Abstract 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. BAA (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 to 0.583) years at CRP z-score 2 compared to 0.121 (95% CI 0.120 to 0.122) years at CRP z-score 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. 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.
Kositsawat et al. (2025) studied this question.