Aging and metabolism in HFpEF: Pathophysiology and therapeutic implications.
- 2026-03
- Metabolism: clinical and experimental 176
- Min Ye
- Shenghui Feng
- Zixuan Xu
- Wenfeng He
- Chen Liu
- Wengen Zhu
- PubMed: 41352525
- DOI: 10.1016/j.metabol.2025.156460
Study Design
- Type
- Review
Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as an age-predominant syndrome characterized by diastolic dysfunction despite preserved systolic performance. In the aged myocardium, fatty acid oxidation capacity declines, while glycolytic flux increases; however, impaired pyruvate oxidation limits mitochondrial glucose oxidation, resulting in suboptimal ATP yield per oxygen molecule and worsening energetic inefficiency. Mitochondrial deficits, marked by reduced biogenesis, NAD+ depletion related to reduced sirtuin activity and consequent hyperacetylation of oxidative enzymes, and impaired electron-transport capacity, further diminish bioenergetic reserve and elevate reactive oxygen species generation. Concurrently, inflammaging and proteostatic collapse promote chronic low-grade inflammation, misfolded protein accumulation, and myocardial fibrosis, collectively contributing to increased ventricular stiffness and progressive HFpEF development. Therapeutic strategies targeting these interconnected pathways show considerable promise. Preclinical studies suggest that interventions such as NAD+ precursor supplementation, mTORC1 inhibition, and β-hydroxybutyrate administration can ameliorate HFpEF-like phenotypes by improving mitochondrial efficiency and reducing inflammation. SGLT2 inhibitors and GLP-1 receptor agonists confer clinically proven benefits in HFpEF, likely via systemic metabolic reprogramming toward more oxygen-efficient substrates and attenuation of inflammation. This review underscores the critical role of aging-associated metabolic and mitochondrial derangements in HFpEF pathogenesis and highlights mechanistically tailored interventions as the next frontier in managing this challenging, age-related syndrome.