Researchers have partially reversed age-related vision decline in mice by injecting lipids directly into the retina [1].
The lipids in the retina
The membranes that surround our cells are made of lipids and proteins. The composition of lipids, which changes as we age, impacts many biophysical properties of these membranes. In this study, the researchers focused explicitly on the age-related changes in the lipid composition of the retina and their link to age-related macular degeneration (AMD) [2].
AMD was previously linked to the age-related decrease in retinal long- and very long-chain polyunsaturated fatty acids (LC-PUFAs and VLC-PUFAs) [3]. Preserving or replenishing proper lipid composition in the aging retina could be used as a strategy to preserve its proper functioning, and one way to achieve this would be to supplement PUFAs in the diet. However, studies investigating dietary supplementation of different forms of PUFAs have given contradicting results [4-6].
The lack of other therapeutic approaches to prevent the age-related decrease in VLC-PUFAs is partly caused by a lack of understanding of its mechanism. However, this lab had shed some light on this mechanism in its previous studies. These researchers have linked the activity of an enzyme, elongation of very long chain fatty acids protein 2 (ELOVL2) to aging processes in the eye [7]. ELOVL2 is an enzyme that plays an essential function in elongating LC-and VLC-PUFAs. Specifically, ELOVL2 elongates docosapentaenoic acid (DPA) from 22:5n-3 to 24:5n-3, which is further converted to VLC-PUFAs and 22:6n-3 (DHA). Methylation of the ELOVL2 regulatory region is a biomarker of chronological aging [8].
In this study, the researchers delved deeper into the impact of ELOVL2 on the aging retina membranes and their lipid composition and proposed “a potential new therapy to reverse the symptoms of aging in the eye and prevent age-related eye diseases.”
The essential gene
Investigating key enzymes in the PUFA elongation pathway, this study found that Elovl2 expression decreases in the aged mouse retina compared to young mice. To investigate its role in age-related vision loss, the researchers used genetically engineered mice that lacked ELOVL2 enzymatic activity and measured lipid profiles in their retinas. Lower levels of PUFAs were synthesized from ELOVL2 in the 18-month-old genetically engineered mice compared to the age-matched wild-type retinas. The authors also observed a decrease in several metrics of visual function compared with age-matched wild-type animals.
A gene expression analysis found that 18-month-old wild-type mice and 12-month-old genetically engineered mice had similarities in their retinas, while the retinas of 12-month-old wild-type mice were different in gene expression from those two groups.
Lipid injection treatment
Following these observations, the researchers hypothesized that “the lack of direct ELOVL2 product, 24:5n-3, in the aging retina is one of the main culprits of age-related visual decline and that supplementation with this fatty acid may improve vision in aged animals.” To test this, they supplemented these lipids by directly injecting them into the retina (intravitreal injection), which allowed for precise administration.
They found the optimal dose and tested several different PUFAs on aged mice. Treatment with 24:5n-3 improved vision parameters and lipid composition in older mice while not causing any side effects or inflammation.
Comparing 18-month-old control retinas to 4-month-old retinas showed an increased inflammatory response. 24:5n-3 supplementation decreased the upregulation of several of those pathways. The treatment also reduced immune and oxidative stress response levels, which contribute to age-related vision loss.
“It’s a proof-of-concept for turning lipid injection into a possible therapy,” says Skowronska-Krawczyk, PhD, the corresponding author in the study. “We have also shown on a molecular level that it actually reverses the aging features.”
Single vs. repeated
While most previous experiments assess the impact of such treatments relatively shortly after they are administered, for a treatment to be applicable in a clinic, it needs to have a long-term effect. Therefore, the researchers tested this effect in two ways. First, they applied long-term follow-ups at 2 and 4 weeks after the initial injection into 18-month-old mice. Second, they used a repeated injection strategy, with injections every 3 weeks, starting at 16 months old. They collected the retina for analysis after the third injection.
The first strategy showed visual improvement, such as rod and cone photoreceptor function, and improvements in the brain’s visual cortex function were still observed at 2 weeks following the injection. At 4 weeks, improvements in rod and cone photoreceptor function were still observed. For the repeated strategy, the researchers observed some improvements after the first two injections but not after the third one.
An analysis of lipid profiles showed a modest increase in VLC-PUFA-containing phospholipids following the first strategy, which was observed even after long-term follow-up. Five days after the first injection, the researchers also noted an accumulation of multiple DHA-containing fatty acids, but only one of them remained increased after the 4-week follow-up, suggesting that the benefits of the treatment might be limited beyond this point.
