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Cited by 499Epigenetics and DNA MethylationGenomics and Chromatin DynamicsGenetics, Aging, and Longevity in Model Organisms

The Aging Epigenome

Open access
Booth, Lauren N., Brunet, Anne·2016·Molecular Cell
DOI 10.1016/j.molcel.2016.05.013PMC PMC4917370
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Abstract

During aging, the mechanisms that normally maintain health and stress resistance strikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how this decline occurs is unknown. Changes in transcriptional networks and chromatin state lie at the heart of age-dependent decline. These epigenomic changes are not only observed during aging but also profoundly affect cellular function and stress resistance, thereby contributing to the progression of aging. We propose that the dysregulation of transcriptional and chromatin networks is a crucial component of aging. Understanding age-dependent epigenomic changes will yield key insights into how aging begins and progresses and should lead to the development of new therapeutics that delay or even reverse aging and age-related diseases.

Verified 2026-10-06 · 1 reference not checked yet

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Crossref · 10.1016/j.molcel.2016.05.013

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Claims the paper makes

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  • Interpretationnone given

    Changes in transcriptional networks and chromatin state are central to age-dependent decline.

    “Changes in transcriptional networks and chromatin state lie at the heart of age-dependent decline.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Aging involves progressive functional decline across molecular, cellular, tissue, and organismal levels.
  • Interpretationreasoning

    Dysregulation of transcriptional and chromatin networks is a crucial component of aging.

    “We propose that the dysregulation of transcriptional and chromatin networks is a crucial component of aging.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Aging involves progressive functional decline across molecular, cellular, tissue, and organismal levels.
  • Premisecitation

    Allele variants at FOXO3 are associated with extreme longevity in humans.

    “Indeed, allele variants at the FOXO3 locus are associated with extreme longevity (centenarians) in humans (for example, Willcox et al., 2008).”
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    Gene expression changes drastically during aging.

    “Indeed, gene expression has been shown to change drastically during aging (for example, Baumgart et al., 2014; Budovskaya et al., 2008; Zahn et al., 2007).”
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  • Premisecitation

    Changes in gene regulation, often through a single transcription factor, are key for cellular identity.

    “Changes in gene regulation (often through expression of a single transcription factor) have been shown to be key for cellular identity.”
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    • cites Herskowitz, 1989 source

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    • cites Graf, 2011 source

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    Premisecitation

    Transient ectopic expression of a small number of transcription factors in adult mammalian cells can convert terminally differentiated cells into pluripotent stem cells or other differentiated states.

    “Furthermore, transient, ectopic expression of a small number of transcription factors in adult mammalian cells can convert terminally differentiated cells into pluripotent stem cells or into other differentiated states (Graf, 2011).”
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    Interpretationreasoning

    Epigenomic changes occur during aging and affect cellular function and stress resistance, contributing to aging progression.

    “These epigenomic changes are not only observed during aging but also profoundly affect cellular function and stress resistance, thereby contributing to the progression of aging.”
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    • Rests on an assumption: Aging involves progressive functional decline across molecular, cellular, tissue, and organismal levels.

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    Premisecitation

    Molecular and cellular decline of aging can be organized into evolutionarily conserved hallmarks.

    “Over the past decades, a large body of research has shown that the molecular and cellular decline of aging can be organized into several evolutionarily conserved hallmarks or pillars of aging (Kennedy et al., 2014; López-Otín et al., 2013).”
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    Premisecitation

    In S. cerevisiae, three transcription factors control cell identity, and their mis-expression causes cell-cycle arrest and inability to mate.

    “This is illustrated by the fact that in Saccharomyces cerevisiae, only three transcription factors control cell identity, and their mis-expression results in cell-cycle arrest and an inability to mate (Herskowitz, 1989).”
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    Non-coding RNAs regulate chromatin states and gene expression.

    “Finally, non-coding RNAs have been found to play important roles in regulating chromatin states and gene expression (Rinn and Chang, 2012).”
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    Premisecitation

    Age-associated changes in transcription factor binding, histone marks, heterochromatin formation, and DNA methylation are pervasive across species and cell types and contribute to gene expression changes.

    “Recent studies in diverse species and cell types have highlighted the pervasiveness of age-associated changes in transcription factor binding, histone marks, heterochromatin formation, and DNA methylation (recently reviewed by Benayoun et al., 2015; Zampieri et al., 2015) that contribute to changes in gene expression.”
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    Premisenone given

    Gene regulation is a natural hub in the cell; transcription regulators and chromatin modifiers receive cytoplasmic and extracellular signals and alter cell responses.

