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 (Elovl2C234W) 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. Finally,
we present human genetic data from the IAMGDC and UK Biobank showing an
association of 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 potential
therapeutic opportunity and defines ELOVL2 as a promising target for
interventions to prevent age-related vision loss.