Age-related Cognitive Changes: Effects of Combined Flavonoid Intake and Physical Exertion Mediated by the Gut Microbiome

Age-related cognitive changes: Effects of combined flavonoid intake and physical exertion mediated by the gut microbiome Age-related cognitive changes can be the first indication of the progression to dementias, such as Alzheimer's. These changes may be driven by a complex interaction of factors including diet, activity levels, genetics, and environment. Recent in vivo experiments and human clinical trials have shown that flavonoid-rich foods can inhibit neuroinflammation and enhance cognitive performance. Improved cognition has also been correlated with a physically-active lifestyle, and with the functionality, composition, and diversity of the gut microbiome. Research has established that 1) the great majority (+90%) of dietary flavonoids are biotransformed into phytoactive phenolic metabolites at the gut microbiome level prior to absorption, 2) prebiotic- like dietary flavonoids alter microbiota profiles, functionality and diversity, 3) health-relevant outcomes from flavonoid ingestion may only be realized in the presence of a robust microbiome and 4) physical exertion (moderate aerobic exercise) dramatically accelerates the uptake of these gut-derived anti-inflammatory and immunomodulatory phenolic metabolites into circulation. This project's hypothesis is that the combination of flavonoid-rich diet and routine physical activity may potentiate cognitive benefits and reduce cognitive decline in an aging population, via mechanisms mediated by the gut microbiome. Aim 1 will examine the effects of routine flavonoid-rich blueberry intake (12-weeks), combined with or in the absence of regular moderate exercise, on cognitive function in a clinical population of older participants identified as experiencing age-related cognitive changes. Aim 2 will investigate, using shotgun metagenomics, the extent to which observed cognitive function is associated with intervention- induced changes in the microbiome and explore synergies. This Aim will leverage a unique and extensive in-house library of gut-derived phenolic metabolite standards. In Aim 3, the ability to abrogate the microbiome in test animals, unlike humans, will clarify its role in linking diet and physical exertion to cognition in aging brains. A mouse cognitive decline model employing antibiotics will isolate and interrogate the role of the microbiome as a mechanistic target by which dietary flavonoids and/or exertion improve cognitive outcomes. We will humanize the mice using fecal samples collected at baseline from human clinical subjects exhibiting age- related cognitive changes. The overall result of this project will determine how dietary flavonoids (e.g. berries) and moderate physical exertion, as reasonable diet and lifestyle modifications, can impact cognitive change in the aging population via the gut microbiome.