Neuroprotective mechanisms resulting from regular physical exercise
The repeated and regular physiological modifications (i.e., increased cerebral blood flow) related to exercise are favorable to the synthesis of cerebral tissue, e.g., [
15,
17]. rPE activates the neurotrophic function and angiogenesis, thereby facilitating neurogenesis and synaptogenesis which improve the memory and the cognitive functions, e.g., [
15,
43-
45].
In order to analyze and describe the mechanisms involved in the protective effect of rPE, studies completed with animal models have been necessary. rPE carried out between moderate and high intensities has a neuroprotective effect by increasing the production of antioxidant enzymes (particularly superoxide dismutase or SOD), endothelial nitric oxide synthases (eNOS), brain-derived neurotrophic factors (BDNF), nerve growth factors (NGF), insulin-like growth factors (IGF-1), and vascular endothelial growth factors (VEGF), and by reducing the production of free radicals (reactive oxygen species or ROS) as well as the concentration of amyloid-ß plaques (Aβ), in particular in the cerebral zones involved in cognitive function (notably the memory) such as the hippocampus [
38,
46,
47]. In a study carried out by Van Praag et al. [
48] rPE induced hippocampic neurogenesis (particularly in the dentate gyrus) which was associated with synaptogenesis and an improvement in the learning capabilities (spatial memory and long-term potentiation) of trained old mice in comparison with control mice (same model and same age), that did not have access to a running wheel. Regular and continuous training of rats (from 5 to 23 months of age) over a period of 18 months, which required them to run on a horizontal treadmill at a speed of 20 m/min for 20 min, twice a day, 5 days a week, also had a neuroprotective effect on the cerebellum [
49]. Larsen et al. [
49] reported that sedentary-aged rats had 11% fewer Purkinje cells and 9% smaller Purkinje cell soma volumes (both two,
p = 0.02) than exercised aged rats, and exercised aged rats had the same number of Purkinje cells as young rats (5 months of age). Evidence suggests that, in the case of animals, rPE results in beneficial structural cerebral adaptations.
In the case of cognitively normal human subjects, rPE is likely to improve the executive function, attentional capacity, processing speed, episodic memory, and procedural memory [
36,
50,
51]. Physical exercise of 40 min repeated four times a week (ergocycle, treadmill, and stair-climbing) for a period of 12 weeks increased the cerebral blood flow in the dentate gyrus of the hippocampus which facilitates its neurogenesis [
52]. rPE engendered an increase of gray matter in the temporal and frontal lobes which improved cognitive performances [
17,
53]. An aerobic program (three weekly sessions of 1 h for a period of 6 months) generated a volume increase (evaluation by means of magnetic resonance imaging or MRI) of gray and white matters in certain prefrontal and temporal cortical regions (i.e., those which are substantially damaged by age advancement) for subjects aged between 60 and 79 [
54]. A longitudinal study showed that there is also a relationship between the amount of physical activity practiced and the volume of the prefrontal and temporal areas as well as the volume of the hippocampus, after 9 years of monitoring of 299 subjects (178 women) aged 78 [
55]. This study specified that greater gray matter volume resulting from rPE reduced the risk for cognitive impairment. One year later, the same laboratory carried out an interventional study and reported that aerobic training over 12 months (3 days/week, 40 min/session, 60% to 75% of the maximum heart rate reserve from the seventh week) generated an increase (+2%) of the hippocampal volume (and it is known that the age-related hippocampal annual volume loss is between −1% and −2% a year) which was associated with an increase in the plasmatic concentration of BDNF in old healthy subjects (120 subjects randomized into two groups, 60 × 68-year-old control subjects versus 60 × 66-year-old experimental subjects who practiced stretching exercises) [
56]. Evidence also suggests that, in the case of humans, aerobic exercise generates beneficial structural and functional cerebral adaptations.
Lange-Asschenfeldt and Kojda [
38] have described the molecular mechanisms of the beneficial effects of rPE on the vasculature, such as activation of the vascular NO/eNOS pathway. These authors concluded that, as well as maintaining neuronal plasticity, rPE may prevent/counteract cerebral pathophysiology by building a vascular reserve. Moreover, in the case of cognitively normal subjects, rPE is associated with Alzheimer’s disease biomarkers. In a study of 61 adults aged between 55 and 88, confirmed to be cognitively normal, Liang et al. [
57] recorded that individuals with elevated Pittsburgh compound-B or PIB (i.e., radiotracers were used to image amyloid-β aggregates with plaque formation, which indicated higher uptake of PIB) and cerebrospinal fluid Tau proteins and phosphorylated Tau proteins (ptau) carried out less exercise whereas active individuals had lower PIB binding. Nevertheless, the mechanical explanation is still uncertain since it has not yet been possible to attribute the causal link between the value of these biomarkers and the amount of physical activity.
rPE that focuses on motor coordination activates cerebral structures that are involved in executive control and perceptual speed, thereby improving not only the quality of motor responses (execution correctness and speed) but also the integration process of visuospatial information [
58]. Voelcker-Rehage et al. [
58] have shown with the use of the functional MRI technique that rPE that focuses on motor coordination enhances the activation level of the cerebral network that treats visuospatial information. These authors have specified that repeated and regular enhancements of the activation level induce structural and functional adaptations of this cerebral network thereby facilitating cognitive functioning.
For adults [
17] and old adults aged between 60 and 79 [
54], stretching and toning or relaxation interventions do not have any effect on the cerebral volume and cognitive function because the metabolic or cognitive demands are too low in comparison with aerobic exercise and coordination tasks. Aerobic exercise induces changes in the cardiovascular function that occur based on the energy demands, while coordination exercise induces changes in information processing that occur based on the cognitive demands. This effect of coordination exercise might be crucial for inducing molecular or cellular changes and thus might show the positive effects of physical activity on cognitive function [
52,
58]. Cardio-vascular training has been associated with increased activation of the sensorimotor network, whereas coordination training has been associated with increased activation of the visual-spatial network [
58]. Nevertheless, other authors have reported that non-aerobic and non-visuo-motor coordination activities such as stretching and toning could improve the executive function in old subjects [
59]. Tai Chi could also be beneficial for cognitive function [
60-
63] even if its effects need to be validated by studies of large cohorts of old subjects [
64].
The contribution of each type of exercise to the cerebral structures and functions of old persons remains to be determined more precisely by future studies in this field. At this point, it is evident that aerobic exercise combined with other types of exercise (e.g., motor coordination, stretching, toning, Tai Chi) generates greater positive effects on cognitive function than aerobic exercise practiced alone [
65].