    “Gene regulation is a natural “hub” in the cell. Transcription regulators and chromatin modifiers receive cytoplasmic and extracellular signals and, in turn, alter the responses of the cell in an orchestrated manner.”
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    Interpretationreasoning

    Age-associated changes in transcription regulatory networks likely impact cell or tissue function and give rise to aging phenotypes and diseases.

    “Thus, age-associated changes in transcription regulatory networks are likely to impact the function of a cell or tissue and give rise to aging phenotypes and diseases.”
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    Interpretationreasoning

    Age-associated changes in transcription factors and chromatin states represent a critical aspect of aging and a hub linking many hallmarks.

    “Because of their crucial role in cellular function, we propose that age-associated changes in transcriptional factors and chromatin states represent a critical aspect of the aging process and an important hub that links many hallmarks of aging.”
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    Premisecitation

    FOXO/DAF-16 promotes longevity and inhibits age-related diseases from worms to humans.

    “FOXO/DAF-16 promotes longevity and inhibits age-related diseases in species ranging from worms to humans (Eijkelenboom and Burgering, 2013; Salih and Brunet, 2008).”
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    Premisecitation

    In yeast and animals, mitochondrial dysfunction increases with age and may contribute to aging progression.

    “For example, in yeast and animals, mitochondrial dysfunction increases with age and may contribute to the progression of aging (Sun et al., 2016).”
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    Hallmarks of aging are interconnected, and perturbation of one can affect others.

    “The hallmarks of aging are interconnected (Kennedy et al., 2014; López-Otín et al., 2013; Zhang et al., 2015a), and age-associated perturbations of one can affect others.”
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    KDM6B/JMJD-3.1 and PHF8/JMJD-1.2 are necessary for lifespan extension induced by mitochondrial dysfunction, and overexpression of either extends lifespan in C. elegans.

    “In addition, KDM6B/JMJD-3.1 and PHF8/JMJD-1.2 are necessary for lifespan extension induced by mitochondrial dysfunction, and overexpression of either of these genes extends lifespan in C. elegans (Merkwirth et al., 2016).”
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    Interpretationcitation

    FOXO/DAF-16 and NRF/SKN-1 both promote changes in chromatin state and are sensitive to chromatin state.

    “Importantly, both FOXO/DAF-16 and NRF/SKN-1 not only promote changes in chromatin state (Riedel et al., 2013; Zaret and Carroll, 2011; Zhang et al., 2006) but also are sensitive to them (Domcke et al., 2015; Eijkelenboom et al., 2013; Webb et al., 2013).”
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    NRF/SKN-1 is implicated in general detoxification, proteostasis, and immunity.

    “Classically considered to control the transcriptional response to oxidative stress, NRF/SKN-1 has also been implicated in general detoxification, proteostasis, and immunity (Blackwell et al., 2015).”
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    Mice with higher PHF8/JMJD-1.2 expression are longer lived, suggesting link between PHF8 and longevity may be conserved from invertebrates to mammals.

    “Interestingly, mice with higher PHF8/JMJD-1.2 expression are longer lived, suggesting that the link between PHF8/JMJD-1.2 and longevity might be conserved from invertebrates to mammals (Merkwirth et al., 2016).”
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    Interpretationreasoning

    FOXO/DAF-16 regulates a gene program promoting stress resistance, which may link to lifespan extension.

    “Thus, FOXO/DAF-16 regulates a program of genes whose major function is to promote stress resistance, and this may be linked with their ability to extend lifespan.”
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    NRF/SKN-1 is a pro-longevity transcription factor; increasing active NRF/SKN-1 extends lifespan in flies and worms.

    “Like FOXO/DAF-16, NRF/SKN-1 is a “pro-longevity” transcription factor. Indeed, increasing the level of active NRF/SKN-1 extends lifespan in flies and worms (Sykiotis and Bohmann, 2008; Tullet et al., 2008).”
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    Interpretationreasoning

    NRF/SKN-1 is an important regulator of stress resistance and its activity is linked with chromatin state.

    “Together, these studies show that NRF/SKN-1 is an important regulator of stress resistance and that its activity is intimately linked with chromatin state.”
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    Premisecitation

    Knockdown of H3K27me3 demethylase UTX-1 increases lifespan in C. elegans, suggesting H3K27me3 levels are beneficial for longevity.

