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Review
. 2018 Dec 20;11(1):73.
doi: 10.1186/s13072-018-0244-7.

Age reprogramming and epigenetic rejuvenation

Prim B Singh  1   2   3 , Andrew G Newman  4
Affiliations
Review

Age reprogramming and epigenetic rejuvenation

Prim B Singh et al. Epigenetics Chromatin. .

Abstract

Age reprogramming represents a novel method for generating patient-specific tissues for transplantation. It bypasses the de-differentiation/redifferentiation cycle that is characteristic of the induced pluripotent stem (iPS) and nuclear transfer-embryonic stem (NT-ES) cell technologies that drive current interest in regenerative medicine. Despite the obvious potential of iPS and NT-ES cell-based therapies, there are several problems that must be overcome before these therapies are safe and routine. As an alternative, age reprogramming aims to rejuvenate the specialized functions of an old cell without de-differentiation; age reprogramming does not require developmental reprogramming through an embryonic stage, unlike the iPS and NT-ES cell-based therapies. Tests of age reprogramming have largely focused on one aspect, the epigenome. Epigenetic rejuvenation has been achieved in vitro in the absence of de-differentiation using iPS cell reprogramming factors. Studies on the dynamics of epigenetic age (eAge) reprogramming have demonstrated that the separation of eAge from developmental reprogramming can be explained largely by their different kinetics. Age reprogramming has also been achieved in vivo and shown to increase lifespan in a premature ageing mouse model. We conclude that age and developmental reprogramming can be disentangled and regulated independently in vitro and in vivo.

Keywords: Age reprogramming; Epigenetic clock; Epigenetic rejuvenation; Reprogramming factors; Somatic cell nuclear transfer (SCNT); eAge; iPS cells.

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Figures

Fig. 1
Fig. 1
(e)Age reprogramming using iPS reprogramming factors. a Schematic depiction of the experiment by Manukyan and Singh [20]. Fluorescence recovery after photo-bleaching (FRAP) analysis showed that the mobility of the epigenetic modifier, HP1β, in senescent HDFs (blue) transduced with OSKML reprogramming factors reached levels found in young HDFs (red) on day 9 after transduction (highlighted with the yellow surround). Epigenetic rejuvenation of HP1β mobility is transient and returns to that found in senescent cells on day 12. b Schematic depiction of the in silico analysis by Olova et al. [26]. Between days 3 and 7 post-transduction of HDFs (eAge ~ 65 years) with OSKM reprogramming factors, eAge (purple line) declines at a steady rate with a gradient (purple dotted line) of 3.8 years per day and falls to zero by day 20. Analysis of the expression of three fibroblast-specific gene clusters, F1, F2 and F3 (given in grey), showed that two (F2 and F3) declined immediately and then plateaued between days 7 and 15. The F1 cluster remained stable over the first 15 days. A red dotted line passes through day 10, when there has been a substantial decrease in eAge that continues to fall, while the expression levels of F1, F2 and F3 remain on a plateau. After day 15, the expression of all three clusters declined with the extinguishing of the F1 cluster at day 35. The increase in expression of a cluster of pluripotency genes (green) showed that they reach steady-state levels only after eAge had reached zero. The genes in the early pluripotency gene cluster and fibroblast-specific gene clusters F1, F2 and F3 are listed in Table 1 of Olova et al. [26]. c Schematic showing that kinetics of eAge and developmental reprogramming are different [26]. eAge reprogramming has fallen to zero by day 20. Fibroblast gene expression is extinguished on day 35 and marks loss of fibroblast identity, whereupon an iPS cell molecular identity is established. The red dotted line corresponds to that which is described in b
Fig. 2
Fig. 2
Age reprogramming in vivo. Schematic depiction of the experiment by Ocampo et al. [28]. Top row: Short-term or cyclic (2 days “on” and 5 days “off”) expression of OSKM reprogramming factors in fibroblasts from LAKI progeria mice (blue) lead to age reprogramming of epigenetic rejuvenation, DNA damage, senescence, mitochondrial dysfunction and stress response. The first four characteristics are known hallmarks of ageing [9]. Age-reprogrammed fibroblast from the LAKI progeria mouse is given in red. Similar results were obtained with old wild-type murine and human fibroblasts. Middle row: Cyclic expression of OSKM reprogramming factors in LAKI progeria mouse leads to age reprogramming of DNA damage, senescence, stress response and epigenetic rejuvenation. The mice also exhibit enhanced regeneration of satellite cells in the muscle after chemical injury. They also have increased median and maximal lifespan. Bottom row: Cyclic expression of OSKM reprogramming factors in 12-month-old wild-type mice promotes regeneration of β cells in the pancreas and satellite cells of the muscle after chemical injury. Other parameters were not tested and are given as a question mark. An upward facing arrow depicts an increase in a particular characteristic after cyclic OSKM expression and the downward arrow a decrease
Fig. 3
Fig. 3
Nuclear reprogramming depicted as a multi-layered process. Nuclear reprogramming can be separated into age and developmental reprogramming. Age reprogramming itself consists of several separate elements the most important of which are the nine hallmarks of ageing [9]. In bold are those hallmarks that have been age-reprogrammed experimentally. These include epigenetic rejuvenation [20, 26, 28], DNA damage [28], cellular senescence [28] and mitochondrial dysfunction [28]. It remains to be seen if the other hallmarks (grey) can be age-reprogrammed without developmental reprogramming. Developmental reprogramming is also depicted as being multi-layered, consisting of many different developmental pathways (1 to n) that have the potential of being reprogrammed independently. In essence, the multi-layered nature of nuclear reprogramming reflects the restriction in developmental and ageing potential that takes place during the transition from egg to adult to old age, where each restriction is reprogrammed to reacquire the potential it once had
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