Aging hearts, fibrotic fears: The sirtuin connection

Sirtuins are NAD⁺-dependent enzymes involved in metabolic regulation, aging, oxidative stress response, and inflammation, all of which are pivotal in the development of myocardial fibrosis. SIRT1, SIRT3, and SIRT6 are shown to exert protective effects by inhibiting fibroblast activation and reducing oxidative and inflammatory damage, while SIRT4 may promote fibrosis depending on context. This review article explores the multifaceted role of sirtuins (SIRT1-SIRT7) in cardiac fibrosis, a key pathological feature of heart failure characterized by excessive extracellular matrix accumulation. The article sheds light on the regulatory influence of non-coding RNAs and histone modifications on sirtuin expression, and illustrates the complex feedback between sirtuins and mitochondrial homeostasis, AMPK activation, and endothelial-to-mesenchymal transition (EndoMT). This review positions sirtuins as both markers and potential therapeutic targets for cardiac fibrosis, acknowledging their dual roles and context-specific effects. Herein, we highlight the importance of understanding the complex regulatory networks involving sirtuins to inform future anti-fibrotic interventions.