Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock

Abstract

The underlying cause of aging remains one of the central mysteries of biology. Recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues. This Review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming. By defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges.

Figure 1. Rejuvenation without Dedifferentiation

With age, distinct changes are evident in any mammalian tissue examined, such as impaired regenerative responses in skeletal muscle, thinning of the skin epithelium, and hypercellularity of the bone marrow. Different interventions have been shown to restore youthful function in each of these tissues in aged mice. Heterochronic parabiosis (or inhibition of Wnt or TGF-β signaling) enhances aged muscle regeneration, increasing the formation of new muscle and reducing fibrosis (left). Inhibition of NF-κB signaling restores the youthful skin phenotype, expanding the thickness of the epithelium (middle). Inhibition of mTOR signaling with rapamycin restores the youthful state of the hematopoietic system, reducing the hypercellularity that characterizes the aged tissue (right). In each case, not only are the youthful cell and tissue phenotypes restored, but the molecular signatures of youthfulness are also induced in the aged cells during the period of treatment.

Figure 2. Epigenetic States in Young and Old Cells

Aging is associated with specific changes in chromatin, some of which are illustrated here. In young cells, Polycomb group proteins (PcG) and sirtuins (SIRTs) silence aging genes by maintaining histone H3 lysine 27 methylation and by deacetylating multiple residues, respectively. Old cells are characterized by the appearance of DNA damage, which can titrate away sirtuins, as well as stress-inducible transcription factors like NF-κB. An exchange of PcG for Trithorax group proteins (Trx) and H3K27 demethylase JMJD3 allows accumulation of active chromatin marks such as H3K4me3 and histone acetylation, removal of H3K27me3, and increased expression of proaging genes such as the cell-cycle inhibitor p16, which drives cell senescence. Additional consequences of epigenetic dys-regulation include increased transcriptional noise and decreased coordination of gene expression that contributes to organismal aging.

Figure 3. Aging and Rejuvenation through the “Epigenetic Lens”

The process of light passing through a film, focused by a lens, and projected to create a complex image is drawn as a metaphor for genetic information being processed and interpreted by epigenetic mechanisms to create complex cellular phenotypes. In this analogy, the film represents the genome (shown as a DNA double helix) containing the fundamental information, the lens represents the epigenome (represented as a string of nucleosomes) that allows that genetic information to be translated, and the Cell cover represents the resulting complex phenotype (shown as a mature neuron). In the vertical axis, the processes first of aging and then of rejuvenation are illustrated. With age, there is clearly a deterioration of the cellular phenotype, reflected by a blurring of the image. This may be due to intrinsic changes to DNA (depicted as double-strand breaks) and also to the epigenome (depicted as less well-organized nucleosomes), the latter resulting both from genomic changes and also from environmental influences. Together, these changes distort the genomic information of youth to create imperfect products, blurred as an image and structurally and functionally disrupted as a cell. Based on the ideas put forth in this Review, we postulate that most, if not all, of the rejuvenating effects, such as those that result from processes (e.g., fertilization, SCNT, iPS cell generation) or interventions (e.g., heterochronic parabiosis, NF-κB inhibition, mTOR inhibition) described, act by restoring the epigenomic lens back toward a more youthful state. The resulting image/cell may not be precisely “young” but has youthfulness restored by these processes and interventions that act by reprogramming the epigenome. It is thus the epigenetic lens that is critical for establishing the aged phenotype and that is the target for rejuvenating interventions and reprogramming that are responsible for the apparent rewinding of the aging clock.