Epigenetic and epitranscriptomic regulation of cardiac metabolism in aging and disease

The heart’s metabolic plasticity, crucial for adapting to energy demands, is governed by epigenetic and epitranscriptomic mechanisms. Aging and cardiovascular diseases disrupt this equilibrium, leading to metabolic inflexibility, mitochondrial dysfunction, and pathological remodeling. This review explores how DNA methylation, histone modifications, and RNA methylation (e.g., m6A, m5C) dynamically regulate cardiac metabolism. Key findings reveal that age-related declines in SIRT1/NAD+ activity and FTO-mediated RNA demethylation impair fatty acid oxidation, while METTL3-driven m6A hypermethylation promotes glycolytic dependency. Dysregulation of TET enzymes and α-ketoglutarate (α-KG) further disrupts DNA hydroxymethylation and RNA modification, exacerbating oxidative stress and mitochondrial inefficiency. These alterations create self-reinforcing cycles of metabolic rigidity, contributing to heart failure, arrhythmias, and ischemia-reperfusion injury. Emerging therapeutic strategies, including BET inhibitors and NAD+ repletion, show promise in restoring metabolic flexibility by targeting epigenetic and epitranscriptomic pathways. Integrating multi-omics approaches and spatial epitranscriptomics offers novel insights into cell-specific regulatory networks, paving the way for precision interventions to counteract cardiac aging and disease.