In today's open access research materials, the authors report that upregulation of the gene expression of an identified marker of aging, ELOVL2, can improve visual function in aging mice. Normally, expression of ELOVL2 declines with age, and consequent effects on visual function may involve the role of ELOVL2 in production of long-chain omega-3 and omega-6 polyunsaturated acids. These metabolites are in high demand in retinal cells, and lowered levels may well cause a sizable fraction of age-related dysfunction.
Any discussion of this change in ELOVL2 expression and visual function is interesting in the context of why degenerative aging takes place. It is clearly the case that considerable dysregulation of cellular metabolism takes place with age. The proximate cause of this degeneration of function is changes in the epigenetic regulation of gene expression, the pace of production of various proteins essential to cell function. In near all cases it is quite obscure as to why exactly these epigenetic changes take place - researchers are far more interested in identifying changes than in the much more arduous work of understanding the full context of any given change. The underlying damage of aging is well catalogued, such as in the SENS view of aging, but linking this damage through a long chain of downstream consequences to specific age-related functional consequences is a sizable project, still in its very earliest stages.
A lengthy-named gene called Elongation of Very Long Chain Fatty Acids Protein 2 or ELOVL2 is an established biomarker of age. Researchers found that an age-related decrease in ELOVL2 gene expression was associated with increased DNA methylation of its promoter. Methylation is a simple biochemical process in which groups of carbon and hydrogen atoms are transferred from one substance to another. In the case of DNA, methylation of regulatory regions negatively impacts expression of the gene. When researchers reversed hypermethylation in vivo, they boosted ELOVL2 expression and rescued age-related decline in visual function in mice.
ELOVL2 is involved in production of long-chain omega-3 and omega-6 polyunsaturated fatty acids, which are used in several crucial biological functions, such as energy production, inflammation response, and maintenance of cell membrane integrity. The gene is found in humans as well as mice. In particular, ELOVL2 regulates levels of docosahexaenoic acid or DHA, a polyunsaturated omega-3 fatty acid abundantly found in the brain and retina. DHA is associated with a number of beneficial effects. Notably, its presence in photoreceptors in eyes promotes healthy retinal function, protects against damage from bright light or oxidative stress and has been linked to improving a variety of vision conditions, from age-related macular (AMD) degeneration to diabetic eye disease and dry eyes.
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.