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Aging Cell. 2020 Feb;19(2):e13100. doi: 10.1111/acel.13100. Epub 2020 Jan 14.

The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina.

Author information

1
Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA.
2
The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology, La Jolla, CA, USA.
3
Department of Medicine, University of California San Diego, La Jolla, CA, USA.
4
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
5
Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, USA.
6
Atkinson Laboratory for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA.

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.

KEYWORDS:

DNA methylation; ELOVL2; PUFA; age-related macular degeneration; aging; retina

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