Association of plasma growth differentiation factor-15 with the frailty phenotype – Evidence from the COGFRAIL study

BACKGROUND: Growth differentiation factor-15 (GDF-15) has been consistently associated with physical frailty. However, it remains unclear whether GDF-15 further discriminates adverse outcomes among older adults who are already physically and cognitively impaired. OBJECTIVES: To evaluate whether GDF-15 is associated with measures of physical frailty - incident weight loss, decline in muscle strength and gait speed, fatigue, and sedentary behaviours - over a 2-year follow-up. DESIGN: Monocentric prospective study SETTING: Frailty and Memory Clinics, Gérontopôle Toulouse University-Hospital. PARTICIPANTS: 206 pre-frail and frail older adults with cognitive impairment from the COGFRAIL study with available plasma GDF-15 concentrations (median age 82.0). Secondary analyses were performed in a subgroup with repeated GDF-15 measurements during follow-up (n = 129). MEASUREMENTS: GDF-15 concentrations were analysed as a continuous variable and by tertiles. Exploratory analyses used two thresholds: 1500pg/mL (eligibility cut-off for GDF-15 inhibitor treatment in cancer-cachexia) and 2443pg/mL (upper tertile of the 6-month distribution). RESULTS: Higher GDF-15 levels were associated with a steeper decline in handgrip strength over time (p = 0.047), with no significant associations for weight loss, gait speed, sedentary behaviour, or fatigue. By tertiles, participants in the highest tertile had greater handgrip strength decline compared to those in the lowest (p = 0.018). Participants in the intermediate group had a higher risk of worsening frailty (p = 0.013) and incident weight loss (SHR 2.51; 95% CI: 1.04-6.04; p = 0.040) compared with the lowest tertile. Individuals with persistently high or increasing GDF-15 concentrations (≥2443pg/mL) experienced greater decline in handgrip strength than those with persistently low levels (p < 0.001). CONCLUSIONS: Higher plasma GDF-15 concentrations consistently predicted a steeper decline in muscle strength over time. Associations with incident weight loss and worsening frailty were also observed, although they appeared weaker at higher concentrations, possibly because of greater competing mortality in participants with very high GDF-15 levels. Further research should clarify the mechanisms linking GDF-15 to physical decline and weight loss, and whether targeting this pathway could help slow frailty progression.