Background

Vitamin D is an important prominent micronutrient that is primarily involved in maintaining calcium homeostasis, which is mainly stored as 25(OH)D in the body [1]. Vitamin D deficiency has become a prevalent global health problem, particularly among individuals residing in develo** nations, including China [2]. A recent meta-analysis of 472 research reports demonstrated that the prevalence of vitamin D deficiency, characterized by serum 25(OH)D level under 50 nmol/L, was 57.7% in the Asian demographic [3]. Associations of vitamin D levels and supplementation with mortality are not exactly consistent in published observational and intervention literatures though vitamin D has been linked to several potential health benefits [4,5,6]. Numerous studies have linked vitamin D deficiency with various negative health consequences, including fractures [7], frailty [8], sarcopenia [9], dementia [10], and premature death [11, 39, 53], which might be a new approach to explain the complex association between vitamin D and multiple health outcomes in the future. Meanwhile, as for CVD mortality, serum 25(OH)D can regulate the renin-angiotensin system and the proliferation of vascular smooth muscle cells [54, 55], reducing the incidence of CVD diseases [56]. Besides, insufficient vitamin D was also found to be associated with depression, schizophrenia, and Alzheimer’s disease [12, 57]. The high prevalence of these diseases contributes to a significantly higher likelihood of future non-CVD mortality.

We also demonstrated that high hs-CRP was associated with increased all-cause, CVD, and non-CVD mortality. Similar findings were obtained from studies performed in the United States [19], Peru [38], and China [21]. A previous meta-analysis involving 22 studies showed significant positive relationships of hs-CRP with all-cause and CVD mortality [58]. Fundamental studies have also showed that hs-CRP could inhibit vascular endothelial growth factor-stimulated angiogenesis and indirectly promote vasoconstriction, thrombosis, and atherosclerosis [59, 60], increasing the risk of death from CVD [61]. Several cohort studies confirmed that hs-CRP was linked to the incidence and progression of cardiovascular and cerebrovascular events [62, 63]. High hs-CRP is also correlated with higher risks of various chronic disorders like diabetes [64], dementia [65], and cancer [66]. Furthermore, hs-CRP has been identified as a biomarker with poor prognosis for many diseases, such as cancer and myocardial infarction [67, 68]. These results suggest that high hs-CRP not only increases the risk of morbidity but also may lead to poor prognosis and thus increase the risk of death.

Although our findings on the separate association of 25(OH)D and hs-CRP with mortality were not novel, the innovative result was that vitamin D deficiency and high hs-CRP jointly increased risks of all-cause mortality by 118%, CVD mortality by 130%, and non-CVD mortality by 119%, which were higher than their individual effects. Significant additive interactions of 25(OH)D and hs-CRP on all-cause and non-CVD mortality were observed (RERIS>0), particularly in men. Some mechanisms may explain the combined association of vitamin D and hs-CRP with mortality. First, previous experimental studies have found that 25(OH)2D3, which is an active version of vitamin D, inhibits the synthesis of multiple inflammatory cytokines [69]. A population-based observational study also found that elevated circulatory 25(OH)D was significantly correlated with lower hs-CRP levels [70]. These results suggested that low serum 25(OH)D might contribute to high hs-CRP because of its anti-inflammatory properties. Therefore, vitamin D deficiency and high hs-CRP could aggravate each other, jointly increasing the risk of death. Second, vitamin D deficiency and high hs-CRP are included in common pathogenic factors of death which may ultimately increase the mortality risk. Previous studies have demonstrated that the coexistence of vitamin D deficiency and high hs-CRP was associated with a higher prevalence of sarcopenia [71, 72], CVD [27], schizophrenia [28], and metabolic syndrome [29]. Considering the potential confounding of clinical factors, we conducted multiple sensitivity analyses to test the stability of the main results. The combined associations of 25(OH)D and hs-CRP with mortality were materially unchanged after excluding participants with cerebrovascular disease, respiratory disease, or cancer at baseline. Interestingly, we found the effects of vitamin D deficiency and high hs-CRP on mortality risk were weaker in older adults who received inpatient or outpatient medical services in the last year (Supplementary Table 4). One possible reason was that vitamin D deficiency and inflammation might be treated with medical intervention when older people were cared for in medical facilities. Thus, we recommended focusing on the heterogeneity between clinical settings and healthy community samples in future studies.

Strengths and limitations

This study focused on the interactions between multiple biomarkers and provides valuable epidemiological evidence. In the current study, 16.3% of older adults exhibited both vitamin D deficiency and high hs-CRP. Considering the combined association of vitamin D and hs-CRP with mortality, intervention strategies for maintaining adequate vitamin D and preventing inflammation may be beneficial in reducing mortality risk in community settings. The current study has several limitations. Firstly, while hs-CRP is a commonly used marker for systemic inflammation [73, 74], the present study did not account for other inflammatory factors, such as acute infections, autoimmune diseases, or anti-inflammatory drug use, etc. However, after excluding the outliers of hs-CRP measurements (≥ 10 mg/L), the main results remained stable, which may have partially eliminated the influence of immune-related diseases (Supplementary Table 2). Secondly, like other observational analyses, it is not possible to eliminate the residual confounding factors even after multivariable adjustment. Specifically, data on sunlight exposure was not available at baseline. To mitigate this limitation, we attempted to control for factors such as outdoor activity frequency, the month of the blood sampling, and residential provinces, following previous studies [39, 40]. Additionally, we were unable to quantify the supplementation of vitamin D. However, in this study, only a very small percentage (5.50%) of older individuals frequently supplemented with vitamins, which might not significantly confound the associations. Furthermore, when they were excluded, the relationship between vitamin D levels and the risk of mortality remained stable (Supplementary Table 5). Thirdly, we only measured serum 25(OH)D and hs-CRP levels from a single time point. Given that both may vary due to changes in lifestyle or health status, it is necessary to explore their dynamic effect on health consequences in in the future. Finally, despite the national representation of CLHLS, caution should be exercised when generalizing the findings to older people of other ethnicities.

Conclusions

This study highlighted that the combination of low 25(OH)D and high hs-CRP levels could jointly elevate the risk of mortality in older adults. Thus, it is crucial to prioritize early detection and appropriate intervention for individuals who exhibit a combination of vitamin D deficiency and systemic inflammation.