SIRT1 Mediates Exercise-Induced Neuroprotection in Parkinson’s Disease via Mitochondrial Restoration: Toward Resveratrol as a Dietary Exercise Mimetic
SIRT1 Mediates Exercise-Induced Neuroprotection in Parkinson’s Disease via Mitochondrial Restoration: Toward Resveratrol as a Dietary Exercise Mimetic
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Original abstract
Abstract Growing evidence indicates that exercise exerts neuroprotective effects in Parkinson’s disease (PD). Silent information regulator 1 (SIRT1), a NAD⁺-dependent deacetylase, is a key regulator of mitochondrial function; however, whether exercise-mediated neuroprotection and SIRT1 upregulation converge on a common pathway in PD remains unclear. Here, we demonstrate that exercise alleviates PD pathology by upregulating SIRT1 expression and restoring mitochondrial homeostasis. In MPTP-induced PD mice, both exercise and the SIRT1 agonist resveratrol significantly improved motor and non-motor behaviors, reduced α-synuclein aggregation, and protected dopaminergic neurons in the substantia nigra. Mechanistically, both interventions enhanced SIRT1 expression, thereby rebalancing mitochondrial fission and fusion through the downregulation of fission-related proteins and the upregulation of fusion-related proteins. In parallel, SIRT1 activation promoted mitophagic clearance and improved mitochondrial function, as evidenced by restoration of mitochondrial membrane potential, increased ATP production, and reduced oxidative stress. Notably, these beneficial effects—from behavioral improvement to mitochondrial protection—were completely abolished by the SIRT1 inhibitor EX527, establishing SIRT1 as an essential mediator of exercise-mediated neuroprotection. Collectively, our findings integrate behavioral, humoral, and pharmacological approaches to delineate a coherent SIRT1-mediated pathway and highlight its potential as a target for exercise mimetic therapeutics. Furthermore, the natural polyphenol resveratrol recapitulates these exercise mimetic effects, supporting SIRT1 as a promising therapeutic target and underscoring the potential of dietary bioactives for PD intervention.