    “Knockdown of the H3K27me3 demethylase UTX-1 increases lifespan in C. elegans (Jin et al., 2011; Maures et al., 2011; Ni et al., 2012), suggesting that H3K27me3 levels are beneficial for longevity.”
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    In mammals, NRF2 recruits BRG2, a SWI/SNF component, to regulatory targets, increasing stress-response gene activation.

    “In mammals, NRF2 recruits BRG2, a component of the SWI/SNF nucleosome remodeling complex, to its regulatory targets (Zhang et al., 2006). This interaction results in increased transcriptional activation of stress-response genes (Zhang et al., 2006), presumably through changes in the chromatin landscape.”
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    Loss of Utx in mice is associated with severe developmental defects in females but not males, and shortened male lifespan.

    “In mice, loss of Utx is associated with severe developmental defects in females, but not males, and a shortened male lifespan (Welstead et al., 2012).”
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    Loss of Polycomb components increases lifespan in male Drosophila, suggesting increased H3K27me3 is detrimental for male lifespan.

    “Furthermore, loss of components of Polycomb, the H3K27 methyltransferase, increases lifespan in male Drosophila, suggesting that increased levels of H3K27me3 are detrimental for male lifespan (Siebold et al., 2010).”
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    FOXO binds open chromatin, especially enhancers, and can act as a pioneer factor to open closed chromatin.

    “Indeed, FOXO has been found to bind open chromatin, especially at enhancer regions (Eijkelenboom et al., 2013; Webb et al., 2013), and can act as a pioneer factor to open closed chromatin (Zaret and Carroll, 2011).”
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    Overexpression of H3K27me3 demethylase KDM6B/JMJD-3.1 extends lifespan, suggesting increased H3K27me3 at stress-response genes is detrimental.

    “In contrast, overexpression of the H3K27me3 demethylase KDM6B/JMJD-3.1 extends lifespan, suggesting that an increased level of H3K27me3 at specific loci (stress-response genes) is detrimental for lifespan (Labbadia and Morimoto, 2015).”
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    Premisecitation

    DNA methylation patterns can serve as a biomarker for human chronological age and perhaps biological age.

    “Intriguingly, DNA methylation patterns can serve as a biomarker for human chronological age (Horvath, 2013), and perhaps even biological age (i.e., how youthful or decrepit an individual actually is at a particular age).”
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    Hypomethylation is common with age, while some CpG islands and gene-rich regions become hypermethylated with age.

    “While hypomethylation is common with age, some CpG islands and gene-rich regions become hypermethylated with age (reviewed by Benayoun et al., 2015; Zampieri et al., 2015).”
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    Interpretationreasoning

    During aging, changes in histone mark patterning and levels could result from age-associated changes in transcription factor activity via altered expression or recruitment of histone-modifying complexes.

    “During aging, the changes in histone mark patterning and levels could be the result of age-associated changes in the activity of transcription factors, either through changes in the expression of the components of histone-modifying complexes or through the differential recruitment of these complexes to chromatin.”
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    Premisecitation

    Low H3K36me3 levels are correlated with increased cryptic transcription and greater gene expression change with age.

    “Interestingly, low levels of H3K36me3 are correlated with increased cryptic transcription (Sen et al., 2015) and a greater degree of gene expression change with age (Pu et al., 2015).”
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    Loci with age-dependent DNA hypermethylation are preferentially near tissue-specific genes, differentiation/development genes, transcription factor genes, and transcription factor binding sites.

    “Interestingly, the loci that display age-dependent DNA hypermethylation are preferentially near tissue-specific genes, genes involved in differentiation and development, genes encoding transcription factors, and transcription factor binding sites (reviewed by Benayoun et al., 2015; Zampieri et al., 2015).”
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    In mammals, genome-wide DNA methylation pattern changes during aging and could play a role in aging progression.

    “In mammals, the genome-wide pattern of DNA methylation changes during aging (Figure 2), and these changes could play a role in the progression of aging (Benayoun et al., 2015; Zampieri et al., 2015).”
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    Global H3K27me3 increases with age in killifish brain and mouse quiescent satellite cells but decreases during C. elegans aging and in human progeria models.

    “Global H3K27me3 increases with age in the killifish brain and mouse quiescent satellite cells (Baumgart et al., 2014; Liu et al., 2013) but decreases with age during C. elegans aging and in human progeria models (Maures et al., 2011; Ni et al., 2012; Shumaker et al., 2006; Zhang et al., 2015b).”
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    H3K4me3 deposition changes with age in murine hematopoietic stem cells, Drosophila, and cellular senescence in human fibroblasts.

