Vitamin D Deficiency, Supplementation, and Aging-Related Morbidity and Mortality Across Two Longitudinal Population Cohorts

Abstract

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. 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. 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. 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. 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.