The nonlinear U-shaped association between vitamin D deficiency and biological aging acceleration is enhanced in individuals with higher inflammation levels

Dec 13, 2025The journals of gerontology. Series A, Biological sciences and medical sciences

Vitamin D deficiency and faster biological aging show a U-shaped link that is stronger with higher inflammation

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Abstract

Participants with vitamin D deficiency and high C-reactive protein levels exhibited a biological aging acceleration of 0.576 years.

Vitamin D deficiency (VDD) is associated with increased biological aging acceleration (BAA) in individuals with elevated C-reactive protein (CRP) levels.
Higher CRP levels correlate with greater BAA, regardless of vitamin D status.
A U-shaped relationship exists between vitamin D levels and BAA, indicating both deficiency and excess may affect aging.
The interaction between VDD and high CRP levels suggests the need for tailored interventions in aging research.

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BACKGROUND: Aging is multifactorial, yet aging research emphasizes independent risk factors. Endocrine and inflammatory factors have been linked to opposing and synergistic associations with suboptimal aging.

METHODS: Given the importance of multifactorial nonlinear approaches, we interrogated interactions of vitamin D deficiency (VDD; 25-hydroxyvitamin D (25(OH)D) <20 ng/mL) and high C-reactive protein (CRP) levels (≥2.6 mg/L; the third quartile among the included sample) with biological aging acceleration (BAA) in 313 444 UK Biobank participants. Biological aging acceleration (chronological < expected BA) was derived from PhenoAgeAccel (phenotypic age [PhenoAge] adjusted for chronological age and covariates). 25(OH)D and CRP levels were linked to BAA using restricted cubic spline regression models.

RESULTS: We observed moderation effects of CRP on VDD-BAA association, and that of 25(OH)D on the high CRP-BAA association. PhenoAgeAccel values for participants with VDD were 0.576 (95% CI, 0.570-0.583) years at CRP z-score 2, compared to 0.121 (95% CI, 0.120-0.122) years at a CRP z-score of 0. In contrast to a U-shaped relationship between 25(OH)D and BAA, all higher CRP levels were more strongly associated with higher BAA. The association between VDD and BAA was greater in participants with higher CRP levels, yet participants with high CRP levels showed similar BAA regardless of vitamin D levels.

CONCLUSIONS: Our findings illustrate these risk factors' nonlinear and interactive nature, highlighting the importance of targeting resulting heterogeneity in aging trajectories by developing more targeted interventions via Precision Gerontology. Approaches may include interventions targeting inflammation in individuals with both VDD and inflammation.

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The nonlinear U-shaped association between vitamin D deficiency and biological aging acceleration is enhanced in individuals with higher inflammation levels

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