Turning Back Time

It is no secret that eyesight tends to deteriorate with age, but could the decline in secretion of the “youth” protein by the retinal pigment epithelium be the cause? We speak to Patricia Becerra, senior author of a recent study from the National Institutes of Health that aimed to answer this question.

How did  the study take shape?
 

Our research team has always wondered if loss of the pigment epithelium-derived factor (PEDF) protein was driven by aging or was driving aging in the eye.

PEDF protects retinal cells against several types of insults known to trigger retinopathies, such as those of photoreceptor degeneration, including AMD and retinitis pigmentosa. PEDF is also colloquially called the “youth” protein because of its abundance in young skin, lung, and retinas, and the fact that it declines with age, occurring with senescence in skin and lung epithelial cells. PEDF also declines in animal models of retinal degeneration. PEDF for photoreceptors is produced and secreted by the retinal pigment epithelium (RPE).

In patients with AMD or certain types of retinal dystrophies, senescence or death of RPE cells leads to vision loss. To address questions of whether PEDF may contribute to aging prevention in the RPE, we used a mouse model lacking the PEDF gene (Serpinf1).

And what were the key findings?
 

We established that PEDF loss is a cause of senescence-like changes in RPE (1) and highlight PEDF as a regulatory protein of age-related changes.

We found that the deletion of the Serpinf1 gene, which encodes PEDF, increases senescence-associated gene expression. Serpinf1 deletion also increases the senescence-associated β-galactosidase activity in the RPE. The RPE cellular morphology shows enlarged cell nuclei and an increase in the nucleoli number, implying chromatin reorganization when PEDF is missing. Additionally, RPE cells without PEDF have lower levels of unprocessed lipids and photoreceptor outer segments components accumulated in the RPE – likely due to a decline in phagocytic function. Similar changes and defects in RPE metabolism are found in aging RPE.

What are the potential implications of your research?
 

The findings point to applications of PEDF and derivatives as potential therapeutics to counteract the damaging effects of PEDF decline and depletion. However, what may work in mouse models may not translate to humans. One point to consider is that the lack of a macula in the mouse retina means that parallels to some conditions, such as AMD, are not as clear as they might be in species with that structure.

Nevertheless, this is the first time that a mouse without PEDF has been used to study senescence and phagocytosis of RPE. Our study provides evidence of the importance of PEDF signaling in age-related disease processes. The decline in the PEDF receptor, PEDF-R, on the surface of RPE cells in the mouse lacking PEDF implies involvement of the PEDF–PEDF-R axis in lipid metabolism. Furthermore, we postulate that PEDF is required to enhance the activity of PEDF-R in the RPE to promote digestion of the phagocytosed photoreceptor outer segments. Therefore, the decline or lack of PEDF can negatively affect the renewal of photoreceptor outer segments – which is vital for the process of vision.

The mouse without PEDF can be used to provide mechanistic insight studies of senescence and aging, and help delineate new signaling pathways involving phagocytosis that impact lipid and visual pigment recycling in ocular pathologies.

Where next?
 

The importance of the PEDF protein is clear, and we now know that its levels decline with age and degenerative diseases; however, we still do not know what causes its loss. Other factors that may be necessary for reducing or reversing age-related damage also need to be identified. Though the retina contains a high content of lipids, the complex role of lipid metabolism in maintaining a healthy retina, especially photoreceptors, has not been fully delineated. Lipid accumulation caused by PEDF loss associates this factor with lipid metabolism in the retina. These points raise interesting questions that could be investigated in future projects. Our lab will continue exploring ways to use PEDF and PEDF-derivatives or mimics as therapeutics for humans.