The connection between 91 inflammatory cytokines and frailty mediated by 1400 metabolites: An exploratory two-step Mendelian randomization analysis.

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.