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      Cellular reprogramming and epigenetic rejuvenation

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          Abstract

          Ageing is an inevitable condition that afflicts all humans. Recent achievements, such as the generation of induced pluripotent stem cells, have delivered preliminary evidence that slowing down and reversing the ageing process might be possible. However, these techniques usually involve complete dedifferentiation, i.e. somatic cell identity is lost as cells are converted to a pluripotent state. Separating the rejuvenative properties of reprogramming from dedifferentiation is a promising prospect, termed epigenetic rejuvenation. Reprogramming-induced rejuvenation strategies currently involve using Yamanaka factors (typically transiently expressed to prevent full dedifferentiation) and are promising candidates to safely reduce biological age. Here, we review the development and potential of reprogramming-induced rejuvenation as an anti-ageing strategy.

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          The Hallmarks of Aging

          Carlos López-Otín, Maria Blasco, Linda Partridge … (2014)
          Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

            Kazutoshi Takahashi, Shinya Yamanaka (2006)
            Differentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes. Subcutaneous transplantation of iPS cells into nude mice resulted in tumors containing a variety of tissues from all three germ layers. Following injection into blastocysts, iPS cells contributed to mouse embryonic development. These data demonstrate that pluripotent stem cells can be directly generated from fibroblast cultures by the addition of only a few defined factors.
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              The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

              Yi-Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava … (2015)
              The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
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                Author and article information

                Contributors
                Daniel J. Simpson:
                ORCID: http://orcid.org/0000-0002-8431-7384
                s1684303@sms.ed.ac.uk
                Nelly N. Olova: nelly.olova@ed.ac.uk
                Tamir Chandra: tamir.chandra@igmm.ed.ac.uk
                Journal
                Journal ID (nlm-ta): Clin Epigenetics
                Journal ID (iso-abbrev): Clin Epigenetics
                Title: Clinical Epigenetics
                Publisher: BioMed Central (London )
                ISSN (Print): 1868-7075
                ISSN (Electronic): 1868-7083
                Publication date (Electronic): 6 September 2021
                Publication date PMC-release: 6 September 2021
                Publication date Collection: 2021
                Volume: 13
                Electronic Location Identifier: 170
                Affiliations
                GRID grid.4305.2, ISNI 0000 0004 1936 7988, MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, , University of Edinburgh, ; Edinburgh, EH4 2XU UK
                Author information
                http://orcid.org/0000-0002-8431-7384
                Article
                Publisher ID: 1158
                DOI: 10.1186/s13148-021-01158-7
                PMC ID: 8419998
                PubMed ID: 34488874
                SO-VID: 96a0a68a-751c-45bb-8b78-447d9fe7988e
                Copyright © © The Author(s) 2021
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                Date received : 4 June 2021
                Date accepted : 2 August 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MR/S034676/1
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Author(s) 2021

                ScienceOpen disciplines: Genetics
                Keywords: cellular reprogramming,ageing,rejuvenation,epigenetic clocks,transient reprogramming,reprogramming-induced rejuvenation,epigenetic age
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: cellular reprogramming, ageing, rejuvenation, epigenetic clocks, transient reprogramming, reprogramming-induced rejuvenation, epigenetic age

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