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Peer-reviewedCC BYAging cell

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

  • Ariel Israel1,2
  • Abraham Weizman3
  • Sarah Israel4
  • Shai Ashkenazi5,6
  • Eytan Ruppin7
  • Eli Magen5
  • Eugene Merzon2,5
  • Shlomo Vinker2,8
8 affiliations
  1. 1Department of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medical & Health Sciences, Tel Aviv University, Tel-Aviv, Israel.
  2. 2Leumit Research Institute, Leumit Health Services, Tel-Aviv, Israel.
  3. 3Research Unit, Faculty of Medical & Health Sciences, Geha Mental Health Center, Felsenstein Medical Research Center and Sagol School of Neurosciences, Tel-Aviv University, Tel-Aviv, Israel.
  4. 4Department of Clinical Microbiology and Infectious Diseases, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
  5. 5Adelson School of Medicine, Ariel University, Ariel, Israel.
  6. 6Schneider Children's Medical Center, Petah-Tikva, Israel.
  7. 7Translational Research Institute and the Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  8. 8Department of Family Medicine, Faculty of Medical & Health Sciences, Tel Aviv University, Tel-Aviv, Israel.
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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. 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.

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Cite

BibTeXRIS
BibTeX
@article{israel2026vitamin,
  title = {{Vitamin D Deficiency, Supplementation, and Aging-Related Morbidity and Mortality Across Two Longitudinal Population Cohorts.}},
  author = {Ariel Israel and Abraham Weizman and Sarah Israel and Shai Ashkenazi and Eytan Ruppin and Eli Magen and Eugene Merzon and Shlomo Vinker},
  journal = {Aging cell},
  year = {2026},
  month = oct,
  doi = {10.1111/acel.70752},
  url = {https://europepmc.org/article/MED/42850752},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Vitamin D Deficiency, Supplementation, and Aging-Related Morbidity and Mortality Across Two Longitudinal Population Cohorts.
AU  - Ariel Israel
AU  - Abraham Weizman
AU  - Sarah Israel
AU  - Shai Ashkenazi
AU  - Eytan Ruppin
AU  - Eli Magen
AU  - Eugene Merzon
AU  - Shlomo Vinker
PY  - 2026
DA  - 2026/10/01
JO  - Aging cell
DO  - 10.1111/acel.70752
UR  - https://europepmc.org/article/MED/42850752
AB  - 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.
SN  - 1474-9718
SN  - 1474-9726
ER  -