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

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Cell Line
  • DNA Methylation
  • Decitabine / pharmacology
  • Decitabine / therapeutic use
  • Down-Regulation
  • Fatty Acid Elongases / genetics
  • Fatty Acid Elongases / metabolism*
  • Fatty Acids, Unsaturated / metabolism*
  • Female
  • Humans
  • Macular Degeneration / enzymology
  • Macular Degeneration / genetics
  • Macular Degeneration / metabolism*
  • Macular Degeneration / physiopathology
  • Male
  • Mice
  • Mice, Transgenic
  • Point Mutation
  • Promoter Regions, Genetic
  • Retina / metabolism*
  • Retinal Pigment Epithelium / metabolism


  • ELOVL2 protein, human
  • ELOVL2 protein, mouse
  • Fatty Acids, Unsaturated
  • Decitabine
  • Fatty Acid Elongases