A Safer Path to Cellular Rejuvenation: Endogenous Oct4 Activation via CRISPR/dCas9 in Progeria Mouse Models

A recent study in Aging Cell showed that transcriptional activation of endogenous Oct4 using the CRISPR/dCas9 activator system is sufficient for cellular rejuvenation and extending the lifespan of a progeria mouse model. Although transient expression of reprogramming factors Oct4, Sox2, Klf4, and c-Myc (OSKM) has been shown to ameliorate age-related phenotypes in vivo, oncogenic risk, for example, from c-Myc, has raised safety concerns for its use in therapeutics. The authors demonstrated that transient activation of endogenous Oct4 expression restored age-related epigenetic patterns, suppressed expression of mutant progerin, and reduced vascular pathological features associated with the disease. At the same time, the transient Oct4 overexpression resulted in lower incidence of cancer transformation compared with constituent OSKM overexpression. Successful activation of endogenous Oct4 by CRISPR/dCas9 paves the way for novel therapeutic approaches for the treatment of progeria and age-related diseases, with potential implications for the broader field of cellular reprogramming-based rejuvenation.