Cellular reprogramming and epigenetic rejuvenation

Abstract

Ageing is an inevitable condition that afflicts all humans. Recent achievements, such as the generation of induced pluripotent stem cells, have delivered preliminary evidence that slowing down and reversing the ageing process might be possible. However, these techniques usually involve complete dedifferentiation, i.e. somatic cell identity is lost as cells are converted to a pluripotent state. Separating the rejuvenative properties of reprogramming from dedifferentiation is a promising prospect, termed epigenetic rejuvenation. Reprogramming-induced rejuvenation strategies currently involve using Yamanaka factors (typically transiently expressed to prevent full dedifferentiation) and are promising candidates to safely reduce biological age. Here, we review the development and potential of reprogramming-induced rejuvenation as an anti-ageing strategy.

Keywords: Ageing; Cellular reprogramming; Epigenetic age; Epigenetic clocks; Rejuvenation; Reprogramming-induced rejuvenation; Transient reprogramming.

Fig. 1

Cellular reprogramming experiments that induce epigenetic rejuvenation. A Fluorescent recovery of heterochromatin protein 1β (HP1β) in senescent cells was restored to the same level as non-senescent cells after nine days of OSKML treatment [119]. B OSKM treatment increased lifespan of progeria mice, improved the regenerative capacity of muscle and pancreas, as well as glucose tolerance [74]. C Overlaid summary of iPSC reprogramming time-course experiments by [118] and [73]. Upper panel: Horvath multi-tissue age predictor applied to OSKM-expressing adult fibroblasts [118]. The experimental setup of Gill et al. includes OSKM-free culturing at the time points in red for a minimum of four weeks. Day 13 was identified by Gill et al. as most suitable for OSKM withdrawal, where highest stable rejuvenation (eAge reduction) can be achieved: approximately 30 years, same as shown before OSKM withdrawal by Olova et al. Lower panel: The bars align with the time-course and summarise phases and patterns of gene expression as reported in Olova et al. “eAge drop onset” and “Point of no return” cannot be attributed to a precise day in the presented data as they occur between actual experimental time points. D OSKMNL-treatment of aged fibroblasts and endothelial cells results in a significant decrease in eAge (according to the Horvath clock), and a transcription profile resembling that of young fibroblasts/endothelial cells [125]. E 4 weeks of OSK treatment of 12 month old mice resulting in improved DNA methylation ageing signature, rejuvenation of age-related gene expression, and improved visual performance [127]