    “H3K4me3, a mark associated with active transcription, has also been implicated in longevity, and its deposition changes with age in murine hematopoietic stem cells and in Drosophila (Sun et al., 2014; Wood et al., 2010) and cellular senescence in human fibroblasts (Shah et al., 2013).”
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    Knockdown of H3K4me3 demethylases KDM5B/RBR-2 and KDM1A/LSD-1 can extend lifespan often in context of sterility, or has no effect.

    “However, it has also been found that knockdown of the H3K4me3 demethylases (KDM5B/RBR-2 and KDM1A/LSD-1) can extend lifespan, often in the context of sterility (Lee et al., 2003; McColl et al., 2008; Ni et al., 2012), or has no effect on lifespan (Li et al., 2010).”
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    Premisecitation

    Deletion of H3K36me3 demethylase extends lifespan in S. cerevisiae and C. elegans, whereas deletion of H3K36 methyltransferase met-1 shortens lifespan in C. elegans.

    “Consistent with this finding, deletion of the H3K36me3 demethylase extends lifespan in S. cerevisiae and C. elegans (Ni et al., 2012; Sen et al., 2015), whereas deletion of the H3K36 methyltransferase (met-1) in C. elegans shortens lifespan (Pu et al., 2015).”
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    In young vs old murine hematopoietic stem cells, H3K27me3 levels increased at most loci but decreased at some loci with age.

    “A comparison of H3K27me3 deposition in young versus old murine hematopoietic stem cells revealed that while H3K27me3 levels increased at most loci, there were also loci with decreased H3K27me3 levels with age (Sun et al., 2014).”
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    Interpretationnone given

    Chromatin and transcription regulation play key roles in age-dependent manifestation of hallmarks of aging and response to their emergence.

    “Excitingly, chromatin and transcription regulation have been found to play key roles in the age-dependent manifestation of these hallmarks of aging and in the response to their emergence (Figure 3).”
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    Interpretationreasoning

    Potential gene expression effects of age-associated differential DNA methylation are context dependent and may require local changes in histone marks and transcription factor binding before gene expression changes.

    “Thus, the potential gene expression effects of age-associated differential DNA methylation are likely to be context dependent and may require local changes in histones marks and transcription factor binding to occur before gene expression changes are observed.”
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    Premisecitation

    Nucleosome occupancy changes are associated with global upregulation of gene expression with age in yeast and increased FOXA2 binding in aged mammalian livers.

    “Interestingly, nucleosome occupancy changes have also been demonstrated to be associated with the global upregulation of gene expression with age in yeast (Hu et al., 2014) and increased transcription factor (FOXA2) binding in aged mammalian livers (Bochkis et al., 2014).”
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    Premisecitation

    With age, telomere attrition occurs, somatic DNA mutations accumulate, transposons activate, and chromosomal abnormalities increase.

    “With age, telomere attrition occurs, somatic DNA mutations accumulate, and transposons activate. There is also an increase in the rate of chromosomal abnormalities, some of which are oncogenic.”
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    Premisecitation

    Nucleosome occupancy can decrease with age, and ameliorating this loss in yeast increases lifespan.

    “Nucleosome occupancy can decrease with age (Figure 2), and ameliorating this loss in yeast increases lifespan (Feser et al., 2010; Hu et al., 2014; Ivanov et al., 2013).”
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    Premisecitation

    During normal aging in humans and invertebrates, HP1 and H3K9me3 levels decline, suggesting loss of heterochromatin is a common feature of aging.

    “Importantly, during normal aging in humans and invertebrates, HP1 and H3K9me3 levels also decline (Figure 2), suggesting that loss of heterochromatin is a common feature of aging (Larson et al., 2012; Ni et al., 2012; Scaffidi and Misteli, 2006; Wood et al., 2010).”
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    Premisecitation

    The autophagosome can selectively degrade endoplasmic reticulum and nucleus, and this degradation can lead to loss of nuclear lamina.

    “Intriguingly, it was recently discovered that the autophagosome can selectively degrade the endoplasmic reticulum and the nucleus (Mochida et al., 2015), and that this degradation can lead to a loss of the nuclear lamina (Dou et al., 2015).”
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    Premisecitation

    Levels of a cryptic splice isoform that results in truncated lamin A and mimics HGPS mutation increase with age in humans and contribute to loss of heterochromatin.

