Collective exerkines mediate physical activity mitigating new-onset heart failure risk in older adults with prediabetes or diabetes: a community-based longitudinal cohort study

Background: Evidence regarding how collective exerkines mediate the association between physical activity (PA) and heart failure (HF) risk in older adults with prediabetes and diabetes remains limited. Methods: This prospective cohort study enrolled 5,886 older adults with prediabetes or diabetes from community dwellings in Shandong, China, between 2008 and 2011. PA metabolic equivalent task (MET) scores and plasma concentrations of ten exerkines, such as brain-derived neurotrophic factor (BDNF) and interleukin (IL)−6, were evaluated. The new-onset of HF during follow-up served as the outcome. Results: Over a median follow-up of 11.1 years, 615 participants developed HF, with an incidence rate of 9.59 per 1000 person-years. A U-shaped dose-response association emerged between PA MET scores and HF risk. Compared to light PA, moderate and vigorous PA reduced HF risk by 57.0% (HR: 0.43; 95% CI: 0.33–0.56) and 36.0% (HR: 0.64; 95% CI: 0.49–0.83), respectively. A quartile increase across all examined exerkines was associated with a 32% decreased HF risk (HR: 0.68, 95% CI: 0.63–0.73). Among these exerkines, BDNF was the most significant negative contributor, while IL-6 emerged as the predominant positive contributor to HF risk. Principal component analysis revealed IL-6 and BDNF as the primary contributors to component 1, explaining 42.87% of the data variance. Population attributable risk analysis indicated that low BDNF levels carried the highest attributable risk percentage at 18.6%, followed by elevated IL-6 levels at 12.6%. Recreational-leisure PA MET scores demonstrated a significant positive correlation with BDNF and a significant negative correlation with IL-6. In contrast, correlations between occupational PA MET scores and both BDNF and IL−6 were not statistically significant. The collective exerkines mediated 67.83% and 20.48% of the associations of the PA MET scores and hyperglycemic status with HF risk, respectively (Padjustment <0.001). Conclusions: Collective exerkine activity plays a crucial mediating role in the relationship between PA and HF risk among older adults managing prediabetes or diabetes. Cultivating optimal physical activity habits is paramount for preventing HF onset in this vulnerable group. This includes moderately increasing recreational-leisure pursuits, strategically reducing occupational and household activities, enhancing protective exerkines like BDNF, and suppressing harmful ones such as IL-6. Trial registration Retrospectively registered number: ChiCTR-EOC-17013598. Graphical Abstract: Supplementary Information: The online version contains supplementary material available at 10.1186/s12933-026-03170-8.