Molecular Mechanisms Underlying the Beneficial Effects of Exercise on Brain Function and Neurological Disorders

Abstract

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle–brain, liver–brain and gut–brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise–brain communication and their benefits for physiology and brain function.

Effects of COVID-19 on Physical Activity and Its Relationship With Mental Health in a US Community Sample: Cross-sectional, Convenience Sampling–based Online Survey

“…Physical fitness and physical exercise, for example, were shown to be associated with reduced cortisol release when subjects were subjected to psychosocial stressors [ 58 ]. Additionally, recent research indicated that exercise's positive benefits on the brain were associated with possible underlying biological processes, including the gut-brain, muscle-brain, and liver-brain axes [ 59 ]. Future studies may also explore the effect of COVID-19 on PA in countries with more substantial or fewer restrictions to see whether there are differences.…”

Regular Physical Exercise Modulates Iron Homeostasis in the 5xFAD Mouse Model of Alzheimer’s Disease

“…It has been suggested that iron overload occurring in AD is associated with a reduction of iron export due to dysregulation of hepcidin [24]. Thereby a decrease of hepcidin in the brain can potentially have positive effects on stabilization of iron homeostasis in AD [65]. It has been shown that hypoactivity, a model of sedentary behavior, is associated with dysregulation of iron metabolism accompanied by increased hepcidin levels in liver and bone of rats [66,67] and in the spleen and serum of healthy individuals [68].…”

Nutraceuticals and Physical Activity as Antidepressants: The Central Role of the Gut Microbiota

“…It was recently established that the gut and the brain can communicate through these pathways, with gut microbiota influencing this connection [ 157 ]; thus, it has been hypothesized that physical exercise might alleviate stress-related and depression symptoms through a modification of the gut microbiota composition and function, and this thesis is confirmed by some studies conducted on rats [ 158 ]. Indeed, data suggest that gut microbiota could strongly contribute to the benefits that exercise exert on brain function, although the underlying mechanisms remain unclear [ 159 ]. In humans, numerous studies showed a positive correlation between individuals’ levels of fitness and microbiome diversity, and interestingly, improvements in physical exercise and mental health are associated with the alterations of some taxa in the gut [ 159 , 160 , 161 ].…”

“…Indeed, data suggest that gut microbiota could strongly contribute to the benefits that exercise exert on brain function, although the underlying mechanisms remain unclear [ 159 ]. In humans, numerous studies showed a positive correlation between individuals’ levels of fitness and microbiome diversity, and interestingly, improvements in physical exercise and mental health are associated with the alterations of some taxa in the gut [ 159 , 160 , 161 ]. Exercise promotes the increase in microbiota α diversity and richness, and the abundance of beneficial bacteria species.…”

“…In particular: increased levels of Bifidobacterium , Blautia , and Lactobacillus were reported in rats with free access to exercise with respect to a non-exercise group [ 163 ]; Donati Zeppa et al [ 162 ] showed an increase in Blautia , Bifidobacterium , and Ruminococcus in response to 9 weeks of high-intensity training in healthy young males; increased abundance of Faecalibacterium and Roseburia have been reported by Allen et al [ 164 ] after 6 weeks of endurance training in sedentary subjects; abundance of Coprococcus was associated with exercise frequency by McFadzean R. [ 165 ]; and Prevotella and Methanobrevibacter smithii were reported to be increased in a sample of competitive cyclists, with Eubacterium genus being more abundant in a specific sub-group of cyclists characterized by higher richness and alpha diversity [ 166 ]. These modifications have an impact on the microbiota–gut–brain axis through different mechanisms, such as activation of the vagus nerve, the modulation of neurotransmitters metabolism (i.e., tryptophan, which is converted and produces over 90% of the serotonin in the gut), the regulation of the HPA-axis, an increase of SCFAs production (and thus inflammation reduction), and gut hormones (i.e., GABA, neuropeptide Y, and dopamine, that act locally on the enteric nervous system) [ 159 , 167 ]. Indeed, some evidence suggests that a possible mechanism through which exercise might be beneficial in the control and treatment of depression is the ability of the gut microbiota to regulate tryptophan metabolism (via the kynurenine pathway), which is strongly associated with depression [ 14 , 168 ].…”