Multi‐omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

Chondronasiou, Dafni; Gill, Diljeet; Mosteiro, Lluc; Urdinguio, Rocío G.; Berenguer‐Llergo, Antoni; Aguilera, Mònica; Durand, Sylvère; Aprahamian, Fanny; Nirmalathasan, Nitharsshini; Abad, María; Martin-Herranz, Daniel E.; Attolini, Camille Stephan‐Otto; Prats, Neus; Kroemer, Guido; Fraga, Mario F.; Reik, Wolf; Serrano, Manuel

doi:10.1111/acel.13578

Cited by 79 publications

(91 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Using multi-omics approach and epigenetic clocks, MPTR has been found to rejuvenate several hallmarks of aging by reducing both transcriptional and epigenetic ages by 30 years and reverse age-associated changes without losing cell identity. These observations have been recently supported by in vivo transient reprogramming studies (Chondronasiou et al, 2022). Altogether, these findings demonstrate that pluripotency reprogramming and the rejuvenation program can be dissociated.…”

Section: Therapeutic Implicationssupporting

confidence: 57%

5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer

Turpin

Salbert

2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

DNA methylation at the fifth position of cytosine (5mC) is one of the most studied epigenetic mechanisms essential for the control of gene expression and for many other biological processes including genomic imprinting, X chromosome inactivation and genome stability. Over the last years, accumulating evidence suggest that DNA methylation is a highly dynamic mechanism driven by a balance between methylation by DNMTs and TET-mediated demethylation processes. However, one of the main challenges is to understand the dynamics underlying steady state DNA methylation levels. In this review article, we give an overview of the latest advances highlighting DNA methylation as a dynamic cycling process with a continuous turnover of cytosine modifications. We describe the cooperative actions of DNMT and TET enzymes which combine with many additional parameters including chromatin environment and protein partners to govern 5mC turnover. We also discuss how mathematical models can be used to address variable methylation levels during development and explain cell-type epigenetic heterogeneity locally but also at the genome scale. Finally, we review the therapeutic implications of these discoveries with the use of both epigenetic clocks as predictors and the development of epidrugs that target the DNA methylation/demethylation machinery. Together, these discoveries unveil with unprecedented detail how dynamic is DNA methylation during development, underlying the establishment of heterogeneous DNA methylation landscapes which could be altered in aging, diseases and cancer.

show abstract

Section: Therapeutic Implicationssupporting

confidence: 57%

5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer

Turpin

Salbert

2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…More recently, there have been in vivo transient reprogramming approaches that elicit similar magnitudes of rejuvenation to our in vitro MPTR method. In mice, 1 week of reprogramming induction followed by 2 weeks of recovery reversed age-associated expression changes (including collagen gene expression) and partially rejuvenated the DNA methylome in the pancreas ( Chondronasiou et al, 2022 ). Interestingly, these outcomes closely mirror those observed in our human fibroblasts after MPTR.…”

Section: Discussionmentioning

confidence: 99%

Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

Gill

Parry

Santos

et al. 2022

eLife

Self Cite

View full text Add to dashboard Cite

Ageing is the gradual decline in organismal fitness that occurs over time leading to tissue dysfunction and disease. At the cellular level, ageing is associated with reduced function, altered gene expression and a perturbed epigenome. Somatic cell reprogramming, the process of converting somatic cells to induced pluripotent stem cells (iPSCs), can reverse these age-associated changes. However, during iPSC reprogramming, somatic cell identity is lost, and can be difficult to reacquire as re-differentiated iPSCs often resemble foetal rather than mature adult cells. Recent work has demonstrated that the epigenome is already rejuvenated by the maturation phase of reprogramming, which suggests full iPSC reprogramming is not required to reverse ageing of somatic cells. Here we have developed the first 'maturation phase transient reprogramming' (MPTR) method, where reprogramming factors are expressed until this rejuvenation point followed by withdrawal of their induction. Using dermal fibroblasts from middle age donors, we found that cells temporarily lose and then reacquire their fibroblast identity during MPTR, possibly as a result of epigenetic memory at enhancers and/or persistent expression of some fibroblast genes. Excitingly, our method substantially rejuvenated multiple cellular attributes including the transcriptome, which was rejuvenated by around 30 years as measured by a novel transcriptome clock. The epigenome, including H3K9me3 histone methylation levels and the DNA methylation ageing clock, was rejuvenated to a similar extent. The magnitude of rejuvenation instigated by MTPR appears substantially greater than that achieved in previous transient reprogramming protocols. In addition, MPTR fibroblasts produced youthful levels of collagen proteins, and showed partial functional rejuvenation of their migration speed. Finally, our work suggests that more extensive reprogramming does not necessarily result in greater rejuvenation but instead that optimal time windows exist for rejuvenating the transcriptome and the epigenome. Overall, we demonstrate that it is possible to separate rejuvenation from complete pluripotency reprogramming, which should facilitate the discovery of novel anti-ageing genes and therapies.

