Despite extensive research on neuroimaging correlates of human brain aging, there is little mechanistic insight into how they are linked to loss of brain function. Previous studies on the role of cerebral blood flow (CBF) in supporting brain function have focused on delivery of nutrients, namely oxygen and glucose. However, CBF is required also to clear the byproducts of energy metabolism, namely CO2 and protons. With the goal of determining whether age-associated reduction in regional CBF may lead to abnormal brain partial pressure of carbon dioxide (pCO2) and pH levels that are sufficient to alter brain activity and cognitive function, we applied a recently introduced homeostatic modeling of nutrients and waste products to human neuroimaging PET data acquired in young and older adults (Goyal et al. in Cell Metab 26(2):353-360, 2017). Our results demonstrate that age-associated reductions in CBF, in the presence of virtually unaltered oxygen consumption rates, show concurrent regional age-associated increases in pCO2 and associated pH acid-shifts of possible functional relevance. We conclude that the implications of altered vascular health in older adults needs to be revisited in light of its central role in removing waste products from energy metabolism at resting state and, in future studies, during external stimulations.

Centro Ricerche Enrico Fermi Rome RM Italy

Department of Anesthesiology Yale University New Haven CT USA

Department of Biomedical Engineering Yale University New Haven CT USA

Department of Cell Biology and Physiology University of New Mexico School of Medicine Albuquerque NM USA

Department of Neurology 1st Faculty of Medicine and General University Hospital 121 08 Prague Czech Republic

Department of Neurology University of Arkansas for Medical Sciences Little Rock AR USA

Department of Neurology Yale University School of Medicine New Haven CT USA

Department of Psychiatry Yale University School of Medicine New Haven CT USA

Department of Psychology Vanderbilt University Nashville TN USA

Department of Radiology Center for Magnetic Resonance Research University of Minnesota Minneapolis MN USA

Department of Radiology Magnetic Resonance Research Center Yale University New Haven CT USA

Division of Biostatistics School of Public Health University of Minnesota Minneapolis MN USA

Fondazione Santa Lucia IRCCS Rome RM Italy

Netabolics SRL Rome RM Italy

Vanderbilt Brain Institute Vanderbilt University Nashville TN USA

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