International Journal of Molecular Sciences 2025, 26, 5773
Autophagy dysfunction characterizes several retinal disorders. This is mostly evident in age-related macular degeneration (AMD). The involvement of autophagy in AMD is documented in vitro and in vivo experiments, and it is strongly suggested by clinical findings in humans. The present man-
uscript provides an overview of the specific types of autophagy, which prevail in the ret-
ina and their alterations in retinal degeneration with an emphasis on AMD.
An extended session of the manuscript analyzes the connection between altered autophagy and cell pathology within retinal pigment epithelium, as well as the site and structure of extracellular aggregates named drusen. The significance of the drusen in relation to visual function is discussed in the light of the role of autophagy in regulating key steps of phototransduction.
Some reports indicate that autophagy activation may be induced either with specific chemical compounds (drugs and/or phytochemicals) or physical agents such as specific wavelengths and even sound pulses. Novel approaches based on gene therapy may be designed to be tailored to each patient’s disease phenotype. This includes the conditional expression of specific autophagy genes within RPE cells in the course of retinal degeneration. It is intriguing that autophagy genes may be specifically induced by selective wave-lengths. For instance, amber light, which is a wavelength of roughly 590 nm, is a powerful autophagy inducer, and it has been suggested, along with red and infra-red light, in specific treatment protocols known as photobiomodulation (PBM) in human patients. These treatments are grounded in solid experimental findings. Amber light activates multiple autophagy steps and increases autophagy-related proteins.
It is demonstrated that amber light interacts with the complex leupeptin/NH4Cl, which produces a baseline inhibition of lysosomal clearance. The interaction of amber light removes such an inhibition, thus releasing autophagy in a quick time frame.
As a consequence, several stagnant, potentially toxic substrates are cleared by pulses of amber light, which may counteract the course of retinal degeneration. Similar to amber light, red light exerts a powerful antioxidant effect, which may lead to the remove of key detrimental proteins, lipids and sugars.
The powerful effects of phytochemicals as autophagy activators have generated a number of clinical reports suggesting the potential use of these plant-derived agents to treat AMD.
Several compounds were recently suggested to produce a significant therapeutic effect in AMD. Among them, a special emphasis was placed on naturally occurring molecules derived from plant extracts and named phytochemicals. These were suggested based on empirical evidence and the experimental data showing a strong antioxidant effect along with the ability to act as powerful autophagy inducers and stimulate the bio-genesis of mitochondria.
These novel therapeutic options encompass the main mechanisms known to be involved in AMD. The efficacy of phytochemicals in experimental settings is based both on the direct antioxidant and pro-autophagic effects in the metabolism of the cell and on altering gene expression through epigenetic effects, which promote the synthesis of antioxidant and pro-autophagy proteins.
These concepts led to challenging phytochemicals at the clinical and experimental level in several retinal disorders, even beyond AMD, including systemic disease affecting retinal integrity, such as diabetes.
The powerful antioxidant effects of phytochemicals suggest that the retinal site where blue light produces most oxidative damage, which corresponds to the RPE and the inner choroid/outer retinal border, is supposed to benefit from most of their therapeutic effects. This is why most of the data concerning the therapeutic potential of phytochemicals are related to AMD. This is strengthened by the findings that these compounds showed additional effects, being able to suppress the genesis of new vessels, which is critical in the development of wet AMD.
These concepts led to challenging phytochemicals at the clinical and experimental level in several retinal disorders, even beyond AMD, including systemic disease affecting retinal integrity, such as diabetes. The powerful antioxidant effects of phytochemicals suggest that the retinal site where blue light produces most oxidative damage, which corresponds to the RPE and the inner choroid/outer retinal border, is supposed to benefit from most of their therapeutic effects. This is why most of the data concerning the therapeutic potential of phytochemicals are related to AMD. This is strengthened by the findings that these compounds showed additional effects, being able to suppress the genesis of new vessels, which is critical in the development of wet AMD.