Reprogramming to recover youthful epigenetic information and restore vision

Abstract

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity 1 – 3 . Changes to DNA methylation patterns over time form the basis of ageing clocks 4 , but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity 5 – 7 . Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information—encoded in part by DNA methylation—that can be accessed to improve tissue function and promote regeneration in vivo.

The Principle of Continuous Biological Information Flow as the Fundamental Foundation for the Biological Sciences. Implications for Ageing Research

“…In other words, by considering damage as the consequence of ageing rather than the cause of it. On top of that, the model is not only fully testable (as detailed above) but has already experimental support by data obtained by Sarkar and colleagues and by Lu and colleagues which shows that by reprograming aged tissues they could obtain a measurable reduction of the damage accumulated (Sarkar et al, 2020;Lu et al, 2020). These studies strongly support than damage is a consequence of ageing rather than its cause and provide evidence for an informationbased nature of ageing.…”

“…Indeed, meiotic genes has been shown to be specifically silenced in somatic (or somatic-like) cells (Hiriart et al, 2012;Harigaya et al, 2006). In germline (or germline-like) cells the old epigenetic information should be substituted by the young epigenetic information, so that, as shown in ectopically induced scenarios (Sarkar et al, 2020;Lu et al, 2020), decrease (or erase) the aged phenotype. This has already been shown to be the case in physiological conditions (Unal et al, 2011).…”

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications

“…(recent studies in non-human primates do not support the use of hydroxychloroquine -either alone or in combination with azithromycin- for the treatment of COVID-19 in humans [ 158 ]; also, chloroquine was not found to inhibit infection of human lung cells with SARS-CoV-2 [ 159 ])…”

Youthful and age-related matreotypes predict drugs promoting longevity

“…The generally accepted assumption is that there is a drift in gene expression during aging, and that restoration of a younger gene expression pattern indicates rejuvenation of cells or tissues. This premise has been extensively used as a biomarker for the restoration of health in clinical trials (NCT02432287, NCT02953093), parsing healthy versus common aging cohorts (Zeng et al, 2020), reprogramming cells into a younger state (Lu et al, 2020), or in previous in-silico approaches (Tyshkovskiy et al, 2019). This premise also requires that longevity or rejuvenating interventions work through temporal scaling, a process that has been shown to be the case for lifespan extension and aging-associated gene expression in C. elegans (Stroustrup et al, 2016;Tarkhov et al, 2019) but not yet for mammals.…”