High-Intensity Interval Training Plus Resveratrol: A Synergistic Strategy to Rejuvenate the Aging Heart via VEGF/FSTL1/DIP2 Signaling

Introduction: Aging impairs cardiac angiogenesis via downregulated molecular pathways. While exercise and resveratrol each exhibit pro-angiogenic potential, their combined effect on vascular endothelial growth factor (VEGF), follistatin-like 1 (FSTL1), and disco-interacting protein 2 homolog A (DIP2A) in the aged heart remains unclear. This study investigated eight-week high-intensity interval training (HIIT) and resveratrol on these proteins in aged rat hearts. Methods: Twenty-four 15-month-old male rats were randomly divided into sedentary control, HIIT only, resveratrol only, and HIIT + resveratrol groups (n = 6 per). The HIIT protocol involved eight weeks of progressive treadmill running, while resveratrol (15 mg/ kg/day) was orally administered throughout the same period. Cardiac tissue was harvested 24 hours post-intervention, and protein expression levels were analyzed via Western blotting. Results: One-way ANOVA revealed significant differences among groups for all proteins (P = 0.001). Post-hoc Tukey’s HSD tests demonstrated that the exercise+resveratrol group had the highest levels of VEGF, FSTL1, and DIP2A, significantly exceeding those of all other groups (P < 0.001). Exercise alone substantially increased all markers compared with the control and resveratrol groups (P < 0.001). Critically, resveratrol alone did not differ from control for any protein (VEGF: P = 0.99; FSTL1: P = 0.47; DIP2A: P = 0.99), indicating that supplementation was ineffective in the absence of exercise. The combined group’s superiority over exercise alone confirmed that resveratrol synergistically potentiated the exercise-induced upregulation of VEGF, FSTL1, and DIP2 in the aged heart. Conclusion: Exercise training was the strongest stimulus for VEGF, FSTL1, and DIP2A. Resveratrol alone had minimal effect, but when combined, they synergistically markedly maximized cardiovascular health benefits.