Scientists Find That the Loss of a “Youth” Protein Could Drive Aging

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The loss of protein pigment epithelium-derived factor, the study found, is a driver of aging-related changes in the retina.

Mice without a protective protein in their eyes have symptoms similar to age-related macular degeneration.

According to a recent National Eye Institute (NEI) study in mice, loss of the protein pigment epithelial-derived factor (PEDF), which protects retinal support cells, can promote age-related changes in the retina.

Age-related retinal disorders, such as age-related macular degeneration (AMD), can cause blindness, as the retina is the light-sensitive tissue at the back of the eye. The new information could help develop drugs to stop AMD and other retinal aging conditions. The research is published in the International Journal of Molecular Sciences. NEI is part of the National Institutes of Health.

“People have called PEDF the ‘youth’ protein because it is abundant in young retinas, but it diminishes with age,” said Patricia Becerra, Ph.D., chief of NEI’s protein structure and function section and senior. author of the study. “This study showed for the first time that removing PEDF alone leads to a large number of gene changes that mimic aging in the retina.”

The retina is made up of layers of cells that work together to recognize and interpret light signals, which the brain uses to produce vision. The retina’s light-sensitive photoreceptors are located on top of a layer of support cells called the retinal pigment epithelium (RPE). When photoreceptors detect light, the RPE feeds them and recycles “outer segments,” which use up and lose their ends each time photoreceptors detect light.

Serpin1 Lipid

RPE from mice lacking Serpin1 accumulate more lipids than wild-type mice. Super-resolution confocal microscopy of RPE tissue from wild-type (upper) and Serpin1-null (lower) mice. Detailed images on the right are magnified areas of the RPE tissue depicted on the left (dotted square area). RPE cell borders are stained red and accumulated lipids are stained green. Credit: Ivan Rebustini, NEI

Photoreceptor cells lose the ability to create new segments and then lose the ability to detect light if the RPE is unable to return recycled components from older outer segment ends. And without the nutrients the RPE provides, photoreceptors die. Senescence (aging) or death of RPE cells in the retina causes vision loss in individuals with AMD or certain types of retinal dystrophies.

Previous research by Becerra’s team and other groups has shown that PEDF shields and protects retinal cells from both cell damage and abnormal blood vessel growth in the retina. RPE cells produce and secrete the PEDF protein. The protein then binds to its receptor, PEDF-R, which is also expressed by RPE cells. Binding by PEDF stimulates PEDF-R to break down lipid molecules, the major components of the cell membranes that enclose the outer photoreceptor segments and other cellular compartments.

This degradation step is an important part of the outer segment recycling process. And while researchers knew that PEDF levels in the retina drop during the aging process, it wasn’t clear whether this loss of PEDF was the cause of, or only related to, age-related changes in the retina.

To investigate the retinal role of PEDF, Becerra and colleagues studied a mouse model that lacks the PEDF gene (Serpin1). The researchers examined the cellular structure of the retina in the mouse model and found that the RPE cell nuclei were enlarged, which may indicate changes in the way the cells behave.[{” attribute=””>DNA is packed.

The RPE cells also had turned on four genes associated with aging and cellular senescence, and levels of the PEDF receptor were significantly below normal. Finally, unprocessed lipids and other photoreceptor outer segment components had accumulated in the RPE layer of the retina. Similar changes in gene expression and defects in RPE metabolism are found in the aging retina.

“One of the most striking things was this reduction in the PEDF receptor on the surface of the RPE cells in the mouse lacking the PEDF protein,” said the study’s lead author, Ivan Rebustini, Ph.D., a staff scientist in Becerra’s lab. “It seems there’s some sort of feedback-loop involving PEDF that maintains the levels of PEDF-R and lipid metabolism in the RPE.”

While at first glance, the retinas of these PEDF-negative mice appear normal, these new findings suggest that PEDF is playing a protective role that helps the retina weather trauma and aging-related wear and tear.

“We always wondered if loss of PEDF was driven by aging, or was driving aging,” said Becerra. “This study, especially with the clear link to altered lipid metabolism and gene expression, indicates the loss of PEDF is a driver of aging-related changes in the retina.”

Reference: “PEDF Deletion Induces Senescence and Defects in Phagocytosis in the RPE” by Ivan T. Rebustini, Susan E. Crawford and S. Patricia Becerra, 13 July 2022, International Journal of Molecular Sciences.
DOI: 10.3390/ijms23147745

The study was funded by the National Eye Institute.


The Valley Voice
The Valley Voicehttp://thevalleyvoice.org
Christopher Brito is a social media producer and trending writer for The Valley Voice, with a focus on sports and stories related to race and culture.

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