    “Interestingly, the nuclear envelope may play a role in heterochromatin loss in both normal and progeroid aging: the levels of a cryptic splice isoform that results in a truncated nuclear envelope protein lamin A, and that mimics the mutation of HGPS, increase with age in humans and contribute to the loss of heterochromatin (Scaffidi and Misteli, 2006).”
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    Premisecitation

    In aged β cells, a significant correlation between DNA methylation and gene expression changes exists for distal regulatory regions (enhancers) but not proximal regulatory regions (promoters).

    “However, at least in the case of aged β cells, a significant correlation between DNA methylation and gene expression changes exists for distal regulatory regions (enhancers), but not proximal regulatory regions (promoters) (Avrahami et al., 2015).”
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    Premisecitation

    In mammalian muscle stem cells, loss of core histones with age is due to changes in gene expression and is linked with H3K27me3 at histone genes.

    “However, in mammalian muscle stem cells, the loss of core histones with age appears to be due to changes in gene expression and is linked with the amount of the repressive H3K27me3 mark at the histone genes (Liu et al., 2013).”
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    Interpretationreasoning

    Positioning of nucleosomes on DNA changes with age, and changes in transcription factor activity and chromatin landscape can trigger these changes.

    “Together, these studies show that the positioning of nucleosomes on DNA changes with age and that changes in transcription factor activity and the chromatin landscape can trigger these changes during aging.”
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    Premisecitation

    Damaged telomeres can lead to reduction in core histone expression, suggesting loss of telomere integrity can cause changes in aging chromatin landscape.

    “Interestingly, damaged telomeres can also lead to a reduction in the expression of core histones in a cell, suggesting that a loss of telomere integrity can cause changes in the aging chromatin landscape (O’Sullivan et al., 2010).”
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    Premisenone given

    Large-scale chromosomal abnormalities differ from mutation accumulation in molecular origin and sensitivity to DNA methylation changes.

    “these large-scale chromosomal abnormalities are distinct from other aspects of genome instability, such as mutation accumulation, in both their molecular origin and sensitivity to DNA methylation changes.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Age-dependent DNA hypermethylation at specific loci may contribute to accumulation of point mutations during aging.

    “This raises the possibility that age-dependent DNA hypermethylation (increased DNA methylation) at specific loci contributes to the accumulation of point mutations during aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In murine embryonic stem cells, DNA damage relocates SIRT1 from promoters to DNA damage sites and changes gene expression resembling organismal aging.

    “In murine embryonic stem cells, DNA damage relocates the transcriptional silencer SIRT1 from promoters to the site of DNA damage and changes gene expression in a way that resembles organismal aging (Oberdoerffer et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oberdoerffer et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In yeast, rate of age-associated mutation accumulation is low and unlikely to play a major role in aging progression.

    “It is important to note, however, that in yeast the rate of age-associated mutation accumulation is low, and thereby is unlikely to play a major role in the progression of aging (Kaya et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kaya et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In yeast, age-related nucleosome loss is associated with increased Ty expression and perhaps retrotransposition.

    “in yeast, the loss of nucleosomes with age is associated with increased expression (and perhaps increased retrotransposition) of the Ty retrotransposable element (Hu et al., 2014).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hu et al., 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recruitment of SIRT6 to DNA damage sites remodels local chromatin via deacetylation of H3K56 and allows DNA repair machinery access.

    “The recruitment of SIRT6 to sites of DNA damage helps to remodel the local chromatin environment through deacetylation of H3K56 and allow DNA repair machinery to access the DNA (Toiber et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Toiber et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Deletion of SIRT6 causes more rapid aging in mice and increased genomic instability, suggesting changes in SIRT6 activity and H3K56 acetylation during normal aging could impact DNA repair.

    “Deletion of SIRT6 causes more rapid aging in mice and increased genomic instability (Mostoslavsky et al., 2006), suggesting that changes in SIRT6 activity and H3K56 acetylation during normal aging could impact the cell’s ability to repair DNA damage.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Mostoslavsky et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Disruption of mitochondrial activity, mtDNA mutations, and changes in mitochondrial biogenesis are functionally implicated in aging progression.

    “mutations in mtDNA, and changes inmitochondrial biogenesis have been functionally implicated in the progression of aging (reviewed by Sun et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sun et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Accumulation of DNA damage and loss of SIRT1 repression may underlie age-associated epigenomic changes.

