Scientists have discovered a link between a protein in red blood cells and age-related decline in cognitive performance. Depleting ADORA2B (adenosine receptor A2B)—a protein known to promote oxygen release to counteract the effects of low levels of atmospheric oxygen at high altitude—results in quick decline in memory, delayed auditory processing, and increased inflammation in the brain.
The study funded by the National Institutes of Health, McGovern Scholar Funds, and The Bob and Hazel Casey Endowment of University of Texas Health Science Center-McGovern Medical School is published in an article in the journal PLOS Biology titled, “Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming.”
Led by Yang Xia, MD PhD, professor at the University of Texas, the team explore the hypothesis that aging in the brain is held at bay by ADORA2B based on the observation that oxygen concentration in blood decreases with age and ADORA2B is responsible for releasing oxygen.
“Red blood cells have an irreplaceable function to deliver oxygen to maintain bioenergetics of every single cell within our body. However, their function in age-related cognition and hearing function remains largely unknown. Our findings reveal that the red blood cell ADORA2B signaling cascade combats early onset of age-related decline in cognition, memory and hearing by promoting oxygen delivery in mice and immediately highlight multiple new rejuvenating targets,” says Xia.
To test the hypothesis, the researchers generate mice without ADORA2B in their red blood cells and compare their behavior and physiology with control mice.
They report that as the mice get older, the hallmarks of cognitive decline—poor memory, hearing deficits, and inflammatory responses in the brain—increase in mice lacking ADORA2B compared to control mice. The authors demonstrate that mice without functional ADORA2B in their red blood cells display larger numbers of activated microglia and macrophages, elevated pro-inflammatory cytokines, and restricted hypoxia-induced glycolytic gene expression to counteract the effects of low oxygen in the hippocampus, cortex, and cochlea.
Moreover, when young mice depleted of ADORA2B are subjected to a period of oxygen deprivation, their behavioral and physiological measures deteriorate to a greater extent than normal young mice subjected to a lack of oxygen.
In normal mice, a lack of adequate levels of oxygen trigger metabolic reprograming in red blood cells to increase oxygen release and delivery. One such metabolic reprogramming involves the enhanced expression of the enzyme, bisphosphoglycerate mutase (BPGM). The authors show mouse red blood cell ADORA2B and BPGM mRNA levels and BPGM activity reduce during normal aging. ADORA2B mutant mice are unable to make the hypoxia-induced metabolic shift, pinpointing the ADORA2B–BPGM axis is a key component for limiting age-related functional decline.
Based on these observations in mice, the authors conclude that aging in the brain is naturally kept in check by ADORA2B, which helps get oxygen to the brain. The next studies by the team will investigate whether ADORA2B protein levels naturally decrease with age and whether treatment with drugs that activate ADORA2B can reduce cognitive and auditory decline in normal mice.
