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



In mice missing a protective protein in their eyes, age-related macular degeneration-like symptoms appear.

The loss of the protein pigment epithelium-derived factor (PEDF), which safeguards retinal support cells, may hasten age-related alterations in the retina, infers a recent National Eye Institute (NEI) study in mice.

Given that the retina is the light-sensitive tissue at the back of the eye, age-related retinal illnesses such age-related macular degeneration (AMD) can result in blindness. The newly discovered facts might aid in the creation of drugs to halt AMD and other age-related disorders of the retina. In the International Journal of Molecular Sciences, the study was published. The National Institutes of Health includes NEI.

According to Patricia Becerra, Ph.D., head of the NEI's Section of Protein Structure and Function and senior author of the study, PEDF has been referred to as the "youth" protein because it is plentiful in juvenile retinas but drops with aging. This study demonstrated for the first time that the simple removal of PEDF induces a variety of gene alterations that resemble the aging process in the retina.

The retina is composed of layers of cells that cooperate to identify and decipher light signals, which the brain uses to produce vision. The photoreceptors that detect light in the retina are situated on top of a layer of supporting cells known as the retinal pigment epithelium (RPE). The RPE nourishes photoreceptors and recycles "outer segments," which wear out and shed their tips each time photoreceptors detect light.

Compared to wild-type mice, RPE from animals lacking Serpin1 collect more lipids. Using confocal microscopy, wild-type (upper) and Serpin1-null (lower) mice's RPE tissue was seen at extreme resolution. RPE tissue imaged on the left is magnified in the detailed photos on the right (dotted square area). The accumulating lipids are stained green, and the RPE cell borders are labeled red. 

If the RPE is unable to provide recycled parts of older outer segment tips back to photoreceptor cells, they lose the ability to develop new segments and eventually lose the ability to detect light. Additionally, photoreceptors degenerate without the nutrients that the RPE provides. Individuals with AMD or some types of retinal dystrophies have visual loss due to the senescence (aging) or death of RPE cells in the retina.

Research conducted in the past by Becerra's team and other teams has demonstrated that PEDF covers retinal cells, guarding against both cellular deterioration and aberrant blood vessel formation in the retina. The PEDF protein is produced and secreted by RPE cells. After then, the protein interacts to the PEDF-R receptor, which is also produced by RPE cells. When PEDF binds to PEDF-R, PEDF-R is stimulated to degrade lipid molecules, essential building blocks of cell membranes that surround photoreceptor outer segments and other cellular compartments.

A crucial step in the recycling of outer segments is this breakdown stage. Even though it is well known that the PEDF levels in the retina decrease with age, it was unclear whether this loss of PEDF was the actual cause of the age-related alterations in the retina or only a correlation with them.

Becerra and associates used a mouse strain lacking the PEDF gene to investigate the function of PEDF in the retina (Serpin1). The RPE cell nuclei were found to be bigger when the researchers looked at the cellular structure of the mouse model's retina. This discovery may be related to alterations in the way the cells' DNA is organized.

Additionally, four genes linked to aging and cellular senescence had been activated in the RPE cells, and the PEDF receptor was drastically below normal levels. Finally, the RPE layer of the retina had accumulated unprocessed lipids and other photoreceptor outer segment constituents. The aged retina has similar abnormalities in RPE metabolism and alterations in gene expression.

According to the study's primary author, Ivan Rebustini, Ph.D., a staff scientist at Becerra's lab, "one of the most surprising things was this reduction in the PEDF receptor on the surface of the RPE cells in the animal lacking the PEDF protein." The levels of PEDF-R and lipid metabolism in the RPE appear to be maintained by some form of feedback-loop involving PEDF.

These new findings imply that PEDF is playing a protective role that aids the retina in withstanding damage and aging-related wear and tear, even if the retinas of these PEDF-negative mice first appear normal.

According to Becerra, "We always questioned if loss of PEDF was driven by aging or was driving aging." This study suggests that the loss of PEDF is a cause of aging-related alterations in the retina, especially given the obvious connection to altered lipid metabolism and gene expression.

The National Eye Institute provided funding for the study.

By NIH/NATIONAL EYE INSTITUTE 

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