Abstract
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.
Highlights
Chronological age predicts relative levels of mental and physical performance, disease risks across common disorders, and mortality 1
We demonstrate that loss of ELOVL2-specific function results in the early-onset appearance of sub-retinal pigment epithelium (RPE) deposits that contain molecular markers found in drusen in age-related macular degeneration (AMD)
Previous studies showed that methylation of the promoter region of ELOVL2 is highly correlated with human age 2
Summary
Chronological age predicts relative levels of mental and physical performance, disease risks across common disorders, and mortality 1. A quantitative model for aging based on genome-wide DNA methylation patterns by using measurements at 470,000 CpG markers from whole blood samples of a large cohort of human individuals spanning a wide age range has recently been developed 2-4 This method is highly accurate at predicting age, and can discriminate relevant factors in aging, including gender, genetic variants, and disease 2,5. We demonstrate that loss of ELOVL2-specific function results in the early-onset appearance of sub-RPE deposits that contain molecular markers found in drusen in AMD This phenotype is associated with visual dysfunction as measured by electroretinography, and it suggests that ELOVL2 may serve as a critical regulator of a molecular aging clock in the retina, which may have important therapeutic implications for diseases such as age-related macular degeneration
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