Preventing frailty in multiple sclerosis is a realistic goal—Commentary

Frailty is emerging as an important clinical challenge in multiple sclerosis (MS), as advances in disease management extend survival and shift the MS population toward older ages.^1,2 Frailty is more common in people with MS (pwMS) than in the general population and is associated with poorer quality of life, hospitalization, and mortality.^1–3 However, an important question remains unresolved: is frailty a realistic target for prevention in MS, or is it an inevitable consequence of neurodegeneration and biological aging?

The two perspectives presented in this debate highlight both opportunities and limitations. Proponents of prevention emphasize that frailty is distinct from disability. Studies show that frailty, disability, and comorbidity only partially overlap in MS and can occur independently, suggesting that frailty may represent a separate therapeutic target. ⁴ Because frailty is dynamic and potentially reversible, particularly in its earlier stages, interventions targeting physiological reserve, physical function, and resilience may delay its onset or reduce its severity. From this perspective, frailty is not simply a consequence of MS progression but a modifiable clinical state that offers an additional opportunity to improve long-term outcomes.

In contrast, opponents argue that frailty is fundamentally driven by the same pathological mechanisms underlying disease progression, including axonal loss, cortical pathology, chronic inflammation, mitochondrial dysfunction, and impaired repair. From this perspective, frailty may be less a modifiable syndrome and more a manifestation of progressive biological decline.

Both viewpoints converge on the concept of accelerated aging in MS. Chronic neuroinflammation, neurodegeneration, and cellular aging contribute to a gradual loss of physiological and neurological reserve. Frailty may therefore represent the clinical expression of declining reserve resulting from both disease-related and age-related processes.

The distinction between primary and secondary frailty provides a useful framework. Secondary frailty develops, as a consequence of MS-related impairments, whereas primary frailty reflects age-related physiological decline. Advocates of prevention argue that secondary frailty creates an opportunity for early intervention before irreversible loss of reserve occurs. Skeptics note that even if some manifestations are reversible, the underlying biological drivers remain largely unmodifiable with current therapies. Most aging pwMS likely experience both forms of frailty.

Frailty also occupies a unique position at the intersection of disability and comorbidity. ⁴ Disability measures neurological impairment, while frailty reflects broader vulnerability to stressors. Comorbidities may further accelerate frailty development. The observation that frailty provides prognostic information beyond disability supports its clinical relevance regardless of whether it is fully preventable.

The debate becomes particularly evident when considering interventions. While evidence that disease-modifying therapies directly influence frailty remains limited, lifestyle and rehabilitative interventions may enhance resilience and improve frailty outcomes.

Ultimately, the disagreement may be more about terminology than biology. Complete prevention of frailty may be unrealistic given ongoing aging and neurodegeneration. However, delaying onset, reducing severity, enhancing resilience, and extending healthspan appear achievable and clinically meaningful goals. Future research should focus on biomarkers, outcome measures, and interventions targeting both disease-specific and aging-related mechanisms. In this context, frailty should be viewed as a dynamic and potentially modifiable consequence of aging with MS.