Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer’s disease (AD). However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes in brain metabolism, cerebral blood flow (CBF), gut microbiome and cognition in aging, and potential implications for AD development. We conducted our study with a group of young mice (5–6 months of age) and compared those to old mice (18–20 months of age) by utilizing metabolic profiling, neuroimaging, gut microbiome analysis, behavioral assessments and biochemical assays. We found that compared to young mice, old mice had significantly increased levels of numerous amino acids and fatty acids that are highly associated with inflammation and AD biomarkers. In the gut microbiome analyses, we found that old mice had increased Firmicutes/Bacteroidetes ratio and alpha diversity. We also found impaired blood-brain barrier (BBB) function and reduced CBF as well as compromised learning and memory and increased anxiety, clinical symptoms often seen in AD patients, in old mice. Our study suggests that the aging process involves deleterious changes in brain metabolic, vascular and cognitive functions, and gut microbiome structure and diversity, all which may lead to inflammation and thus increase the risk for AD. Future studies conducting comprehensive and integrative characterization of brain aging, including crosstalk with peripheral systems and factors, will be necessary to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD.

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Published in Frontiers in Aging Neuroscience, v. 9, article 298, p. 1-14.

Copyright © 2017 Hoffman, Parikh, Green, Chlipala, Mohney, Keaton, Bauer, Hartz and Lin.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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This research was supported by National Institutes of Health (NIH)/National Institute on Aging (NIA) grant K01AG040164, NIH/NIA grant R01AG054459, NIH/CTSA grant UL1TR000117 and American Federation for Aging Research Grant #A12474 to A-LL, NIH/NIA grant R01AG039621 to AMSH, NIH/National Institute of Neurological Disorders and Stroke (NINDS) grant 1R01NS079507 to BB and NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Training Grant T32DK007778 to JDH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIA or the NIH. The 7T ClinScan small animal MRI scanner of the UK was funded by the S10 NIH Shared Instrumentation Program Grant (1S10RR029541-01).