{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T00:58:53Z","timestamp":1791939533340,"version":"4.3.4"},"posted":{"date-parts":[[2025,6,4]]},"group-title":"Public and Global Health","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,22]]},"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-term 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 containing de-identified electronic health records from over 120 million individuals.<\/jats:p>\n                <jats:p>We examined more than 1.67 million serum 25-hydroxyvitamin D [25(OH)D] measurements from over 468,500 adults in LHS (2009-2020). Longitudinal matched analyses were performed in LHS, and associations involving severe deficiency were externally validated in 223,000 propensity score-matched pairs from TriNetX.<\/jats:p>\n                <jats:p>In both populations, severe deficiency was associated with increased risks across metabolic, cardiovascular, neurodegenerative, renal, microvascular, and mortality-related outcomes, including diabetes mellitus, myocardial infarction, cerebrovascular disease, dementia, dialysis, diabetic retinopathy, and foot\/toe amputation. To assess the potential health benefits and modifiability of supplementation, we modeled vitamin D supplementation longitudinally using pharmacy-dispensed purchases calibrated to predict serum 25(OH)D changes over time. Supplementation was independently associated with dose-dependent reductions across mortality and multiple aging-related outcomes, while showing no corresponding protective association for skin malignancy, a negative-control outcome strongly linked to ultraviolet exposure.<\/jats:p>\n                <jats:p>To strengthen causal interpretation, we additionally implemented inverse-probability-of-treatment-weighted marginal structural Cox models for mortality, which yielded results consistent with, and in several cases stronger than, conventional adjusted models.<\/jats:p>\n                <jats:p>Together, these findings support severe vitamin D deficiency as an important and potentially modifiable determinant of systemic aging vulnerability and age-related multimorbidity in human populations.<\/jats:p>","DOI":"10.1101\/2025.05.29.25328548","type":"posted-content","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T16:20:13Z","timestamp":1749054013000},"source":"Crossref","is-referenced-by-count":1,"title":["Vitamin D Deficiency, Supplementation, and Aging-Related Morbidity and Mortality Across Two Longitudinal Population Cohorts"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4389-8896","authenticated-orcid":false,"given":"Ariel","family":"Israel","sequence":"first","affiliation":[{"name":"Leumit Research Institute, Leumit Health Services; Tel-Aviv, Israel"},{"name":"Department of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medical & Health Sciences, Tel Aviv University; Tel-Aviv, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abraham","family":"Weizman","sequence":"additional","affiliation":[{"name":"Research Unit, Geha Mental Health Center, Felsenstein Medical Research Center and Sagol School of Neurosciences, Faculty of Medical & Health Sciences, Tel-Aviv University, Tel-Aviv, 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 and Department of Internal Medicine, Hadassah-Hebrew University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7244-0679","authenticated-orcid":false,"given":"Shai","family":"Ashkenazi","sequence":"additional","affiliation":[{"name":"Adelson School of Medicine, Ariel University; Ariel, Israel"},{"name":"Schneider Children\u2019s Medical Center, Petah-Tikva, 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-Sinai Medical Center, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Magen","sequence":"additional","affiliation":[{"name":"Medicine A Department, Assuta Ashdod University Medical Center, Ben Gurion University of the Negev; Beer Sheva, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Merzon","sequence":"additional","affiliation":[{"name":"Leumit Research Institute, Leumit Health Services; Tel-Aviv, 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; 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