Polyunsaturated Fatty Acid - mediated Cellular Rejuvenation for Restoration of Vision in Aging

ABSTRACT: 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 significantly 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 of younger retina. Finally, we present the first human genetic data showing significant association of two variants in the ELOVL2 locus with the onset of intermediate AMD, underlying the translational significance of our findings. In sum, our study identifies novel therapeutic opportunities and defines ELOVL2 as a promising target for interventions aimed at preventing age-related vision loss.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Retina

SUBMITTER: Fangyuan Gao  

LAB HEAD: Skowronska-Krawczyk, Dorota

PROVIDER: PXD066430 | Pride | 2025-11-02

REPOSITORIES: Pride