Effects of ageing and exercise training on cerebrovascular vasomotor reactivity, depressive behaviour and the hippocampal transcriptome

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The ageing global population is experiencing an increased prevalence of cerebrovascular diseases, such as stroke and dementia. This highlights a need for understanding the pathophysiological mechanisms of age-related cerebrovascular alterations, alongside benefits of interventions such as physical activity. Therefore, our aims were to: (1) examine the impact of ageing and exercise training on cerebrovascular function and (2) to characterize age- and exercise training-related changes in the hippocampus transcriptome. Young and old male rats were randomized to a sedentary condition or exercise training for 10 weeks. In the first protocol, cerebral arteries were isolated to test vasomotor reactivity, quantify gene/protein expression and assess nitric oxide production. In the second protocol, anhedonia was assessed and hippocampal tissue collected for RNA-sequencing. Bioinformatic analyses (i.e. protein-protein interaction mapping) were performed. Ageing impaired endothelium-dependent vasoreactivity in the posterior communicating artery (PCoA), with a shift from endothelial nitric oxide synthase (NOS)- to neuronal NOS-mediated vasorelaxation, as well as alterations in oxidative stress production. In support, PCoA superoxide-mediated vasoreactivity and neuronal NOS-mediated production of NO decreased with age. Exercise enhanced vasodilatation in young rats, but the results suggested reduced cerebrovascular plasticity in older animals. In the second protocol, exercise training attenuated the age-related increase in anhedonia behaviour. Hippocampal RNA-sequencing revealed altered inflammatory and oxidative stress pathways with ageing that were mitigated by exercise training. Our findings underscore the complex interplay between vascular/neuronal factors in the ageing brain. Furthermore, these findings highlight the therapeutic potential of exercise in mitigating the adverse effects of ageing on cerebral health. KEY POINTS: Ageing is associated with increased risks of cerebrovascular disease and neurocognitive decline. Little is known about the underlying mechanisms involved in this process, limiting our ability to design appropriate interventions. Ageing is associated with alterations in cerebrovascular function, including possible changes in the mechanisms underlying vasomotor reactivity. Hippocampal RNA-seq revealed age-related alterations in neuronal, vascular, immune and oxidative-stress related signalling pathways. Exercise training may have mitigated many of these age-related changes, suggesting that enhancing physical activity may be a feasible means to preserve cerebral health in older individuals.

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