Causal Effect of 91 Inflammatory Cytokines on Intrinsic Capacity Domains: A Two-Sample Mendelian Randomization Study

Background:

The progressive decline in intrinsic capacity represents a major challenge in aging societies, yet its underlying inflammatory mechanisms remain poorly understood.

This two-sample Mendelian randomization (MR) study aimed to investigate the causal relationships between 91 circulating inflammatory cytokines and five intrinsic capacity domains—locomotion, vitality, cognition, psychology, and sensory function.

Methods:

Genetic instruments for inflammatory cytokines were obtained from a large genome-wide association study involving 14,824 European participants. The primary causal estimates were obtained using the inverse variance-weighted (IVW) method, with sensitivity analyses performed using the MR-Egger and weighted median approaches.

Results:

Thirty-one cytokines were significantly associated with at least one intrinsic capacity domain. Notably, interleukin-13 (IL-13), CD40 ligand, and IL-8 exhibited pleiotropic protective effects on cognition, vitality, and psychological health, while elevated C-C Motif chemokine ligand 11 levels were consistently linked to increased risk of abnormalities of gait and mobility (odds ratio [OR] = 1.266; 95% confidence interval [CI]: 1.027–1.560; P  = 0.027) and increased anxiety (OR = 1.001; 95% CI: 1.000–1.003; P  = 0.031).

Conclusion:

This study provides genetic evidence for cytokine-mediated regulation of intrinsic capacity and identifies potential therapeutic targets for mitigating intrinsic capacity decline. However, the present MR approach was restricted to European ancestry, functional validation through experimental and clinical studies is warranted.