Frailty, a common, multifaceted, and significant geriatric condition, involves crucial roles of inflammation and metabolic factors in its onset and progression. Nevertheless, the ambiguities and complexities in earlier observational studies make current research into their interactions somewhat insufficient. Our goals were to clarify the causal link between inflammatory cytokines and frailty and to explore the potential mediating effect of metabolites using Mendelian randomization (MR) analysis. Utilizing detailed summary-level data from genome-wide association studies, we conducted two-sample Mendelian randomization analyses to evaluate the potential causal connection between 91 inflammatory cytokines and the frailty index, along with the possible mediating pathways that involve 1400 metabolites. For our main analysis, we applied the inverse variance weighted method. To evaluate the potential mediating pathways of metabolites, a two-step MR analysis was utilized. We identified 8 inflammatory cytokines that were genetically associated with the frailty index, we subsequently identified 2 mediated relationships, with 2 metabolites acting as potential mediators between 2 inflammatory cytokines and frailty index. The 8 inflammatory cytokines were fractalkine (CX3CL1), interleukin-33 (IL-33), leukemia inhibitory factor receptor (LIF-R), monocyte chemoattractant protein-1 (CCL8), CC motif chemokine 4 (CCL4), C-X-C motif chemokine 10 (CXCL10), fibroblast growth factor 5 (FGF-5), and TNF-beta (TNFB) levels. The findings of this study demonstrate a direct connection between inflammatory cytokines and the frailty index, as well as two pathways mediated by metabolites. These biomarkers contribute valuable insights into the foundational mechanisms of frailty, presenting a novel research avenue for upcoming clinical studies.

Although observational studies have revealed a link between frailty and serum micronutrient levels, it remains unclear whether these 2 states are directly connected. Thus, Mendelian randomization (MR) was used to investigate the causal relationship between frailty and blood micronutrient levels. Summary-level data for 15 blood micronutrients (copper, selenium, zinc, calcium, iron, magnesium, potassium, folate, carotene, vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin D, and vitamin E) were obtained from people of European ancestry from the Integrative Epidemiology Unit. Single nucleotide polymorphisms associated with the frailty index were extracted from a published meta-analysis study in the UK Biobank and Swedish TwinGene. We used the inverse variance weighted (IVW) method for the primary analysis. We employed pleiotropy residual sum and outlier (MR-PRESSO) tests, MR-Egger intercepts, Cochran Q tests, and leave-one-out analysis to assess causality validity and robustness. Reverse MR analysis was used to determine reverse causation. The IVW results revealed that vitamin D (odds ratio [OR] = 1.096; 95% confidence interval [CI]: 1.019–1.178; P = .014) increased the likelihood of a high risk of frailty, whereas the frailty index had a protective effect on selenium (OR = 0.622; 95% CI: 0.396–0.977; P = .039), carotene (OR = 0.916; 95% CI: 0.858–0.979; P = .009), vitamin C (OR = 0.895; 95% CI: 0.837–0.957; P = .001), iron (OR = 0.921; 95% CI: 0.859–0.988; P = .022), and vitamin E (OR = 0.907; 95% CI: 0.847–0.971; P = .005). The reverse IVW analysis revealed no significant correlation between micronutrient levels and frailty indices. The study revealed causal links between vitamin D and the risk of frailty. Notably, our findings highlight the necessity of adjuvant vitamin D in frailty management.