Abstract: The phrase “Mens sana in corpore sano” taken from Juvenal’s Satires (127 a. C.) represents one of the best-known and most used sentences of all time, whose meaning in the modern age refers to the importance of physical activity for mental health and wellbeing. Robust literature demonstrated the positive role of exercise in counteracting several diseases, such as diabetes, cardiovascular diseases, neurodegenerative diseases, cancers and age-related disorders including muscle atrophy, the reduction of aerobic capacity, bone and cartilage loss. Moreover, physical exercise ensures brain health and acts as a key player in preventing cognitive decline related to aging. Exercise represents a promising strategy to ensure optimal aging, whose benefits in healthy adults were observed in attention, processing speed, memory, and executive functions. Studies performed on human and animal models showed the ability of physical activity to increase the volume of different brain regions and enhance brain plasticity and neurogenesis through the stimulation of neural progenitor cell proliferation and the sustainment of the developing neurons. Interestingly, the systemic administration of blood plasma derived from exercised mice on aged animals increased the number of newly born neurons in the dentate gyrus region, ameliorating the impaired neurogenesis and cognition in the aged hippocampus (Horowitz et al., 2020). The strict association between physical exercise and neurogenesis was recently confirmed in adult zebrafish. Here, in a spinal cord injury model, the exercise showed to activate the nicotinic-ACh receptors and inhibit the GABAA receptors, by increasing the number of newborn neurons and promoting motor function restoration (Chang et al., 2021). This evidence also corroborates previous results showing the positive role of exercise to enhance motor and sensory functions in spinal cord injury-affected patients as well as axonal regeneration and sprouting in rodent models. The positive relationship between exercise and neurogenesis is also due to the ability of physical activity to increase the expression levels and the secretion of neurotrophic and growth factors, including brain-derived neurotrophic factor, insulin-like growth factor-1, nerve growth factor and vascular endothelial growth factor. Brain-derived neurotrophic factor plays a key role in cognition, neuroplasticity, and angiogenesis. It promotes neural connectivity and is involved in the development of learning and memory. Insulin-like growth factor-1 is a neuroprotective factor, which supports brain development, neural survival and vasculature. Nerve growth factor is considered to play an essential role in mediating neuronal development and survival, and its treatment inverts the effects of lesions and age-related degeneration. Exercise also stimulates the release of vascular endothelial growth factor, which through angiogenesis also directly enhances neurogenesis and synaptic function.