Researchers from the National Institutes of Health (NIH) uncovered the role of pigment epithelium-derived factor (PEDF) by studying a mouse model that lacks the gene for the protein. Deletion of the Serpinf1 gene turned on four genes associated with aging and cellular senescence and a reduction in levels of the PEDF receptor on the surface of retinal pigment epithelium (RPE) cells (International Journal of Molecular Sciences, July 9, 2022).

An earlier study at the lab of Patricia Becerra, PhD, senior author of the new paper and chief of the National Eye Institute's Section of Protein Structure and Function, showed PEDF protects retinal cells by preventing damage and abnormal blood vessel growth. RPE cells secrete PEDF, which then binds to its receptor to trigger the breakdown of lipids and drive the outer segment recycling process. Other researchers have shown PEDF levels decline with age.

"We always wondered if loss of PEDF was driven by aging, or was driving aging," said Becerra in a July 18 statement. "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."

To understand if PEDF causes, or is just correlated to, age-related changes in the retina, Becerra and her collaborators studied mice that lacked the gene needed to make the protein. Examinations of the cellular structure of the retina in the mouse model shed light on the role of PEDF.

The cell nuclei of the RPE cells were enlarged, possibly because of changes in the packing of DNA, and four genes associated with aging and cellular senescence were turned on. The turning on of the genes increased levels of histone H2AX protein, p21 protein, and β-galactosidase, all of which have previously been associated with senescence.

Other changes included the accumulation of unprocessed lipids and other photoreceptor outer segment components in the RPE layer of the retina and a significant fall in levels of the PEDF receptor. The NIH team highlighted the change in levels of the receptor as particularly interesting.

"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 Ivan Rebustini, PhD, the study's lead author and 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."

Collectively, the findings suggest loss of PEDF over time may drive age-related changes in the retina and, by extension, the pathogenesis of some of the eye diseases seen in older people. The protective role of PEDF points to potential ways to prevent diseases such as age-related macular degeneration.

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