Epigenetic Modulation and Brain Function in Parkinson's Disease: The Role of Exercise Alone or Combined With...

Parkinson's disease (PD) is a complex, progressive neurodegenerative disorder that affects millions worldwide and is a growing contributor to disability. While pharmacological treatments remain central to symptom management, they often fall short in altering disease progression. Increasing evidence points to epigenetic modifications, such as DNA methylation, histone acetylation, and noncoding RNA regulation, as crucial factors in PD pathogenesis and promising targets for intervention. These molecular mechanisms govern gene expression without changing the DNA sequence and are influenced by environmental and lifestyle factors. Among these, physical exercise and dietary polyphenols have emerged as potent, noninvasive modulators of the epigenome. Exercise has been shown to alter DNA methylation, increase histone acetylation, and regulate microRNAs and long noncoding RNAs in ways that support neuronal resilience. Similarly, polyphenols affect epigenetic marks and reduce oxidative stress and inflammation, both key drivers of PD pathology. Therefore, in this review, we explore how these interventions, individually and in combination, influence epigenetic mechanisms relevant to PD. We summarize current evidence on the neuroprotective and regulatory effects of exercise, and highlight studies investigating the potential synergy of exercise and polyphenols. By synthesizing these findings, our goal is to provide insight into how these strategies may contribute to personalized, epigenetically informed approaches for managing and potentially modifying the course of PD.