Sirtuin1: A Potential Key Regulator in Alzheimer's Disease Pathophysiology and Therapeutics

Abstract: Sirtuin 1 (SIRT1), an NAD+-dependent deacetylase, plays a vital role in neurodegenerative diseases, particularly Alzheimer's disease (AD). SIRT1 exerts neuroprotective effects by modulating oxidative stress, neuroinflammation, and mitochondrial function while promoting neuronal survival. It enhances amyloid-β (Aβ) clearance by activating α-secretase and inhibiting β-secretase, thereby reducing Aβ aggregation. Beyond protein aggregation, SIRT1 also influences mitochondrial biogenesis and function via peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), thereby enhancing energy metabolism and reducing oxidative damage. Moreover, SIRT1-mediated deacetylation of nuclear factor kappa B (NF-κB) suppresses neuroinflammation, further contributing to neuroprotection. Preclinical studies highlight the therapeutic potential of SIRT1 activators, such as resveratrol, in improving cognitive function and reducing AD pathology. However, challenges such as bioavailability, pharmacokinetics, and the lack of definitive clinical validation hinder its therapeutic translation. Emerging research suggests that lifestyle factors, including caloric restriction, exercise, and sleep modulation, may naturally enhance SIRT1 activity, offering alternative approaches for AD prevention. Despite promising evidence, further research is required to fully elucidate the mechanisms underlying SIRT1's role in AD and to develop effective, targeted therapies. This review underscores SIRT1's multifaceted involvement in AD pathophysiology and its potential as a therapeutic target, calling for multidisciplinary efforts to advance its clinical application.