Abstract / Summary
Neurological and psychiatric disorders share several biological mechanisms, including mitochondrial dysfunction, oxidative stress, neuroinflammation, impaired protein homeostasis, and changes in synaptic plasticity. Sirtuins (SIRT) are nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that regulate cellular metabolism, gene expression, mitochondrial function, inflammation, and neuronal survival. This narrative review examines the roles of SIRT1–SIRT7 in neurodegenerative and psychiatric disorders and discusses pharmacological approaches that target sirtuins or related pathways. The review was complemented by a bibliometric analysis of publications indexed in the Web of Science Core Collection. Keyword co-occurrence analysis was used to identify the main themes and emerging research directions in the field. Current evidence suggests that activation of SIRT1 and SIRT3 generally supports mitochondrial function and neuronal resistance to stress, whereas inhibition of SIRT2 may be beneficial in some models of protein aggregation and cerebral ischemia. However, the effects of sirtuins vary according to the isoform, cell type, disease, and stage of disease. Pharmacological modulators were grouped into targeted activators, natural compounds that indirectly support sirtuin signaling, NAD+-boosting agents, synthetic inhibitors, and endogenous inhibitors with context-dependent effects. Among the more selective activators, SRT2104 and MDL-800 appear particularly relevant, while most natural compounds act as indirect pleiotropic modulators of sirtuin-associated signaling, although their translational validation remains limited. Overall, sirtuin modulation is a promising but complex therapeutic approach. Its clinical translation is still limited by poor isoform selectivity, indirect mechanisms of action, dose- and timing-dependent effects, uncertain blood–brain barrier penetration and insufficient clinical validation.