Main research question: Does exercise have an impact on global cognition, hippocampus-dependent memory function and the gut microbiota in a middle-aged human population?~Middle-age is a critical time for cognitive/mood changes and precedes prodromal dementia, which is mediated by changes in neuroplasticity and altered gut microbiota. This period of the lifespan is also associated with weight gain, decline in metabolism and physical fitness. Yet, it is unclear if cognitive and mood changes can be ameliorated in response to exercise and the role of gut microbiota.~The hippocampus plays a role in cognition and mood and is vulnerable to gut-mediated and metabolic changes. It is capable of generating new neurons from neural stem cells throughout life. This is a modifiable process of neuroplasticity called adult hippocampal neurogenesis (AHN), which decreases with age in the human and rodent brain. Exercise is a robust enhancer of AHN and attenuates deficits in the aged brain. Rodent studies have shown that AHN underlies antidepressant effects and certain forms of memory. In particular, pattern separation, the ability to discriminate between similar experiences or environments. A reduced ability to pattern separate is evident in older individuals and is an early symptom in mild cognitive impairment, which can present during middle-age. Moreover, pattern separation has been shown to be impaired and AHN decreased in middle-aged relates compared to young rats. Pattern separation has also been implicated as critically sensitive to exercise. However, the potential for exercise to prevent/reverse a deficit in AHN and pattern separation in middle-age has not yet been investigated. A major gap in knowledge is the identification of the mechanisms underlying cognitive impairment in middle-age, and how modulating factors, such as exercise, could attenuate them.~The investigators propose that the composition of the gut microbiota and their metabolites in middle-age may predict reduced AHN and pattern separation, which may be rescued/improved by exercise, and is thus a key mechanistic target for investigation. In support, ageing is associated with a decline in gastrointestinal function and a change in microbiota composition. Middle-age is particularly vulnerable for gut microbiota compositional and metabolite changes coupled with neuroinflammation in mice, and that these effects are modified in response to prebiotic supplementation. An altered gut microbiota is associated with low mood/depressive behaviour through metabolic changes, and germ-free mice display an aberrant increase of neurogenesis. Moreover, preliminary data show that gut microbiota depletion (induced by long-term antibiotic administration) leads to a decrease in pattern separation and AHN, albeit in young adult rats.~Accumulating evidence suggests that exercise can change gut microbial composition and serum metabolites. Interestingly, human and rats present the same metabolic signature in plasma after exercise. Moreover, the effects of exercise on metabolic profiles are transmissible via faecal microbiota transplantation (FMT). Considering the gut microbiota (i) is sensitive to exercise and age, (ii) regulates AHN and, (iii) is involved in pattern separation and mood, the investigators propose that the gut microbiome-AHN communication is important in maintaining hippocampal integrity and cognitive function during middle-age.~Aim The overall aim of the NeuroFit study is to develop and test the impact of a group-based exercise intervention to identify specific gut microbiota and metabolic signatures that may influence cognitive and mood changes in middle-aged adults.~Hypothesis Reduced pattern separation in middle age can be rescued/improved by exercise accompanied by changes in the gut microbiota and related metabolites.~Objectives The NeuroFit study has 3 main objectives.~Determine the impact of a 12-week exercise intervention (30 minutes, 3 days a week) compared to a control group (continued habitual behaviour) in healthy, middle-aged participants on cognition and mood.~Identify specific gut microbiota and metabolic signatures in middle age which is responsive to exercise and predictive of cognitive and mood changes in a randomised controlled trial.~Assess the impact of exercise on neuropsychiatric symptoms, serum BDNF, dietary intake, quality of life, habitual physical activity, cardio-respiratory fitness, anthropometry and cardiometabolic health on cognition and mood.
The NeuroFit study will be investigating the impact of exercise on global cognition, hippocampus-dependent memory function and the gut microbiota in a middle-aged population.