The authors suggest two paths that supplemented 24:5n-3 might follow. First, 24:5n-3 is elongated into VLC-PUFAs and incorporated into phospholipids, which can be incorporated into membranes, restoring age-related VLC-PUFA loss and supporting visual improvement. Second, 24:5n-3 is converted into 22:6n-3 and stored in triglycerides.
The repeated injection approach led to the accumulation of several DHA-containing triglycerides and free VLC-PUFA, with no vision improvement. The researchers discuss that this “suggested that excessive lipid supplementation may diminish the beneficial effects of treatment” since no vision improvements were also observed with single injections at higher doses.
Identifying people at higher risk
The demonstrated importance of ELOVL2 in mice prompted the researchers to see whether human data might suggest its importance as well.
Investigation into the association between genetic variants within the ELOVL2 gene and the age of onset of intermediate AMD in the human population showed that two of the ELOVL2 gene variants were correlated with almost 5 months of earlier earlier AMD onset.
“Now we actually have a genetic connection to the disease and its aging aspect,” said Skowronska-Krawczyk, “so we could potentially identify people at higher risk for vision loss progression.”
Optimization needed
Overall, this therapeutic approach reversed several functional and structural signs of aging and restored a more youthful retinal gene expression profile.
However, the authors are also aware of some shortcomings of their approach, and they discuss that if their approach were to be used as a therapy, it would need to be optimized. Their research showed the importance of choosing a proper dose and treatment frequency. The mode of administration would also need to be adjusted to be more feasible, for example, eye drops instead of injection, and most importantly, the results would need to be confirmed in humans.
Literature
[1] Gao, F., Tom, E., Rydz, C., Cho, W., Kolesnikov, A. V., Sha, Y., Papadam, A., Jafari, S., Joseph, A., Ahanchi, A., Balalaei Someh Saraei, N., Lyon, D. C., Foik, A., Nie, Q., Grassmann, F., Kefalov, V. J., & Skowronska-Krawczyk, D. (2025). Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice. Science translational medicine, 17(817), eads5769.
[2] Gordon, W. C., Kautzmann, M. I., Jun, B., Cothern, M. L., Fang, Z., & Bazan, N. G. (2023). Rod-specific downregulation of omega-3 very-long-chain polyunsaturated fatty acid pathway in age-related macular degeneration. Experimental eye research, 235, 109639.
[3] Skowronska-Krawczyk, D., & Chao, D. L. (2019). Long-Chain Polyunsaturated Fatty Acids and Age-Related Macular Degeneration. Advances in experimental medicine and biology, 1185, 39–43.
[4] Gorusupudi, A., Rallabandi, R., Li, B., Arunkumar, R., Blount, J. D., Rognon, G. T., Chang, F. Y., Wade, A., Lucas, S., Conboy, J. C., Rainier, J. D., & Bernstein, P. S. (2021). Retinal bioavailability and functional effects of a synthetic very-long-chain polyunsaturated fatty acid in mice. Proceedings of the National Academy of Sciences of the United States of America, 118(6), e2017739118.
[5] Yang, Z. H., Gorusupudi, A., Lydic, T. A., Mondal, A. K., Sato, S., Yamazaki, I., Yamaguchi, H., Tang, J., Rojulpote, K. V., Lin, A. B., Decot, H., Koch, H., Brock, D. C., Arunkumar, R., Shi, Z. D., Yu, Z. X., Pryor, M., Kun, J. F., Swenson, R. E., Swaroop, A., … Remaley, A. T. (2023). Dietary fish oil enriched in very-long-chain polyunsaturated fatty acid reduces cardiometabolic risk factors and improves retinal function. iScience, 26(12), 108411.
[6] Age-Related Eye Disease Study 2 Research Group (2013). Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA, 309(19), 2005–2015.
[7] Chen, D., Chao, D. L., Rocha, L., Kolar, M., Nguyen Huu, V. A., Krawczyk, M., Dasyani, M., Wang, T., Jafari, M., Jabari, M., Ross, K. D., Saghatelian, A., Hamilton, B. A., Zhang, K., & Skowronska-Krawczyk, D. (2020). The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina. Aging cell, 19(2), e13100.
[8] Garagnani, P., Bacalini, M. G., Pirazzini, C., Gori, D., Giuliani, C., Mari, D., Di Blasio, A. M., Gentilini, D., Vitale, G., Collino, S., Rezzi, S., Castellani, G., Capri, M., Salvioli, S., & Franceschi, C. (2012). Methylation of ELOVL2 gene as a new epigenetic marker of age. Aging cell, 11(6), 1132–1134.
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