Esha Mukherjee, Amity University Noida
The age-related functional decline has a significant impact on the elderly’s ability to do daily living activities independently and is strongly linked to age-related disorders (ARDs), putting a strain on modern society and driving up healthcare costs. The most prevalent, least understood, and poorly treated age-related functional decline is cognitive and hearing function decrease. At the moment, much of the research on the age-related decline has been on genetics and changes in gene expression in end organs.
However, changes in gene expression in end organs do not entirely explain how cognition and hearing deteriorate as people age. Thus, the purpose of this study is to define the cellular, molecular, and metabolic foundation of age-related decline to develop novel techniques to characterize aging and the early onset of age-related decline, as well as to slow down the progression of age-related decline.
Researcher Qiang and colleagues established a relationship between a protein in red blood cells and age-related deterioration in cognitive performance in their research. The study, which was published on June 17th, 2021 in the open-access journal PLOS Biology, indicates that depriving mouse blood of the so called anti-aging protein ADORA2B (adenosine A2B receptor) causes faster memory deficits, delays in auditory processing, and higher inflammation in the brain.
Multiple assays were performed to evaluate learning and memory (novel object recognition [NOR] and the Barnes Maze test [BM]) as well as hearing (auditory brainstem response [ABR]) in controls and Adora2bf/f/EpoR-Cre+ mice (eAdora2b/) with erythrocyte-specific ablation of the Adora2b gene. The mice were all bred in a normoxic environment. First, as compared to Adora2bf/f littermate controls, mice lacking erythrocyte anti-aging protein ADORA2B showed no evident disadvantages in survival or fertility.
At the functional, cognitive, auditory, structural, and cellular levels, erythrocyte ADORA2B is a previously unknown purinergic component that counteracts aging. Functionally, It showed that genetic ablation of erythrocyte-specific ADORA2B (eAdora2b/) causes early onset of aging. It also causes cognitive and cochlear functional decline as well as a profound inflammatory response in the CTX, HIP, and cochlea at a young age. This is often accompanied by elevated activation of the cells involved in innate immunity and increased cytokines in the HIP, CTX, and cochlea.
It was showed that hypoxia accelerates the aging process and that erythrocyte ADORA2B signaling has a previously unappreciated positive effect in preventing hypoxia-exacerbated aging by maintaining cognitive and cochlear function and reducing hypoxia-induced cerebral and cochlear inflammation. We discovered that aging and hypoxia activate the erythrocyte-specific ADORA2B–AMPK–BPGM signaling pathway, which plays a role in cognitive and cochlear function deterioration and inflammatory response.
The signaling axis promotes hypoxic metabolic reprogramming in erythrocytes, favoring glycolysis and 2,3-BPG (2,3-Bisphosphoglyceric acid) synthesis, which enhances HGB O2 off-loading and counteracts hypoxia. It was identified that the down-regulation of BPG mutase activity in red blood cells (RBCs) is a natural process during normal aging in WT mice by mimicking eAdora2b/ animals. These observations lead to the discovery that Adora2b and BPGM mRNA levels in CD71+ erythroblasts in WT (wild-type) elderly mice are already considerably lower than in young mice.
Reduced erythroblast ADORA2B–BPGM gene expression and erythrocyte BPGM activation leads to chronic hypoxia, attenuated hypoxia-induced adaptive responses such as decreased glycolytic gene expression and pro-inflammatory response, and thus the progression of memory and hearing decline during normal aging.
Injection of young mouse plasma, heterochronic parabiosis, and transplantation of young bone marrow have all been shown to rejuvenate and increase cognitive and memory function in elderly animals. Specific enzymes, chemokines, and other substances found in youthful blood have been attributed to rejuvenation. The main component of blood, however, is erythrocytes, which have the unique duty of delivering oxygen to every cell in our body.
These studies support the work presented here that erythrocytes have a significant role to counteract aging and that hypoxia is an underestimated key factor promoting aging and function decline. However, the so-called anti-aging protein ADORA2B needs to be analysed and studied further to confirm about its effects in animals other than mice, such as humans.
Also read: Purdue Biosensor makes images of tissues and organs
REFERENCES:
- Qiang, Q., Manalo, J. M., Sun, H., Zhang, Y., Song, A., Wen, A. Q., Wen, Y. E., Chen, C., Liu, H., Cui, Y., Nemkov, T., Reisz, J. A., Edwards Iii, G., Perreira, F. A., Kellems, R. E., Soto, C., D’Alessandro, A., & Xia, Y. (2021). Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming. PLoS biology, 19(6), e3001239. https://doi.org/10.1371/journal.pbio.3001239
- Fong J. H. (2019). Disability incidence and functional decline among older adults with major chronic diseases. BMC geriatrics, 19(1), 323. https://doi.org/10.1186/s12877-019-1348-z
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