Heart failure with preserved ejection fraction represents a growing crisis as populations age, affecting millions who maintain normal heart pumping function yet experience debilitating symptoms. This condition exposes a fundamental weakness in how aging hearts generate and use energy at the cellular level.
The aging heart undergoes a metabolic catastrophe characterized by declining fatty acid processing capacity while simultaneously increasing reliance on glucose metabolism. However, this metabolic shift backfires because impaired pyruvate oxidation prevents efficient glucose utilization in mitochondria, creating an energy deficit. The cellular powerhouses themselves deteriorate through multiple mechanisms: reduced NAD+ cofactor availability, diminished sirtuin enzyme activity leading to oxidative enzyme dysfunction, and compromised electron transport chains that generate excessive reactive oxygen species while producing insufficient ATP.
This metabolic dysfunction occurs alongside inflammaging—chronic low-grade inflammation that accumulates with age—and proteostatic collapse where misfolded proteins accumulate and damage heart muscle. These processes drive myocardial fibrosis and increased ventricular stiffness, the hallmark mechanical dysfunction in HFpEF.
The therapeutic landscape appears promising based on emerging interventions targeting these core pathways. NAD+ precursor supplementation, mTOR pathway inhibition, and ketone body administration show potential for restoring mitochondrial efficiency in preclinical models. Clinically proven SGLT2 inhibitors and GLP-1 receptor agonists likely work by shifting cellular metabolism toward more oxygen-efficient fuel utilization. This mechanistic understanding suggests that metabolic interventions, rather than traditional heart failure treatments, may offer the most effective approaches for this age-related cardiac syndrome affecting millions of older adults.
