MTR4 reduced signs of vascular aging in mice, and increased expression of the related gene mtr-4 extended lifespan in worms

MTR4 reduced signs of vascular aging in mice, and increased expression of the related gene mtr-4 extended lifespan in worms

In a paper in Aging Cell published on October 16, the authors described MTR4, a protein involved in processing and degrading RNA in the nucleus, as a regulator of endothelial aging. They studied it in human cells, mouse endothelium, and the roundworm C. elegans, with each model addressing a different question.

The endothelium lines the inside of blood vessels and regulates vascular tone, permeability, and inflammatory signaling. MTR4 levels declined in human endothelial cells after repeated cell divisions, oxidative stress, or DNA damage. MTR4 levels remained unchanged in cells that had stopped dividing because of close contact with neighboring cells.

Senescence is a stable arrest of cell division accompanied by changes in cell function and the release of inflammatory signals. Suppressing MTR4 in dividing cells increased signs of senescence, while raising MTR4 levels in cells that were already senescent reduced those signs. These interventions showed that MTR4 contributes to the development of cellular features of aging.

Senescence increases levels of SYVN1, an enzyme that attaches a molecular tag to proteins to mark them for degradation. SYVN1 tags MTR4, which is then degraded by the cell's protein degradation machinery. MTR4 binds BUB3 and maintains its levels; BUB3 works with BUBR1 to help cells distribute chromosomes correctly during division. Suppressing MTR4 reduced BUB3 and BUBR1 levels and increased signs of DNA damage. Signs of senescence remained high with an MTR4 variant unable to bind BUB3.

In old mice, the authors genetically increased Mtr4 expression specifically in the endothelium. In groups of 4–6 animals, depending on the measurement, blood flow velocity, aortic diameter, markers of cellular senescence in the aorta and several organs, and serum levels of inflammatory signals shifted toward the values seen in young control animals. In young mice, suppressing Mtr4 reduced movement and exploratory behavior, altered vascular measurements, and increased markers of cellular senescence.

The authors measured lifespan in a separate model. Transgenic overexpression of mtr-4 in C. elegans, a genetic intervention that increases gene expression, extended the worms' lifespan, preserved movement and pharyngeal function, and increased survival under heat and oxidative stress. The cell experiments explain the mechanism, the mouse experiments connect it to vascular function and age-related changes, and the worm experiments provide a separate finding on whole-organism lifespan.