    “This suggests that an accumulation of DNA damage and loss of SIRT1 repression may underlie age-associated epigenomic changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mitochondrial turnover declines and mitochondrial dysfunction increases as cells age.

    “As cells age, mitochondrial turnover declines and mitochondrial dysfunction increases (Sun et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sun et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During human aging, mutations accumulate in blood cell genome and C-to-T mutations are most prevalent.

    “Interestingly, during human aging, mutations accumulate in the genome of blood cells and C-to-T mutations are the most prevalent (Welch et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Welch et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Older yeast have less active Sir2 and increased H4K16 acetylation at telomeres.

    “Consistent with a link between longevity and telomere silencing, older yeast have less active Sir2 (a sirtuin) and, as a result, increased H4K16 acetylation at telomeres (Dang et al., 2009).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dang et al., 2009 source

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  • May combine two claims.

    Premisecitation

    DNA damage can result in transient gene repression and stable gene expression changes observed in humans as young as 40.

    “DNA damage can result in transient gene repression (Kim et al., 2016) as well as more stable changes in gene expression that can be observed in humans as young as 40 years of age (Lu et al., 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kim et al., 2016 source

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    • cites Lu et al., 2004

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In yeast, mitochondrial signals trigger nuclear gene expression changes, and this retrograde regulation is required for longer replicative lifespan of yeast lacking mtDNA.

    “In yeast, signals from the mitochondria can trigger gene expression changes in the nucleus (retrograde regulation), and this regulation is required for the longer replicative lifespan of yeast lacking mtDNA (Kirchman et al., 1999).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kirchman et al., 1999 source

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  • May combine two claims.

    Interpretationcitation

    Accumulation of DNA damage during life could be a source of age-associated epigenomic changes, and chromatin state could affect DNA repair.

    “Interestingly, sensing and responding to DNA damage involves the recruitment of chromatin modifiers, suggesting that an accumulation of DNA damage during life could be a source for age-associated epigenomic changes and that changes in chromatin state could affect DNA repair (Burgess et al., 2012; Oberdoerffer and Sinclair, 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Burgess et al., 2012 source

      Not checked in the free run.

    • cites Oberdoerffer and Sinclair, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UPRmt responds to mitochondrial unfolded proteins, unbalanced nuclear:mitochondrial-encoded OXPHOS enzymes, mtDNA depletion, and respiratory chain decline.

    “the UPRmt responds to unbalanced levels of nuclear:mitochondrial-encoded oxidative phosphorylation enzymes, mtDNA depletion, and decline of the respiratory chain (Schulz and Haynes, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Schulz and Haynes, 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. elegans, the XBP-1 branch of UPRER declines early with age, and neuronal XBP-1 overexpression extends lifespan.

    “In C. elegans, the XBP-1 branch of the UPRER declines relatively early with age and overexpression of XBP-1 in neurons can extend lifespan, suggesting an important role for the UPRER in longevity (reviewed by Taylor, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor, 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    XBP1 and UPRER play a role in human neurodegenerative diseases including Alzheimer's, with early neuroprotective and later neuronal death contributions.

    “XBP1 and the UPRER have also been found to play a role in human neurodegenerative diseases, including Alzheimer’s disease, where UPRER/XBP1 activation is thought to be neuroprotective early in the disease onset but then a contributor to neuronal death during later disease stages (reviewed by Taylor, 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Taylor, 2016 source

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  • May combine two claims.

    Premisecitation

    Overexpression of KDM6B/JMJD-3.1 extends C. elegans lifespan and improves stress tolerance.

    “overexpression of the H3K27me3 demethylase KDM6B/JMJD-3.1 extends C. elegans lifespan and improves stress tolerance (Labbadia and Morimoto, 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Labbadia and Morimoto, 2015

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  • May combine two claims.

    Premisecitation

    Proteostasis and the HSF-1 response decline with age.

    “Proteostasis and the HSF-1 response decline with age (Labbadia and Morimoto, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Labbadia and Morimoto, 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This H3K27me3 change occurs at the beginning of adulthood and may be linked to germline signals.

    “This change occurs at the very beginning of adulthood and, similar to DAF-16 regulation, may be linked to signals from the germline (Hsin and Kenyon, 1999; Labbadia and Morimoto, 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hsin and Kenyon, 1999

      Not checked in the free run.

    • cites Labbadia and Morimoto, 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Epigenomic changes are among the first to occur during aging and trigger other hallmarks of aging.

