Linking the exposome to frailty: pathways, mechanisms, clinical implications, and prevention

Abstract

Frailty is a state of vulnerability that emerges from cumulative, non-genetic influences acting across the life course. This review applies an exposome lens, integrating general external exposures, specific external exposures, and internal biologic processes. We aimed to synthesize how social, environmental, behavioural, clinical, and biological exposures contribute to frailty and identify clinically actionable prevention targets. Methods This structured narrative review synthesized epidemiological, clinical, environmental, and mechanistic evidence linking exposome-related exposures to frailty in older adults. Literature was identified through targeted searches of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, supplemented by reference screening. Evidence was organized across exposome domains and narratively appraised according to study design, temporality, consistency, biological plausibility, and clinical relevance. Results Socioeconomic disadvantages, loneliness, and social isolation are consistently associated with higher frailty risk, whereas green and walkable environments may support healthier aging through mobility and social participation. Protective factors include specific high-quality dietary patterns and physical activity, whereas ultra-processed foods, sedentary behaviour, air pollution, climate stressors, infections, and selected chemical exposures are linked to adverse outcomes. Cardiometabolic, cardiorespiratory, and neurological vulnerability further connect external exposures with frailty progression. Internal pathways, including chronic inflammation, mitochondrial dysfunction, endocrine-metabolic dysregulation, gut microbiome dysbiosis, and epigenetic aging support plausible mechanistic pathways through which exposures may contribute to frailty. Conclusion Exposome-informed frailty care should combine validated frailty assessment with brief screening for actionable risks, including social connection, diet, physical activity, pollution and temperature vulnerability, infection history, vaccination status, and chronic disease burden. Practical strategies include social prescribing, healthier dietary patterns (e.g., Mediterranean-style diets), physical activity in green and low-pollution spaces, seasonal health planning, vaccination, and cardiometabolic optimization.