SIRT1 in Neurodegenerative Diseases: Molecular Mechanisms, Disease Relevance, and Therapeutic Potential

Abstract

Neurodegenerative diseases are characterized by progressive protein aggregation, mitochondrial dysfunction, neuroinflammation, and cognitive decline, yet effective mechanism‐based interventions remain limited. Sirtuin 1 (SIRT1), an NAD+‐dependent deacetylase, has emerged as a multifunctional regulator linking stress adaptation, proteostasis, and metabolic homeostasis to disease progression. Increasing evidence indicates that SIRT1 supports cognitive resilience by coordinating synaptic plasticity, autophagy–lysosomal function, mitochondrial homeostasis, and inflammatory control. In Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), reduced or dysregulated SIRT1 is associated with protein aggregation, mitochondrial dysfunction, and cognitive decline, although its effects may be disease‐ and stage‐dependent, particularly in HD. This review summarizes the structural and catalytic features of SIRT1, examines the mechanisms linking SIRT1 to cognitive impairment across major neurodegenerative diseases, and evaluates the opportunities and limitations of SIRT1‐targeted therapeutic strategies.