    “This suggests the exciting idea that epigenomic changes are one of the first to occur during aging and that these changes trigger the emergence of other hallmarks of aging (Labbadia and Morimoto, 2015).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Labbadia and Morimoto, 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In mammals, SRF and HSF2 contribute to the heat shock transcriptional response.

    “In mammals, additional transcription factors, including SRF and HSF2, are important contributors to the transcriptional response to heat shock (Mahat et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mahat et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    REST and its invertebrate ortholog SPR-4 protect neurons from amyloid β-protein toxicity and oxidative stress.

    “REST, and its invertebrate ortholog SPR-4, protects neurons from amyloid β-protein toxicity as well as oxidative stress (Lu et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lu et al., 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clearing senescent cells from adult mice by ABT263 or inducible transgene rejuvenates hematopoietic and muscle stem cells, slows age-related disease, and increases lifespan.

    “Clearing senescent cells from adult mice by inducing apoptosis with the drug ABT263 or an inducible transgene rejuvenates hematopoietic and muscle stem cells, slows the onset of age-related disease, and increases lifespan (Baker et al., 2016; Chang et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Baker et al., 2016 source

      Not checked in the free run.

    • cites Chang et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increases in senescent cells and declines in tissue regeneration due to stem cell proliferation loss are hallmarks of aging.

    “An increase in the number of senescent cells and a decline in tissue regeneration due to the loss of stem cell proliferation are both hallmarks of aging (López-Otín et al., 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites López-Otín et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nuclear lamin defects can activate p53 and induce p53 target genes.

    “nuclear lamin defects can activate p53 and induce expression of p53 target genes (Varela et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Varela et al., 2005 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p300 knockdown causes H3/H4 hypoacetylation and increased senescence in human cells, providing evidence for a causative chromatin-senescence link.

    “knockdown of the histone acetyltransferase p300 results in hypoacetylation of histones H3 and H4 and an increase in senescence in human cells, providing evidence for a causative link between changes in chromatin state and senescence (Prieur et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Prieur et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    REST dysregulation is a key early event in Alzheimer's disease, identified in human brain tissue.

    “a recent study using human brain tissue identified dysregulation of the transcription factor REST (also known as NRSF) as a key, early event in the development of Alzheimer’s disease (Lu et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lu et al., 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Changes in NAD+ availability during aging can affect sirtuin activity, causing altered gene expression and chromatin state.

    “Changes in the availability of NAD+ during aging can affect the activity of the sirtuins, yielding altered gene expression and chromatin state with age.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Appropriate p53 regulation is key for longevity, and dysregulation can lead to more rapid aging and increased senescence.

    “Thus, appropriate regulation of the transcription factor p53 is key for longevity, and its dysregulation can lead to more rapid aging and increased senescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mammals, p300/CBP acts as a CREB co-activator through histone acetylation, linking nutrient sensing, chromatin, and gene expression.

    “in mammals, p300/CBP also acts as a CREB co-activator through histone acetylation (e.g., H3K27ac and H3K14ac), suggesting a link between nutrient sensing, chromatin, and gene expression (Altarejos and Montminy, 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Altarejos and Montminy, 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Patients with HGPS and Werner syndrome have high senescent cells and low proliferative potential, thought to result from loss of lamin-associated heterochromatin.

    “Patients with the progeroid diseases HGPS and Werner syndrome have abnormally high levels of senescent cells and low proliferative potential, and these changes are thought to be the result of a loss of lamin-associated heterochromatin (Shumaker et al., 2006; Zhang et al., 2015b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Shumaker et al., 2006 source

      Not checked in the free run.

    • cites Zhang et al., 2015b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT1 activity is circadian and helps control circadian gene expression through interaction with circadian transcription network and an H3K4 methyltransferase.

    “SIRT1 activity is circadian, and through an interaction with components of the circadian transcription regulatory network and an H3K4 methyltransferase, SIRT1 helps to control circadian gene expression patterns (Aguilar-Arnal et al., 2015; Orozco-Solis and Sassone-Corsi, 2014).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Aguilar-Arnal et al., 2015 source

      Not checked in the free run.

    • cites Orozco-Solis and Sassone-Corsi, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activity of these transcription factors increases with age in humans, and reducing NF-κB activity ameliorates mouse progeria models and reverses age-associated pathology.

    “the activity of these transcription factors increases with age in humans, and reducing NF-κB activity ameliorates mouse models of progeria and reverses age-associated pathology (O’Brown et al., 2015; Tilstra et al., 2011).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites O’Brown et al., 2015 source

      Not checked in the free run.

