Retinal polyunsaturated fatty acid supplementation reverses aging-related vision loss in mice

The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), which are primarily localized in cell membranes, where they govern membrane biophysical properties such as diffusion, permeability, domain formation, and curvature generation. During aging, alterations in lipid metabolism lead to reduced content of very long-chain PUFAs (VLC-PUFAs) in the retina, and this decline is associated with normal age-related visual decline and pathological age-related macular degeneration (AMD). ELOVL2 (Elongation of very-long-chain fatty acids-like 2) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs, and methylation level of its promoter is currently one of the best predictors of chronological age. Here, we show that mice lacking ELOVL2-specific enzymatic activity (Elovl2C234W) have impaired contrast sensitivity and slower rod response recovery following bright light exposure. Short-term and long-term intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals improved visual function and reduced accumulation of ApoE and C3d in sub-RPE deposits. At the molecular level, the gene expression pattern observed in retinas supplemented with 24:5n-3 exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature similar to younger retinas. Finally, we present human genetic data showing significan t association of two variants in the ELOVL2 locus with the onset of intermediate AMD, underlining the translational importance of our findings. In sum, our study identifies potential therapeutic opportunities and defines ELOVL2 as a promising target for interventions aimed at preventing age-related vision loss. RNA-seq profiling of retinas from 12-month-old wildtype and Elovl2^C234W and 18-month-old wildtype C57BL6/J mice; vehicle- and 24:5-supplemented retinas from 18-month-old mice 5 days after intravitreal injection