A new study has demonstrated that increasing the expression of a single gene was enough to reverse age-related visual decline in the eyes of old mice.
Elongation of Very Long Chain Fatty Acids Protein 2 (ELOVL2) is both a bit of a tongue twister and a known aging biomarker. The results of a new study from researchers at the University of California San Diego School of Medicine suggest that the ELOVL2 gene plays a pivotal role in both the functional and anatomical aging of the retinas of mice and may also have relevance to human age-related eye conditions.
The ELOVL2 gene, present in both mice and humans, is involved in the production of the long-chain fatty acids omega-3 and omega-6, which are important for energy metabolism, inflammatory response, and maintaining cell membrane structure. ELOVL2 regulates docosahexaenoic acid (DHA), an omega-3 fatty acid that is one of the primary structural components of the brain, skin, and retina.
DHA has been linked with various beneficial effects, and in the photoreceptors of the eyes, it promotes healthy retinal function and helps to protect the eyes from damage caused by bright light and oxidative stress.
Reversing visual decline
The researchers discovered that an age-related decline in ELOVL2 gene expression was linked to the increased DNA methylation of the gene promoter. In simple terms, methylation is a process in which groups of carbon and hydrogen atoms move from one substance to another. When methylation occurs in DNA, it reduces or even silences the expression of a gene.
In fact, age-related changes to methylation are so predictable that researchers can actually examine an individual’s genome, study that person’s genes, and use the placement and amounts of methylation to accurately determine how biologically old that person is. Methylation changes are part of epigenetic alterations, one of the hallmarks of aging.
The research team wanted to find out what would happen if they reversed the methylation of the ELOVL2 promoter, and when they did, they found that the visual decline of aged mice was reversed.
Methylation of the regulatory region of the elongation of very‐long‐chain fatty acids‐like 2 (ELOVL2) gene, an enzyme involved in elongation of long‐chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age‐associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age‐related eye diseases. We show that an age‐related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5‐Aza‐2’‐deoxycytidine (5‐Aza‐dc) leads to increased Elovl2 expression and rescue of age‐related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2‐specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well‐established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age‐related eye diseases.
The researchers have essentially demonstrated that ELOVL2 plays a central regulatory role in the aging of the mouse retina and paves the way for developing therapies that might reverse age-related visual decline. This data adds further support to the proposal that epigenetic alterations and their influence on gene expression are likely a primary driver of aging. It also opens the door for therapies that reverse those changes, including partial cellular reprogramming, with which scientists are finding out how to hit the reset button on aging cells.
 Chen, D., Chao, D. L., Rocha, L., Kolar, M., Nguyen Huu, V. A., Krawczyk, M., … & Ross, K. D. (2019). The Lipid Elongation Enzyme ELOVL2 is a molecular regulator of aging in the retina. Aging Cell, e13100.