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

The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), primarily localized in cell membranes, where they govern membrane biophysical properties. During aging, alterations in lipid metabolism lead to reduced content of very long-chain PUFAs (VLC-PUFAs) in the retina, which is associated with normal age-related reductions in contrast sensitivity, diminished photoreceptor function and delayed rod-mediated dark adaptation recovery, 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. The methylation status of the ELOVL2 promoter is currently one of the best predictors of chronological age. Here, we show that lower VLC-PUFA abundance in the aged mouse retina is accompanied by a reduction in visual function. Similarly, mice lacking ELOVL2-specific enzymatic activity (Elovl2^C234W) demonstrate reduced contrast sensitivity and slower rod-mediated dark adaptation. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals improved visual function for up to 4 weeks and reduced accumulation of APOE- and C3d-positive sub-RPE deposits. The gene expression pattern observed in supplemented retinas exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature resembling younger retinas. Last, human genetic data from the IAMDGC and UK Biobank linked two variants in the ELOVL2 locus with the onset of intermediate AMD, underlining the translational importance of our findings. Our work highlights VLC-PUFA supplementation as a potential therapeutic opportunity and defines ELOVL2 as a promising target for interventions to prevent age-related vision loss.