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Scientists find loss of ‘young’ protein may lead to aging

The study found that the loss of the protein pigment epithelium-derived factor is a driver of retinal ageing-related changes.

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

Loss of the protein pigment epithelium-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 may help develop drugs to stop AMD and other retinal aging conditions.The study was published in international journal of molecular sciences. NEI is part of the National Institutes of Health.

“PEDF is referred to as a ‘youth’ protein because it is abundant in the young retina, but declines during aging,” said Patricia Becerra, PhD, head of the NEI’s Division of Protein Structure and Function and the study’s senior author. “This study shows for the first time that removing PEDF alone causes a series of genetic changes that mimic retinal aging.”

The retina is made up of layers of cells that work together to recognize and interpret the light signals that the brain uses to produce vision. The retina’s photoreceptors are located on top of a layer of supporting cells called the retinal pigment epithelium (RPE). When photoreceptors detect light, the RPE nourishes them and recycles “outer segments” that are depleted each time the photoreceptors detect light, and their tips fall off.

Serpin1 lipid

RPE from mice without Serpin1 accumulated more lipids than wild-type mice. Super-resolution confocal microscopy of RPE tissue from wild-type (top) and Serpin1-null (bottom) mice. The detailed image on the right is a magnified area of ​​the RPE tissue imaged on the left (dotted square area). RPE cell borders are stained red and accumulated lipids are stained green. Credit: Ivan Rebustini, NEI

If the RPE fails to supply the recycled components of the old outer segment tip back to the photoreceptor cells, the photoreceptor cells lose their ability to create new segments and subsequently lose their ability to detect light. Without the nutrients provided by the RPE, the photoreceptors die. Senescence (aging) or death of RPE cells in the retina can lead to vision loss in people with AMD or some types of retinal dystrophies.

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

This decomposition step is a critical part of the outer segment recovery process. While researchers have known that PEDF levels in the retina decline during aging, it was unclear whether this loss of PEDF leads to age-related changes in the retina, or just age-related changes.

To examine the effects of PEDF on the retina, Becerra and colleagues studied a mouse model lacking the PEDF gene (Serpin1). The researchers examined the cellular structure of the retina in a mouse model and found that the RPE cells had enlarged nuclei, which may indicate changes in the cellularity of the cells.

DNA or deoxyribonucleic acid is a molecule made up of two long chains of nucleotides that twist around each other to form a double helix. It is the genetic material in humans and almost all other organisms, with genetic instructions for development, function, growth and reproduction. Almost every cell in the human body has the same DNA. Most DNA is located in the nucleus (called nuclear DNA), but small amounts of DNA can also be found in mitochondria (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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