Scientists have discovered that losing a 'young' protein can lead to aging

The study found that loss of epithelial pigment-derived protein factor is a driver of age-related changes in the retina.

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

Loss of protein pigment-derived factor (PEDF), which protects retinal supporting cells, may promote age-related changes in the retina, according to a recent National Eye Institute (NEI) study in mice.

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

“People have called PEDF the 'youth' protein because it's abundant in the young retina, but it declines with age," said Patricia Becerra, PhD, chair of the division of protein structure and function at the National Institute of Medical Research and lead author of the study. "This study shows for the first time that a simple deletion of PEDF results in a range of genetic changes that mimic retinal aging."

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 light-sensitive photoreceptors in the retina are located at the top of a layer of supportive cells called the retinal pigment epithelium (RPE). When the photoreceptors detect light, the RPE feeds them and recycles their "outer parts," which burn off and cut their tips each time the receptors detect light.

Mouth Serpin1

RPEs from mice without Serpin1 accumulate more lipids than from wild-type mice. Ultra-resolution microscopy of tissues from wild-type (upper) and Serpin1-null (lower) RPE mice. Detailed images on the right are enlarged regions of RPE tissue depicted on the left (dotted square area). RPE cell borders are colored red and accumulated lipids are colored green. Credit: Ivan Ripostini, NEI

Photoreceptor cells lose the ability to create new segments and thus lose the ability to detect light if the RPE is unable to supply them with components recycled from the ends of the old outer segment. Without the nutrients provided by the RPE, the photoreceptors would die. Aging (senescence) or death of RPE cells in the retina leads to vision loss in people with AMD or certain types of retinal atrophy.

Previous research by Becerra and other groups has shown that PEDF protects retinal cells, protecting them from cell damage and abnormal retinal blood vessel growth. RPE cells produce and secrete the protein PEDF. 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, key components of cell membranes that surround the outer parts of photoreceptors and other cellular compartments.

This decomposition step is an essential part of the outer part recycling process. And while researchers knew that PEDF levels decline in the retina during the aging process, it was not clear whether the loss of PEDF was caused or simply associated with age-related changes in the retina.

To study the retina's role for PEDF, Becerra and colleagues studied a mouse model lacking the PEDF gene (Serpin1). The researchers examined the structure of retinal cells in a mouse model, and found that the nuclei of RPE cells enlarged, which may indicate changes in the way the cells are.[{”attribute=”">DNAispacked[{”attribute=””>DNAispacked

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.