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Causal relationships between sarcopenia, frailty, and health outcomes: A systematic review of Mendelian randomization
Justina Kilaitė1, Erinija Pranckevičienė2, Valentina Ginevičienė3
1Vilnius University, Faculty of Medicine, Institute of Clinical Medicine, Clinic of Internal Diseases and Family Medicine, M. K. Čiurlionio st. 21, Vilnius, LT-03101, Vilnius, Lithuania.
Background:
The development of frailty and sarcopenia is influenced by age-related physiological changes and gene-environment interactions, accelerating musculoskeletal decline and systemic dysfunction in older adults. Mendelian randomization (MR) use genetic variants as instrumental variables to assess causality. This study systematically reviewed two-sample MR studies investigating causal relationships of frailty and sarcopenia-related traits with various health outcomes.
Methods:
Following PRISMA guidelines, PubMed and Scopus were searched (last accessed June 27, 2025) using terms including "Mendelian randomization", "sarcopenia", "lean mass" or "fat free mass", "strength", "walking pace", "gait", and "frailty." Study quality was assessed via STROBE-MR checklist. Extracted data included exposure/outcome details, MR results (odds ratios or beta values with 95 % confidence intervals, p-value of the causal association), and instrumental variable sources.
Results:
The final analysis included a total of 68 articles on sarcopenia-related traits and 96 on frailty. Gait speed causally affected 25 traits and was affected by 26 traits. Handgrip strength causally affected 20 traits and was affected by 83 traits. Lean mass related phenotypes causally affected 45 traits and were affected by 85 traits. Frailty had a causal effect on 191 traits and was affected by 75 traits. Causal links between 19 groups of disease traits and sarcopenia and frailty were confirmed in observational studies (OS) and MR studies. In the majority of studies, increased muscle strength, lean mass, a faster walking pace, and lower frailty served as protective factors against the risk of many diseases and were positively associated with cognitive function.
Conclusion:
In this systematic review, we identified robust evidence supporting causal associations of both frailty and sarcopenia with a range of health-related outcomes, including sociodemographic and lifestyle factors, respiratory and musculoskeletal disorders, autoimmune disorders, inflammatory bowel disease, changes in gut microbiota, and neurological and vascular conditions.
Study Registration:
This review was preregistered with PROSPERO (CRD420251110335).
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