Erythrocytes, the red blood cells that carry oxygen around the body, are not often the topic of the day in aging research. Red blood cells are made by the hematopoietic cells that reside in the bone marrow, and a great deal of effort is spent on studying the aging of the hematopoietic system. This research is largely focused on changes in the production and behavior of white blood cells and consequent harms to the function of the immune system, however.
In today's open access paper, researchers report on an analysis of the biochemistry of erythrocytes in a study population that included a group of long-lived individuals over the age of 90. The long-lived individuals exhibited a more youthful erythrocyte metabolism. The researchers propose mechanisms linking this to improved function throughout the body, but as is always the case in aging and cell biochemistry, the challenge lies in determine which of the many options on the table is actually the most important. The only way to find out in certainty is to fix that one mechanism in isolation and observe the outcomes.
Longevity Humans Have Youthful Erythrocyte Function and Metabolic Signatures
Individuals who live past the age of 90 are defined as longevity individuals and are examples of highly successful aging, often referred to as increased healthspan. These individuals are equipped with a better capability to counteract chronic tissue hypoxia, inflammation, and oxidative stress and thus a lower susceptibility to age-related diseases including cardiovascular disease and Alzheimer's disease. Such an advantage makes longevity individuals an ideal population for the investigation of cellular and molecular mechanisms underlying better aging with the ultimate goal of promoting lifespan and healthspan and decreasing the burden of degenerative diseases with important social and economic benefits.
We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity individual from the elderly individual. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids.
Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward the Rapoport-Luebering Shunt pathway to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals.
As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function.
View the full article at FightAging
