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The risk of frailty among persons with MS (pwMS) exceeds that of other chronic diseases, and the interactions between frailty and MS pathologies can aggravate physical disability. The hallmarks of frailty include increased vulnerability, reduced ability to respond to stressors, and elevated risk of adverse health outcomes. Although frailty is often conflated with aging, it can affect individuals with chronic conditions, such as MS, regardless of chronological age. The overlap between MS-related disability and frailty and the nexus among ambulatory impairment, fatigue, and metabolic alterations contribute to accelerated frailty risk. The utility and limitations of frailty measures such as the Fried Frailty Phenotype and the Frailty Index in MS are presented. The shared pathophysiology of MS and frailty includes metabolic dysregulation, sarcopenia, and systemic inflammation. 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