientific Reports"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.70198"},{"key":"e_1_2_10_27_1","unstructured":"The Commonwealth Fund. n.d.Diabetes\u2010Related Lower Extremity Amputation Rates Per 100 000 Population|Commonwealth Fund.https:\/\/www.commonwealthfund.org\/international\u2010health\u2010policy\u2010center\/system\u2010stats\/diabetes\u2010related\u2010lower\u2010extremity\u2010amputation."},{"key":"e_1_2_10_28_1","doi-asserted-by":"crossref","DOI":"10.1186\/s12902-015-0029-y","article-title":"The Relationship Between Microvascular Complications and Vitamin D Deficiency in Type 2 Diabetes Mellitus","volume":"15","author":"Usluogullari C. A.","year":"2015","journal-title":"BMC Endocrine Disorders"},{"key":"e_1_2_10_29_1","doi-asserted-by":"crossref","DOI":"10.3390\/nu16213651","article-title":"Vitamin D Supplementation: Shedding Light on the Role of the Sunshine Vitamin in the Prevention and Management of Type 2 Diabetes and Its Complications","volume":"16","author":"Vasdeki D.","year":"2024","journal-title":"Nutrients"},{"key":"e_1_2_10_30_1","doi-asserted-by":"crossref","DOI":"10.1136\/bmj.l4673","article-title":"Association Between Vitamin D Supplementation and Mortality: Systematic Review and Meta\u2010Analysis","volume":"4673","author":"Zhang Y.","year":"2019","journal-title":"BMJ"},{"key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1093\/eurheartj\/ehx235","article-title":"Effect of Vitamin D on All\u2010Cause Mortality in Heart Failure (EVITA): A 3\u2010Year Randomized Clinical Trial With 4000\u2009IU Vitamin D Daily","volume":"38","author":"Zittermann A.","year":"2017","journal-title":"European Heart Journal"}],"container-title":["Aging Cell"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70752","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/acel.70752","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/acel.70752","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:21:14Z","timestamp":1791519674000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/acel.70752"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":30,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/acel.70752"],"URL":"https:\/\/doi.org\/10.1111\/acel.70752","archive":["Portico"],"relation":{},"ISSN":["1474-9718","1474-9726"],"issn-type":[{"value":"1474-9718","type":"print"},{"value":"1474-9726","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-05-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70752"}}