Reprogramming Factors Activate a Non-Canonical Oxidative Resilience Pathway That Can Rejuvenate RPEs and Restore Vision

Lu, Y. R., Cameron, J. C., Hu, Y., Shen, H., Shirahama, S., Tyshkovskiy, A., Chen, Z., Ai, J., Zhu, D. Y., Karg, M. M., Chew, L. A., Bell, G. W., Jena, S. G., He, Y., Seifert, P., Shu, D. Y., El-Brolosy, M. A., Lou, Q., Zhang, B., Puszynska, A. M., Qiu, X., Tian, X., Gregory-Ksander, M., Gladyshev, V. N., Sinclair, D. A., Saint-Geniez, M., Buenrostro, J. D., Rickman, C. B., Ksander, B. R., Weissman, J. S.

Whitehead Institute for Biomedical ResearchWhitehead Institute for Biomedical Research · biorxiv

Paper

Abstract

Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.

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Research summary

The paper claims that OSK factors activate a non-canonical oxidative resilience pathway that rejuvenates retinal pigmented epithelium and restores vision in aged mice. This research addresses mechanisms of rejuvenation and oxidative stress resilience, which are central to understanding and potentially mitigating age-related degeneration.

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