Targeting chromatin aging - The epigenetic impact of longevity-associated interventions

Field, Adam E.; Adams, Peter D.

doi:10.1016/j.exger.2016.12.010

Cited by 19 publications

(14 citation statements)

References 39 publications

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“…Such age-associated signatures in the DNA methylome have also been recently described in dogs and wolves [ 78 ]. These findings have led to the notion that there exists an ‘epigenetic’ or ‘methylome’ clock, and that this dynamic, age-associated change in genome-wide DNA methylation patterns could influence the ageing process itself and in turn be influenced by therapeutic interventions [ 79 – 81 ]. While many tissues do indeed show evidence of such age-associated alterations, some tissues, such as the murine hippocampus, do not exhibit any detectable change in DNA methylation or the expression of cytosine-modifying enzymes during ageing of either sex [ 82 ].…”

Section: Similar Epigenetic Alterations May Occur In Senescence Cancmentioning

confidence: 99%

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

Harrington

Pucci

2018

Phil. Trans. R. Soc. B

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The integrity of chromosome ends, or telomeres, depends on myriad processes that must balance the need to compact and protect the telomeric, G-rich DNA from detection as a double-stranded DNA break, and yet still permit access to enzymes that process, replicate and maintain a sufficient reserve of telomeric DNA. When unable to maintain this equilibrium, erosion of telomeres leads to perturbations at or near the telomeres themselves, including loss of binding by the telomere protective complex, shelterin, and alterations in transcription and post-translational modifications of histones. Although the catastrophic consequences of full telomere de-protection are well described, recent evidence points to other, less obvious perturbations that arise when telomere length equilibrium is altered. For example, critically short telomeres also perturb DNA methylation and histone post-translational modifications at distal sites throughout the genome. In murine stem cells for example, this dysregulated chromatin leads to inappropriate suppression of pluripotency regulator factors such as Nanog. This review summarizes these recent findings, with an emphasis on how these genome-wide, telomere-induced perturbations can have profound consequences on cell function and fate.This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.

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Section: Similar Epigenetic Alterations May Occur In Senescence Cancmentioning

confidence: 99%

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

Harrington

Pucci

2018

Phil. Trans. R. Soc. B

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“…Our ensemble approach provides a framework that supports heterogeneity of epigenetic states as an engine that facilitates cancer hallmarks and other aging diseases. On the one hand, the ability of resilient states to maintain large epigenetic barriers refractory to non-physiologic cell fate transitions might explain why the NAD+-dependent HDAC/sirtuin pathway is one of the few mechanisms described to mediate the correction or resetting of the abnormal chromatin state of aging cells induced by calorie restriction, the most robust life span-extending and cancer preventing regimen [ 2 , 66 – 68 ]. On the other hand, the ability of plastic states to lower epigenetic barriers, and increase the sensitivity of primed cells to undergo reprogramming-like events leading to loss of cell identity is consistent with the ability of certain metabolites to promote oncogenesis by epigenetically blocking the HDM-regulated acquisition of differentiation markers [ 17 , 69 – 71 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic regulation of cell fate reprogramming in aging and disease: A predictive computational model

et al. 2018

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Understanding the control of epigenetic regulation is key to explain and modify the aging process. Because histone-modifying enzymes are sensitive to shifts in availability of cofactors (e.g. metabolites), cellular epigenetic states may be tied to changing conditions associated with cofactor variability. The aim of this study is to analyse the relationships between cofactor fluctuations, epigenetic landscapes, and cell state transitions. Using Approximate Bayesian Computation, we generate an ensemble of epigenetic regulation (ER) systems whose heterogeneity reflects variability in cofactor pools used by histone modifiers. The heterogeneity of epigenetic metabolites, which operates as regulator of the kinetic parameters promoting/preventing histone modifications, stochastically drives phenotypic variability. The ensemble of ER configurations reveals the occurrence of distinct epi-states within the ensemble. Whereas resilient states maintain large epigenetic barriers refractory to reprogramming cellular identity, plastic states lower these barriers, and increase the sensitivity to reprogramming. Moreover, fine-tuning of cofactor levels redirects plastic epigenetic states to re-enter epigenetic resilience, and vice versa. Our ensemble model agrees with a model of metabolism-responsive loss of epigenetic resilience as a cellular aging mechanism. Our findings support the notion that cellular aging, and its reversal, might result from stochastic translation of metabolic inputs into resilient/plastic cell states via ER systems.

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“…Aging is associated with increased cellular senescence, which is characterized by profound chromatin/secretome changes and is associated with an abnormal microenvironment (Avrahami et al., 2015; Field & Adams, 2017). With dramatically increased bone marrow inflammatory factor levels, a sharply diminished blood supply and a markedly impaired local “stem cell niche” during aging, multiple cell types, especially “mesenchymal stromal/stem cells” in the bone microenvironment, become senescent.…”

Section: Discussionmentioning

confidence: 99%

Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti‐inflammatory and angiogenic environment in aging mice

et al. 2018

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SummaryAging drives the accumulation of senescent cells (SnCs) including stem/progenitor cells in bone marrow, which contributes to aging‐related bone degenerative pathologies. Local elimination of SnCs has been shown as potential treatment for degenerative diseases. As LepR+ mesenchymal stem/progenitor cells (MSPCs) in bone marrow are the major population for forming bone/cartilage and maintaining HSCs niche, whether local elimination of senescent LepR+ MSPCs delays aging‐related pathologies and improves local microenvironment need to be well defined. In this study, we performed local delivery of tetramethylpyrazine (TMP) in bone marrow of aging mice, which previously showed to be used for the prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP). We found the increased accumulation of senescent LepR+ MSPCs in bone marrow of aging mice, and TMP significantly inhibited the cell senescent phenotype via modulating Ezh2‐H3k27me3. Most importantly, local delivery of TMP improved bone marrow microenvironment and maintained bone homeostasis in aging mice by increasing metabolic and anti‐inflammatory responses, inducing H‐type vessel formation, and maintaining HSCs niche. These findings provide evidence on the mechanisms, characteristics and functions of local elimination of SnCs in bone marrow, as well as the use of TMP as a potential treatment to ameliorate human age‐related skeletal diseases and to promote healthy lifespan.

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Targeting chromatin aging - The epigenetic impact of longevity-associated interventions

Cited by 19 publications

References 39 publications

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

In medio stat virtus : unanticipated consequences of telomere dysequilibrium

Epigenetic regulation of cell fate reprogramming in aging and disease: A predictive computational model

Local delivery of tetramethylpyrazine eliminates the senescent phenotype of bone marrow mesenchymal stromal cells and creates an anti‐inflammatory and angiogenic environment in aging mice

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