The ageing epigenome and its rejuvenation


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.

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Fig. 1: The epigenetic bases of ageing and rejuvenation.
Fig. 2: Caloric restriction regulates epigenetic pathways.
Fig. 3: Reprogramming overcomes senescence barriers and rejuvenates aged cells.
Fig. 4: Model of mitochondria as nodes linking intervention strategies to epigenetic regulation.
Fig. 5: Repeating sequences form ‘blocks’ to maintain chromatin structure.
Fig. 6: The sequence of heterochromatin loss, retrotransposon activation and inflammation is a critical target for rejuvenation.
Fig. 7: Epigenetic regulation is at the nexus of ageing rejuvenation.


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Due to limitations of space, the authors apologize for not being able to cite all important studies in this Review. The authors thank Y. Wang, S. Wang, X. He, X. Liu and J. Li for their assistance in preparing the manuscript. This work was supported by the National Key Research and Development Program of China (2018YFC2000100), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2017YFA0102802, 2017YFA0103304, 2018YFA0107203, 2018YFC2000400, 2015CB964800), the National Natural Science Foundation of China (81625009, 81330008, 91749202, 81861168034, 81921006, 91749123, 31671429, 81671377, 81771515, 31601158, 81701388, 81601233, 31601109, 81822018, 81870228, 81801399, 31801010, 81801370, 81861168034), the Key Research Program of the Chinese Academy of Sciences (KJZDEWTZ-L05), the Beijing Natural Science Foundation (Z190019), the Beijing Municipal Commission of Health and Family Planning (PXM2018_026283_000002), the Advanced Innovation Center for Human Brain Protection (3500-1192012) and the State Key Laboratory of Membrane Biology. J.C.I.B. was supported by the Glenn Foundation, the Moxie Foundation, the G. Harold and Leila Y. Mathers Charitable Foundation, Fundación Dr. Pedro Guillen, Fundación Teléfonica, Fundación MAPFRE and Universidad Católica San Antonio de Murcia.

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Correspondence to Guang-Hui Liu or Juan Carlos Izpisua Belmonte.

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Ten–eleven translocation enzymes

TET enzymes. A family of dioxygenases, including TET1, TET2, and TET3, involved in DNA demethylation. They function by converting 5-methylcytosine into 5-hydroxymethylcytosine.

Constitutive heterochromatin

Constitutive heterochromatin encompasses highly repetitive DNA sequences, is enriched around the pericentromeric and telomeric regions of chromosomes and is consistently stable in many cell types of most eukaryotes.

Epigenetic drifts

Age-associated heterogeneity of the epigenome which will lead to increased noise of gene expression during ageing.


A macrolide compound approved by the US Food and Drug Administration to prevent organ transplant rejection and also thought to be able to extend lifespan in diverse species.

Senescent cell

Aged cells characterized by irreversible cell cycle arrest, along with acquisition of a proinflammatory secretome and activation of the cyclin-dependent kinase inhibitor p16.

Senescence-associated heterochromatin foci

In some types of senescent cells, such as oncogene-induced senescent cells, domains of facultative heterochromatin are formed to silence the expression of proliferation-promoting genes.

Phenotypic discordance

Phenotypic variability can be caused by accumulation of environmental effects on the epigenetic state of cells and tissues during ageing.

Satellite cells

Adult stem cells of muscle tissue, quiescent under normal physiological conditions and activated on injury.

Pioneer factor

Bookmarking transcription factor that can directly bind and recruit other chromatin remodellers to condensed chromatin, allowing initiation of new molecular programmes and cell fate transition.

Stem cell exhaustion

The number or function of stem cells declines with age, which dampens tissue homeostasis.


Selective elimination of damaged mitochondria through autophagy.

Mitochondrial unfolded protein response

Imbalance between mitochondrion-encoding and nucleus-encoding protein and accumulation of misfolded protein in mitochondria cause mitochondrial unfolded protein response, a conserved transcriptional response that activates genes involved in antioxidant response, mitophagy and protein homeostasis and promotes lifespan extension in animal models.

Senescence-associated secretory phenotype

Senescent cells in vivo and in vitro secrete numerous inflammatory cytokines, proteases and growth factors in an autocrine or a paracrine manner, which leads to chronic inflammation.

Innate immune activity

As the first line of immune defence, innate immunity is an evolutionarily conserved defence system that recognize ‘foreign’ components, such as DNA, RNA and protein, and triggers non-specific inflammatory responses.

cGAS−STING pathway

A major DNA-sensing mechanism in mammalian cells that starts from cyclic GMP–AMP synthase (cGAS), which senses cytosolic DNA, produces cyclic GMP–AMP, activates STING and triggers innate immune response that plays a critical role in senescence.

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Zhang, W., Qu, J., Liu, G. et al. The ageing epigenome and its rejuvenation. Nat Rev Mol Cell Biol (2020).

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