Sirtuin 1 is a key molecular link between cellular senescence and heart failure

Cellular senescence, a state where cells permanently exit the cycle but remain metabolically active, plays a role in cardiovascular diseases (CVD), including heart failure (HF). Senescent cells accumulate in aging and stressed heart tissue, releasing pro-inflammatory cytokines, chemokines, and enzymes that affect endothelial cells. This ongoing inflammation exacerbates cardiac damage, induces endothelial dysfunction, and triggers secondary senescence across various cardiac cell types. Senescent cardiomyocytes contribute to reduced systolic function by causing mitochondrial damage, impaired contractility, and metabolic dysfunction, leading to lower cardiac output and symptoms such as fatigue and exercise intolerance in HF patients. Additionally, inflammation from senescent endothelial cells and loss of microvasculature impair coronary blood flow and oxygen delivery, worsening symptoms such as shortness of breath, angina-like discomfort, and fluid retention by disrupting cardiac energy metabolism and increasing filling pressures. A key factor linking cellular senescence with HF is sirtuin 1 (SIRT1), a histone deacetylase with antioxidant activity. SIRT1 acts as a hormetic regulator in the heart, being beneficial within a narrow range but potentially harmful when overstimulated. As drugs targeting senescence are emerging to treat CVD, it is important to evaluate how SIRT1 may influence the connection between senescence and HF to improve anti-senescent therapies. In this narrative/perspective review, we explore the molecular mechanisms underlying senescence in HF development and how SIRT1 might modulate these processes for therapeutic benefit.