Resveratrol engages SIRT1/AMPK networks to restore BDNF signaling, autophagy, and mitochondrial function in age-related cognitive decline: A geroscience perspective

Age-related cognitive decline and neurodegenerative disorders present significant challenges in neuropsychiatry, as current therapeutic strategies largely fail to adequately address the complexities of cerebral aging. Resveratrol, a natural polyphenol, has become a promising multi-target neuroprotective agent that can affect multiple important pathways that are involved in aging and neurodegeneration at the same time. This review consolidates evidence indicating that resveratrol, particularly through bioavailability-enhanced formulations, activates SIRT1, stimulates AMPK, inhibits mTORC1, restores autophagic flux, and promotes mitochondrial biogenesis at plasma concentrations (1-10 μmol/L) achievable in humans. Preclinically, resveratrol augments BDNF-TrkB-CREB signaling, facilitates hippocampal neurogenesis, diminishes amyloid-β and tau pathology, and alleviates neuroinflammation and glial senescence. In clinical research, resveratrol has been associated with enhanced cognitive function and hippocampal connectivity in certain trials, as well as reduced inflammatory and metabolic markers associated with brain aging, although findings remain inconsistent. Resveratrol has emerged as a potential multi-target neuroprotective agent for mitigating age-related cognitive decline, owing to its proven safety record and enhanced pharmacokinetic properties. We asserted that the accumulated evidence necessitates the initiation of extensive randomized controlled trials in middle-aged and elderly individuals to assess its efficacy in maintaining cognitive function, alleviating brain aging, and delaying the onset of neurodegenerative diseases.