Reprogramming involves exposing cells to the Yamanaka factors, a set of transcription factors that are involved in the conversion of adult cells into embryonic stem cells in the earliest stages of embryogenesis. In addition to converting an adult somatic cell into a pluripotent stem cell, Yamaka factor expression also rejuvenates epigenetic control over nuclear DNA structure and gene expression and restores youthful mitochondrial function. This latter process of rejuvenation has become an area of strong research interest, and a few well funded biotech companies are attempting to build therapies to treat aging and age-related conditions based on partially reprogramming the cells of a living individual.
More than one of these programs is focused on the eye, for a number of reasons. Firstly, diseases of the aging eye represent a large market. Secondly, the eye is relatively isolated from the rest of the body, making it an easier target for novel classes of therapy, such as gene therapies, that carry unknown risks. Thirdly, treating the eye requires only small doses of a drug, making it a good target for classes of treatment where manufacture remains relatively expensive. Today's open access paper arises from one program focused on reversal of retinal aging, but the discovery reported is of broader interest, with potential applications beyond reprogramming therapies. Within the field of reprogramming, this appears to be another incremental step towards to capacity to separate change of cell state from rejuvenation of cell function - a desirable goal for the research community.
Age-related macular degeneration (AMD), the leading cause of irreversible vision loss affecting over 200 million people worldwide, is a prime example of oxidative stress-driven pathology. The dry form of AMD, which accounts for 90% of cases, is driven by degeneration of the retinal pigment epithelium (RPE), a layer highly vulnerable to oxidative damage from chronic light exposure and bisretinoid lipofuscin buildup which elevates reactive oxygen species (ROS) over time. The causal role of ROS in AMD is supported by the AREDS2 study, where antioxidant supplementation slowed disease progression. The two recently approved therapies for dry AMD treatment provide only modest benefit, likely reflecting the fact that they target components of the alternative complement pathway, a cascade that is activated after oxidative stress has already injured the retina, rather than addressing that upstream damage directly. This highlights an unmet need to identify novel pathways that enhance oxidative resilience and counteract ROS-induced damage.
Over the past decade, partial epigenetic reprogramming through transient expression of all or subsets of the Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc, aka OSKM) has emerged as a promising strategy to restore youthful tissue function in vivo. Dual AAV-mediated delivery of OSK without the c-Myc oncogene has been shown to rejuvenate post-mitotic retinal ganglion cells (RGCs), promoting axon regeneration and restoring vision in either glaucomatous or aged mice, with long-term expression via AAV2 proving safe for up to 18 months. Notably, it has also shown promise in a non-human primate model of non-arteritic anterior ischemic optic neuropathy, a common optic neuropathy.
Despite its therapeutic potential, the mechanisms through which OSK(M) exerts functional rejuvenation remain poorly defined. A few mediators of partial epigenetic reprogramming, including Tet1/Tet2 and Top2a, have been identified, that facilitate chromatin and DNA modifications in cooperation with OSK. However, the broader network of OSK downstream effectors, those functional units that directly carry out the biological effects, remain less well explored. Here we explore the effect of OSK partial reprogramming in RPE cells, which operate under high oxidative load offering a robust model for probing how rejuvenation programs confer resistance to oxidative challenges.
Enabled by a functional genomics approach, our study uncovers a rejuvenation axis involving GSTA4 activation, that bypasses reprogramming-induced dedifferentiation. GSTA4 is 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.
View the full article at FightAging
