Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming
Authors: Sylvere Durand
Daniel E Martin-Herranz
Antonio Berenguer-Llergo
Camille Stephan-Otto Attolini
Dafni Chondronasiou
Mario F Fraga
Rocio G Urdinguio
Nitharsshini Nirmalathasan
Lluc Mosteiro
Neus Prats
Fanny Aprahamian
Wolf Reik
Guido Kroemer
Diljeet Gill
Maria Abad
Mònica Aguilera
Manuel Serrano
Journal: Aging Cell (2022)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: OSKM; Yamanaka; aging; epigenetic clocks; pluripotency
Affiliations: Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain., Epigenetics Programme, Babraham Institute, Cambridge, UK., Genentech, San Francisco, California, USA., Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN CSIC), Oviedo, Spain., Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France., Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Chronomics Ltd, Cambridge, UK.

Abstract:  The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum. 

Retracted: No

PubPeer comments:
 One of the authors (W.R.) has the following affiliation Altos Labs Cambridge Institute, Cambridge, UK . https: twitter.com AlexJColville status 1499504085661151256 , 
 #1 Dear Alex thanks for bringing this to our attention and you are correct in the last minute addition of the (new) affiliation we omitted the conflict of interest listing. We will bring this to the journal s attention. Kind regards , 
 In section **2.3**, the authors state that  Cellular senescence is a potent barrier for reprogramming , citing ([Haridhasapavalan et al. 2020] ) in support. However, the experiments performed in this paper concern *in vivo* reprogramming, while (Haridhasapavalan et al. 2020) concerns *in vitro* reprogramming. The senior author of this paper, **Manuel Serrano**, has previously published two papers arguing the opposite of this claim: - Tissue damage and senescence provide critical signals for cellular reprogramming *in vivo* [(Mosteiro et al. 2016)] - Senescence promotes *in vivo* reprogramming through p16INK4a and IL-6 [(Mosteiro et al. 2018)] Additionallyu2014the first author of those papers, **Lluc Mosteiro**, is the third author on this paper. This was likely just a small oversight, but worth pointing out given its incompatibility with the lab s prior publications. , 
 Dear colleague, This is an interesting point. Please, note the difference between the  intrinsic (cell autonomous) and the  extrinsic (non-cell autonomous) effects of senescence. Senescent cells are intrinsically less amenable to be reprogrammed, probably due to their dramatic epigenetic reconfiguration, including de novo heterechromatinization. This has been reported by several laboratories (reviewed in Hardhasapavalan et al. 2020). At the same time, senescent cells secrete a complex mixture of factors, notably including IL-6, that is known to facilitate the reprogramming of the neighbour, non-senescent, cells. Therefore, senescent cells are intrinsically resistant to reprogramming, while senescent cells potentiate extrinsically the reprogramming of neighbour cells. I hope this clarifies your concern. Best regards, Manuel Serrano ,