Integrating Mendelian randomisation, pairwise genome-wide association studies, and epigenetic-protein prediction across nine frailty phenotypes, this analysis establishes that genetic liability to chronic pain robustly elevates frailty severity (β = 0.70 for the Frailty Index), while cumulative frailty reciprocally raises chronic pain risk (β = 0.37). Rheumatoid arthritis selectively increases cumulative and disability-related frailty, and general frailty nearly quintuples RA susceptibility (OR = 4.59). Shared causal loci — SLC39A8, NLGN1, IL2RA, ERBB3, MAGI3 — implicate neuroimmune and synaptic convergence. Proteomic axes split into inflammatory drivers (CRP, C5, CCL18) accelerating frailty versus neuronal adhesion and ECM proteins (NCAM1, CNTN4, NTRK3, ADAMTS13) conferring resilience.
This preprint, not yet peer-reviewed, represents a methodologically ambitious attempt to move frailty research from descriptive epidemiology toward causal molecular architecture. The bidirectional pain-frailty feedback loop has real clinical weight: it suggests that undertreating chronic pain in older adults may accelerate biological ageing trajectories, not merely worsen quality of life. The resilience proteins identified — particularly NTRK3 (a neurotrophin receptor) and ADAMTS13 — open speculative but intriguing therapeutic angles. Key limitations include reliance on summary-level GWAS data, European-ancestry bias in the underlying cohorts, and the inherent assumption of Mendelian randomisation that genetic instruments are valid proxies. The strikingly high OR of 4.59 for RA warrants replication before clinical translation. Still, the convergent neuroimmune-ECM framework is conceptually generative and, if validated, could reframe frailty prevention as partly an anti-inflammatory and neurostructural maintenance challenge.
