Proteostatic Imbalance Drives the Pathogenesis and Age-Related Exacerbation of Heart Failure With Preserved Ejection...

Heart failure with preserved ejection fraction (HFpEF) is a leading cause of hospitalization and mortality in older adults, yet the role of aging in its pathogenesis remains unclear. Old male mice subjected to chronic metabolic and hypertensive stress (2-hit) developed a more severe HFpEF phenotype compared with young counterparts. We identified that age-related disruptions in protein quality control (PQC) worsens proteostatic stress in HFpEF. Mammalian target of rapamycin complex 1 (mTORC1), a key regulator of PQC, is activated by both aging and 2-hit stress, and cardiac-specific mTORC1 inhibition protects against HFpEF. Our findings highlight the need to integrate aging into preclinical models of HFpEF and suggest targeting PQC as a therapeutic strategy.