The sirtuin family: from mechanisms to therapy

Sirtuins (SIRT1-SIRT7) are evolutionarily conserved NAD⁺-dependent deacylases that function as metabolic sensors, coupling cellular metabolic state to epigenetic, transcriptional and post-translational regulatory programs across distinct subcellular compartments. Despite two decades of research, isoform- and disease-specific aspects remain poorly integrated, limiting both conceptual clarity and therapeutic translation. This review synthesizes recent advances in sirtuin biology into a family-wide framework. Rather than functioning as isolated longevity factors, sirtuins operate as a distributed compartmentalized regulatory network in which nuclear SIRT1, SIRT6 and SIRT7, cytosolic SIRT2 and mitochondrial SIRT3, SIRT4 and SIRT5 collectively govern glucose and lipid metabolism, mitochondrial quality control, autophagy, inflammation and immune tolerance. This network operates across metabolic disorders, cardiovascular and neurodegenerative diseases, inflammatory conditions and cancer, where dysregulated sirtuin signalling influences disease development in a disease- and tissue-specific manner. Therapeutic strategies are evaluated, ranging from isoform-selective small-molecule modulators and NAD⁺-targeted interventions to emerging protein-degradation approaches, with isoform selectivity, off-target effects and the systemic consequences of NAD⁺ modulation identified as key translational barriers that have contributed to heterogeneous clinical outcomes. Viewing sirtuins as a context-sensitive compartmentalized network, not isolated targets, offers a coherent framework to guide mechanistic interrogation and the design of more precise sirtuin-based therapies, with priority areas including tissue-selective degradation and network-level biomarkers.