Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming.

Qingfen Qiang,George Edwards Iii,Travis Nemkov,Julie A Reisz,Yujin Zhang,Changhan Chen,Hong Sun,Yang Xia,Anren Song,Fred A Perreira,Y Edward Wen,Ying Cui,Hong Liu,Rodney E Kellems,Angelo D’Alessandro,Jeanne M Manalo,Alexander Q Wen,Claudio Soto,Judith Campisi

doi:10.1371/journal.pbio.3001239

Abstract

Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline. Here, we report that loss of murine erythrocyte–specific ADORA2B (eAdora2b−/−) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b−/− mice. Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging. Overall, we determined that erythrocyte ADORA2B–BPGM axis is a key component for anti-aging and anti-age–related functional decline.

Highlights

With an increasing trend in longevity worldwide over the past 2 centuries, the mean age of the population is rising rapidly
In keeping with our previous studies on high-altitude hypoxia, we report that this signaling axis promotes erythrocyte hypoxic metabolic reprogramming to favor glycolysis and 2,3-BPG production, which promote HGB O2 off-loading and counteract hypoxia
Mimicking eAdora2b−/− mice, we further discovered that down-regulation of BPG mutase activity in red blood cell (RBC) is a natural process during normal aging in WT mice

Summary

Introduction

With an increasing trend in longevity worldwide over the past 2 centuries, the mean age of the population is rising rapidly. Age-related functional decline profoundly affects elderly’s ability to perform daily living activities independently and are highly related to age-related diseases (ARDs), resulting in a heavy burden on modern society with rising healthcare expenditures [1,2]. Age-related functional decline such as decline of cognitive and hearing function (hearing loss [HL]) is the most common, least understood, and poorly treated age-related functional decline [3,4]. Substantial research in age-related decline has largely focused on genetics and gene expression changes in end organs. Gene expression changes in end organs do not fully explain how cognition and hearing decline develop during aging. Here, we sought to define the cellular, molecular, and metabolic basis underlying age-related decline with a goal to develop novel approaches to define aging and early onset of age-related decline and ameliorate the progression of age-related decline

Methods

Results

Conclusion