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

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. 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 compared severe deficiency (< 10 ng/mL) with sufficiency (> 30 ng/mL) in LHS and were externally validated in 223,175 propensity score-matched TriNetX pairs; matched cohorts were approximately 54 years old, 65%-67% female, and followed for up to 10 years. In both populations, severe deficiency was associated with increased risks across multiple aging-related outcomes. All-cause mortality was higher in LHS (adjusted HR 2.57, 95% CI 2.38-2.79) and TriNetX (HR 1.59, 1.55-1.63). To assess modifiability, 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; for > 10 ng/mL-equivalent supplementation, mortality HR was 0.72 (0.68-0.76), while showing no corresponding association for skin malignancy. To strengthen causal interpretation, we additionally implemented inverse-probability-of-treatment-weighted 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-related multimorbidity in human populations.