Scientists have discovered that the loss of the ‘youth’ protein can lead to aging

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

Mice that did not have a protective protein in their eyes had symptoms similar to age-related macular degeneration.

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

Age-related retinal diseases, such as age-related macular degeneration (AMD), can cause blindness because 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 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 is abundant in the young retina, but declines during aging,” said Patricia Becerra, PhD, chair of the division of protein structure and function at the National Institute of Statistics and lead author of the study. “This study shows for the first time that simply removing PEDF leads to a set of genetic 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 light-sensing photoreceptors in the retina are located on top of a layer of supporting cells called the retinal pigment epithelium (RPE). When the photoreceptors detect light, the RPE feeds them and recycles the “outer sections”, which are used up and drop tips each time the photoreceptors detect light.

Serpin1 fat

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

Photoreceptor cells lose the ability to create new segments and subsequently lose the ability to detect light if the RPE is unable to supply the recycled components to the old outer segment tips again. Without the nutrients provided by the RPE, the photoreceptors would die. Senescence (senescence) or death of RPE cells in the retina causes vision loss in individuals with AMD or certain types of retinal atrophy.

Previous research by Becerra and other groups showed that PEDF protects retinal cells, protecting them from cellular 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 segments of photoreceptors and other cellular compartments.

This breakdown step is an essential part of the exterior recycling process. While researchers know that PEDF levels decrease in the retina during the aging process, it was not clear whether this loss of PEDF causes, or only is 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 cellular structure of the retina in a rat model, and found that the nuclei of the RPE cell were enlarged, which may indicate changes in how the cells function.

DNA, or deoxyribonucleic acid, is a molecule consisting of two long strands of nucleotides that coil around each other to form a double helix. It is the genetic material in humans and almost all other living things that carries the genetic instructions for development, function, growth and reproduction. Almost every cell in the human body has the same DNA. Most of the DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).

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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.

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