The Sinclair Lab has provided evidence that epigenetic changes are a conserved cause of aging. The RCM Hypothesis posits that aging involves epigenetic dysregulation due to the redistribution of chromatin-modifying proteins to DNA damage sites, altering gene expression and cellular identity. Experiments with the ICE mouse model showed that inducing DNA breaks accelerates this process, while interventions to stabilize epigenetic states mitigate aging phenotypes, suggesting a mechanistic link between DNA repair and epigenetic maintenance.
Legend: On the left, a normal 20 month old mouse and on the right, a sibling treated 16 months earlier with a system called ICE (for inducible changes to the epigenome) that was designed to test if epigenetic changes lead to aging in mammals
In a 2020 Nature study, the lab investigated epigenetic reprogramming in murine retinal ganglion cells. By expressing Oct4, Sox2, and Klf4, they observed a restoration of DNA methylation patterns and transcriptomes characteristic of younger cells, alongside enhanced axon regeneration and improved visual function in aged and glaucoma models. The findings indicate that mammalian cells retain latent epigenetic information that can be accessed to reverse aspects of cellular aging, providing a framework for studying age-related functional decline and potential therapeutic strategies (Lu et al., Reprogramming to recover youthful epigenetic information and restore vision, 2020)
Legend: In adults, the optic nerve does not regenerate when damaged. On the top panel, are orange-stained retinal ganglion nerves (RGCs) in the optic nerve after a nerve crush about 1/5 of the distance from the eye. On the bottom panel, is the same nerve type in a mouse treated with AAV-OSK, which expressed Oct4, Sox2 and Klf4 (OSK) in the RGCs for 6 weeks after the damage. Nerves are seen to survive the insult and regrow towards the brain, which was shown to be coincident with epigenetic age reversal and more youthful gene expression patterns that depended on DNA demethylation.