Circulating Mitokines GDF-15 and FGF21 are associated with Frailty, Sarcopenia, and Malnutrition in Older Adults: Evidence from the FRASNET Study

Background: Mitochondria-derived GDF15 and FGF21, known as mitokines, are emerging biomarkers of metabolic stress and aging-related decline. Their roles in energy balance, inflammation, and muscle metabolism suggest potential for predicting geriatric syndromes, yet prospective evidence is limited. Methods: Plasma GDF15 and FGF21 and multidimensional geriatric assessment at baseline and at 6-year follow-up in 52 community-dwelling adults aged ≥ 65 years from the FRASNET cohort. Results: Over a six-year follow-up, participants exhibited signs of functional decline, including increased waist circumference, greater fatigue severity, and higher medication use. FGF21 levels declined significantly over time (p=0.03), whereas GDF15 levels remained stable. Higher baseline GDF15 levels identified individuals at higher risk to become frail (AUC= 0.85 with Fried Phenotype and AUC= 0.96 with Clinical Frailty Scale) or malnourished (AUC=0.94) and at risk to fall (AUC=0.98). FGF21 associated to malnutrition (AUC=0.98). GDF15 prospectively associated to high risk of frailty and negatively associated with physical performance and nutritional status after six years. Conclusions: In this cohort, higher baseline levels of GDF15 and FGF21 were associated with the risk to become frail or malnourished. These findings support the integration of mitokines into early risk stratification tools for older adults. Further validation in larger cohorts is warranted.