The ageing epigenome and its rejuvenation
Authors: Jing Qu
Juan Carlos Izpisua Belmonte
Weiqi Zhang
Guang-Hui Liu
Journal: Nature Reviews Molecular Cell Biology (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Ageing; Functional decline; Ageing-associated disorders; Rejuvenating interventions; Healthspan
Affiliations: Beijing Institute for Brain Disorders, Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China., Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China., University of Chinese Academy of Sciences, Beijing, China., Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China., State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China., Beijing Institute for Brain Disorders, Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China. ., University of Chinese Academy of Sciences, Beijing, China. ., Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. ., State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. ., Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. .

Abstract:  Ageing is characterized by the functional decline of tissues and organs and the increased risk of ageing-associated disorders. Several 'rejuvenating' interventions have been proposed to delay ageing and the onset of age-associated decline and disease to extend healthspan and lifespan. These interventions include metabolic manipulation, partial reprogramming, heterochronic parabiosis, pharmaceutical administration and senescent cell ablation. As the ageing process is associated with altered epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodelling, and non-coding RNAs, the manipulation of these mechanisms is central to the effectiveness of age-delaying interventions. This Review discusses the epigenetic changes that occur during ageing and the rapidly increasing knowledge of how these epigenetic mechanisms have an effect on healthspan and lifespan extension, and outlines questions to guide future research on interventions to rejuvenate the epigenome and delay ageing processes. 

Retracted: No

PubPeer comments:
 There is controversy over where the notion that iPS  reprogramming factors can be used to induce epigenetic rejuvenation without de-differentiation was first put forward and tested (see comments in https: pubpeer.com publications E006ECA3F03CA48839B631F5682C7A. , 
  Due to limitations of space, the authors apologize for not being able to cite all important studies in this Review. Notwithstanding the above, the authors failed to cite the early work on epigenetic rejuvenation. Namely, the first study that measured the ability of reprogramming factors to epigenetically rejuvenate cells without de-differentiation. That foundational work is documented in doi: 10.1038 srep04789 and described in Olova et al., (2018) where they say: u201cTo avoid this risk, a parallel concept of epigenetic rejuvenation has been proposed: the aging process in cells can be reversed whilst avoiding dedifferentiation (Manukyan Singh, 2012; Singh Zacouto, 2010). In other words, an old dysfunctional heart cell could be rejuvenated without the need for it to be passed through an embryonic iPSC state. The concept of epigenetic rejuvenation requires that rejuvenation and dedifferentiation each follow a distinct pathway. Nevertheless, it is not well understood whether rejuvenation and dedifferentiation are invariably intertwined, or instead whether it is possible to manipulate age without risking dedifferentiation. The epigenetic rejuvenation potential of partial reprogramming with OSKM factors was previously shown by the forced expression of OSKM+LIN28 in senescent human fibroblasts, which led to recovering the high mobility of histone protein 1u03b2 by day 9, a feature characteristic for young fibroblasts (Manukyan Singh, 2014). Ocampo et al. further demonstrated that partial reprogramming by transient cyclic induction of OSKM ameliorates signs of aging and extends lifespan in progeroid mice, with no resulting teratoma formation (Ocampo et al., 2016).u201d ,