Dietary metabolomic determinants of frailty through inflammation in the Canadian Longitudinal Study on Aging

Frailty is a modifiable aging-related condition driven by chronic inflammation and metabolic dysregulation, which are influenced by diet. Metabolomic profiling captures individual metabolic responses and can uncover mechanisms linking diet to frailty. This study examined the effects of food-derived metabolites on changes in frailty risk, both directly and through inflammatory pathways. This longitudinal study included baseline and three-year follow-up data from 9992 participants aged 45-85 years from the Canadian Longitudinal Study on Aging with plasma metabolomic profiling. Inflammation was assessed using tumor necrosis factor alpha, interleukin-6, and C-reactive protein. Frailty was operationalized using Fried's frailty phenotype and the deficit accumulation model. Metabolomic clusters reflecting shared dietary sources and/or biological function were associated with frailty risk, mediated by inflammation. Plasmalogens and furan fatty acids from protein-based foods, and those with anti-inflammatory properties from fruits, vegetables, nuts and legumes, were associated with reduced frailty risk both directly and indirectly through lower inflammation. Conversely, higher omega-6 to omega-3 ratio from fish/eggs and trans-4-hydroxyproline from processed meat increased frailty risk through pro-inflammatory mechanisms. These findings emphasize inflammation as an important mechanism linking diet to frailty and highlight the importance of nutrient balance and interactions to inform nutrition strategies and promote healthy aging.