show abstract

“…Therefore, in order to avoid the adverse effects and early lethality associated with in vivo reprogramming, most studies have typically focused on the short-term expression of the reprogramming factors at organismal level, or more recently, the tissue- or organ-specific expression. In this line, to induce whole body expression of OSKM in the absence of side effects, researchers have commonly used short-term cyclic expression of the OSKM factors, such as 2 days (Browder et al, 2022; Ocampo et al, 2016) or 3 days (Rodriguez-Matellan et al, 2020) of doxycycline (1mg/ml) followed by 5 or 4 days withdrawal, or lower concentration of doxycycline (0.2 mg/ul) for 7 days (Chondronasiou et al, 2022). Alternatively, the generation of tissue-specific reprogrammable mouse models such as skeletal muscle-specific (Wang et al, 2021), heart-specific (Chen et al, 2021; de Lázaro et al, 2021) and liver-specific (Hishida et al, 2022), or the ectopic local expression of Yamanaka factors by using adeno-associated virus (Lu et al, 2020; Senis et al, 2018) have allowed to circumvent the negative consequences of organismal reprogramming.…”

Section: Discussionmentioning

confidence: 99%

“…In this line, in vivo reprogramming can induce beneficial effects on skin (Doeser et al, 2018), heart (Chen et al, 2021), skeletal muscle (de Lazaro et al, 2019; Wang et al, 2021) and liver (Hishida et al, 2022) regeneration. Furthermore, reprogramming of aged mice has the capacity to improve memory (Rodriguez-Matellan et al, 2020), regenerate skeletal muscle and pancreas following injury (Chiche et al, 2017; Ocampo et al, 2016), restore vision loss in injured retina (Lu et al, 2020), and recently, rejuvenate multiple tissues and organs (Browder et al, 2022; Chondronasiou et al, 2022). Finally, cyclic induction of reprogramming has been shown to extend lifespan in a progeria mouse model (Alle et al, 2021; Ocampo et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

In vivo reprogramming leads to premature death due to hepatic and intestinal failure

Parras

Vílchez-Acosta

Desdin-Mico

et al. 2022

Preprint

View full text Add to dashboard Cite

The induction of cellular reprogramming by forced expression of the transcription factors OCT4, SOX2, KLF4, and C-MYC (OSKM) has been shown to allow the dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. Yet to date, the benefits of in vivo reprogramming are limited by the occurrence of detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous in vivo induction of the reprogramming factors leads to hepatic and intestinal dysfunction resulting in decreased body weight and premature death. By generating a novel transgenic reprogrammable mouse strain, which avoids OSKM expression in both liver and intestine, we drastically reduced the early lethality and adverse effects associated with in vivo reprogramming. This new reprogramming mouse allows safe and long-term continuous induction of OSKM and might enable a better understanding of in vivo reprogramming as well as maximize its potential effects on rejuvenation and regeneration.

show abstract

Multi‐omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming

Cited by 79 publications

References 73 publications

5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer

5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer

Multi-omic rejuvenation of human cells by maturation phase transient reprogramming

In vivo reprogramming leads to premature death due to hepatic and intestinal failure

Contact Info

Product

Resources

About