This Research Insight covers a recent publication from the Apte Lab. Here, we highlight how Ryo Terao, MD, PhD, Mitsukuni Yoshida, MD, PhD, and colleagues explore how excessive cholesterol accumulation in the retina contributes to the degeneration of light-sensing photoreceptors, leading to vision loss. The evidence presented in this study suggests that targeting a process called cellular senescence could open new doors for treating age-related eye diseases, such as macular degeneration.
In their recent paper published in Investigative Ophthalmology & Visual Science, scientists in the lab of Rajendra Apte, MD, PhD, professor of ophthalmology at WashU Medicine, demonstrate that excessive cholesterol accumulation can cause cellular senescence in photoreceptors and visual decline.
Here, Ryo Terao, MD, PhD and Mitsukuni Yoshida, MD, PhD—postdoctoral fellows in the Apte Lab—and colleagues disrupted cholesterol removal from photoreceptors and show that its buildup induces cellular senescence.
They further show that targeting senescent cells might be a viable therapeutic approach to improve visual function in disease.
Cellular senescence: A response to cellular stress and damage
As we age, our cells face many forms of stress, from DNA damage to waste buildup and cellular “wear and tear.” In response, some cells enter a state called senescence, in which they stop dividing and start releasing inflammatory signals that can harm neighboring cells and tissues. This process is increasingly recognized as a contributor to aging and age-related disease, including age-related macular degeneration (AMD)—a leading cause of vision loss in older adults. While aging is the strongest risk factor for developing AMD, dysregulated lipid metabolism has been strongly linked to AMD risk in patients and connected to AMD-like vision loss in mice.
Cholesterol and the aging retina
Lipids—such as cholesterol—are essential for maintaining healthy cell membranes. However, with aging, cholesterol and other lipids can accumulate pathologically in cells and contribute to the development of age-related diseases. In the retina, lipid-rich deposits—such as drusen and drusenoid deposits—accumulate beneath the retina and in the retinal pigment epithelium (RPE).
These fatty deposits are one of the hallmark features of AMD. Despite the pervasiveness of lipid deposits in AMD and strong associations between dysregulated lipid metabolism and AMD, the precise role cholesterol plays in the disease progression remains unclear.
Previously, the Apte Lab showed that excess cholesterol in photoreceptors leads to photoreceptor degeneration and lipid accumulation in the RPE. In this new study, Terao and colleagues asked whether cholesterol overload could trigger cellular senescence in the photoreceptor cells and drive vision loss.
Linking cholesterol buildup to senescence and vision loss
To investigate, Terao and colleagues used a mouse model in which key cholesterol-removing genes (Abca1 and Abcg1) were deleted specifically in rod photoreceptors. When these mice were fed a high-fat diet, cholesterol built up in the retina, resulting in photoreceptor degeneration and lipid accumulation in the RPE, as previously shown.
Importantly, Terao and colleagues found elevated levels of senescence markers (p16 and p21) in the photoreceptors and inflammatory cytokines (including Tnf-α) in the RPE/choroid complex.
Together, these elevated markers indicated that cholesterol accumulation in the photoreceptors had induced a state of senescence in the retina.
Terao and colleagues observed similar responses in photoreceptor cell lines. As cholesterol levels increased, the photoreceptor cell line showed increased expression of p16, p21, and Tnf-α. The cell line also showed decreased expression of a proliferation marker, Ki67, further confirming the cells had entered the non-dividing, senescent state.
Can clearing senescent cells preserve vision?
The most exciting part of the study came when Terao and colleagues tested whether removing senescent cells could reverse visual dysfunction. The team treated genetically modified mice to selectively kill senescent cells expressing p16. Selectively removing the p16+ senescent cells preserved the architecture of the retina, limited lipid accumulation, and improved the retina’s ability to detect light at low light levels without affecting other parts of the mouse’s body.
Finally, Terao and colleagues tested a combination of senolytic drugs—dasatinib and quercetin (D+Q)—that have been used to treat age-related conditions in humans by eliminating senescent cells.
The D+Q drug cocktail likewise improved visual function and reduced hallmark features of AMD.
This work shines a light on how cholesterol buildup in the retina can drive retinal degeneration by triggering photoreceptor senescence. More importantly, it shows that removing these damaged or stressed cells could help restore visual function. As the field of senescence-targeted therapy continues to grow, this research offers hope for new ways to treat age-related eye diseases, such as AMD.