Reduced removal of waste products from energy metabolism takes center stage in human brain aging

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.