Selenoproteins: The fountain of youth?

Osaka, Japan – Many foods are often advertised for their antioxidant properties. Antioxidants counteract what are known as reactive oxygen species (ROS), chemically reactive molecules that can disrupt the normal functions of lipids, proteins, and DNA in human cells. Accumulation of ROS contributes to the development of age-related diseases, including cancer, emphasizing the importance of keeping the oxidant/antioxidant balance in check. In a recent article published in Blood, researchers from Osaka University and other institutions in Japan describe the key antioxidant role of molecules called selenoproteins and how disrupting their production can affect various cell types and hematopoiesis, which is the production of blood cells.

Human cells have 25 different selenoproteins. These antioxidant enzymes help convert dangerous ROS, such as lipid peroxides, into a safer form. Buildup of lipid peroxides can affect critical cells called hematopoietic stem cells (HSCs), a phenomenon observed in aging diseases.  

“We observed that aged HSCs frequently display impaired selenoprotein synthesis, but it was unclear how this could contribute to cell aging and if it could be reversed,” says Yumi Aoyama, co-lead author of the study. “We hypothesized that selenoproteins are a critical part of the antioxidant system that fights age-related changes in HSCs.”

To investigate this, the team used a mouse model with a certain gene knocked out, leading to disrupted selenoprotein production. They then examined how this affected different cell types, finding that the knockout negatively impacted HSCs and immune cells with B cell lineage (types of white blood cells) but had few effects on myeloid cells (a different family of immune cells).

“The most notable results of the knockout included B lymphocytopenia, which means there were fewer B cells than expected,” explains Hiromi Yamazaki, the other co-lead author. “The HSCs also had a limited ability to self-renew.”

These observations, along with increased expression levels of aging-related genes in these cell types, were consistent with what is frequently seen in age-related diseases. Further investigation indicated that the effects were driven by lipid peroxidation. Additionally, experiments with cells from the mouse model revealed that the disruption in selenoprotein synthesis could support B progenitors switching to the myeloid cell family.

“Our data suggest clear lineage-specific effects when the protective role of selenoproteins is lost,” says Daichi Inoue, senior author of the study. “These enzymes are critical for counteracting the lipid peroxides that accumulate during the aging process.”

The researchers also investigated the mechanisms underlying hematopoiesis with a feeding experiment on the knockout mice. They revealed that dietary Vitamin E can protect hematopoiesis and has the ability to repair impaired B cell differentiation.

This study shows the antioxidant functions of selenoproteins and how they ensure proper HSC self-renewal and B cell-lineage immune cell maturation. Because the knockout mice displayed similar phenotypes to aged normal mice, the findings demonstrate how potentially addressing selenoprotein production-related issues could help fight age-related diseases.

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The article, “Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature Lineages,” was published in Blood at DOI: https://doi.org/10.1182/blood.2024025402

About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en