Genetic elimination of senescent cells completely reversed heart failure with preserved ejection fraction (HFpEF) in mice subjected to a comprehensive "four-hit" stress model combining high-fat diet, diabetes induction, hypertension, and aging over 10 months. The intervention normalized 821 altered cardiac proteins and reduced inflammation without affecting body weight or blood sugar, pinpointing cellular senescence as the primary driver rather than metabolic dysfunction itself. The research identified the cGAS-STING pathway as the critical link between DNA damage in senescent cells and cardiac inflammation, with validation across mouse, human tissue samples, and fruit fly models. This mechanistic clarity represents a paradigm shift for HFpEF, which affects over 3 million Americans and lacks effective treatments. Unlike traditional heart failure, HFpEF patients maintain normal pumping function but suffer severe exercise intolerance and fluid retention. The findings suggest senolytic drugs—already in clinical trials for other age-related diseases—could offer the first targeted therapy for this complex syndrome. The cross-species validation and human tissue confirmation strengthen the translational potential, though the mouse model's compressed timeline may not fully capture human disease progression spanning decades.