Researchers from the National Eye Institute (NEI) report they have discovered that the loss of the protein pigment epithelium-derived factor (PEDF) may drive age-related changes in the retina. PEDF protects human retinal pigment epithelial (RPE) cells against oxidative stress. Their new findings in mice may pave the way for new therapies to prevent aging-associated diseases of the retina such as age-related macular degeneration (AMD).

The findings are published in the International Journal of Molecular Sciences in a paper titled, “PEDF Deletion Induces Senescence and Defects in Phagocytosis in the RPE,” and led by Patricia Becerra, PhD, chief of NEI’s Section of Protein Structure and Function and senior author of the study.

“The RPE expresses the Serpinf1 gene to produce PEDF, a retinoprotective protein that is downregulated with cell senescence, aging, and retinal degenerations,” wrote the researchers. “We determined the expression of senescence-associated genes in the RPE of 3-month-old mice that lack the Serpinf1 gene and found that Serpinf1 deletion induced H2ax for histone H2AX protein, Cdkn1a for p21 protein, and Glb1 gene for β-galactosidase.”

“People have called PEDF the ‘youth’ protein because it is abundant in young retinas, but it declines during aging,” said Becerra. “This study showed for the first time that just removing PEDF leads to a host of gene changes that mimic aging in the retina.”

To examine the retinal role of PEDF, the researchers studied a mouse model that lacks the PEDF gene (Serpin1). The researchers examined the cellular structure of the retina in the mouse model, finding that the RPE cell nuclei were enlarged, which may indicate changes in how the cells’ DNA is packed.

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.

“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, PhD, 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.”

“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.”

“Our findings establish PEDF loss as a cause of senescence-like changes in the RPE, highlighting PEDF as both a retinoprotective and a regulatory protein of aging-like changes associated with defective degradation of the photoreceptor outer segment in the RPE,” concluded the researchers.