    • cites Tilstra et al., 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MLL1 is required for SASP-related gene expression and promotes increased inflammation.

    “the H3K4 methyltransferase MLL1 is required for expression of SASP-related genes and promotes increased inflammation (Capell et al., 2016).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Capell et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NF-κB activates Jmjd3 expression in immune cells, causing H3K27me3 loss.

    “NF-κB activates the expression of the H3K27me3 demethylase Jmjd3 in immune cells, leading to a loss of H3K27me3 (De Santa et al., 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites De Santa et al., 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Perturbing circadian rhythm shortens lifespan and causes metabolic defects and diseases including obesity and diabetes.

    “Genetic and environmental manipulations that perturb circadian rhythm shorten lifespan and result in metabolic defects and diseases including obesity and diabetes (Kondratov, 2007).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kondratov, 2007 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reprogramming cells from elderly humans (up to 101 years) into pluripotent cells erases many hallmarks of aging and restores youthful gene expression maintained during differentiation.

    “Reprogramming cells from elderly humans (as old as 101 years of age) into pluripotent cells erases many of the hallmarks of aging and restores a youthful gene expression profile that is maintained during differentiation (Lapasset et al., 2011; Mertens et al., 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lapasset et al., 2011 source

      Not checked in the free run.

    • cites Mertens et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Induction of pluripotency and trans-differentiation require different transcription factors and likely produce distinct changes in transcriptional networks and chromatin state.

    “The induction of pluripotency and the trans-differentiation of cells require different sets of transcription factors (Graf, 2011) and are thus likely to result in distinct changes in transcriptional networks and chromatin state.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Graf, 2011 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Epigenetic state is highly responsive to environment, so exposure to youthful circulating factors could reverse or slow age-related epigenetic changes.

    “Epigenetic state (including chromatin marks and gene expression) are highly responsive to the environment, and, therefore, one might expect that exposure to more youthful circulating factors could reverse or slow the appearance of age-related epigenetic changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    HGPS patient-derived cells treated with Remodelin had improved nuclear architecture and increased chromatin compaction, consistent with heterochromatin gain.

    “when cells derived from patients with the progeria disease HGPS were treated with the drug Remodelin, the cells had improved nuclear architecture and increased chromatin compaction, consistent with a gain of heterochromatin (Larrieu et al., 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Larrieu et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An old nucleus can become pluripotent and youthful again after fertilization, and this can be mimicked by nuclear transfer or induced pluripotency.

    “The ability of an old nucleus to become pluripotent and youthful again is a phenomenon that occurs as a result of fertilization and that can be mimicked in the lab through nuclear transfer or by inducing pluripotency through the expression of particular transcription factors (Rando and Chang, 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rando and Chang, 2012 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Reprogramming can reset the aging clock even for very old cells, suggesting no point during aging when this therapeutic would be ineffective.

    “This suggests that reprogramming can reset the aging clock even for very old cells and could indicate that there is no point during aging when this therapeutic would not be effective (Figure 4).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These drugs could potentially slow aging or treat age-related diseases.

    “it is possible that these drugs could be utilized to slow the progression of aging or to treat age-related diseases.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Gene regulation is a crucial hub in the aging network.

    “Gene regulation is a crucial hub in this network”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Effects of caloric restriction can be long lasting and passed to next generation.

    “The effects of caloric restriction can be long lasting and even be passed on to the next generation (Fontana and Partridge, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fontana and Partridge, 2015 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Many molecular signatures of aging including stem cell exhaustion, altered intercellular signaling, and loss of genome integrity are reversed by heterochronic parabiosis, suggesting epigenome and gene expression could also be restored.

    “Many of the molecular signatures of aging, including stem cell exhaustion, altered intercellular signaling, and a loss of genome integrity, are reversed in an old mouse as a result of heterochronic parabiosis, suggesting that the epigenome and gene expression could also be restored to a more youthful state by this treatment (Rando and Chang, 2012; Sinha et al., 2014)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Rando and Chang, 2012 source

      Not checked in the free run.

    • cites Sinha et al., 2014 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Initiation timing and duration of metabolic interventions can alter their effect on longevity, indicating context matters and they are not one-size-fits-all.

    “the initiation timing and duration of these metabolic interventions (exercise and diet changes) can alter their effect on longevity, suggesting that context is an important factor and that these are not “one size fits all” interventions (Fontana and Partridge, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Fontana and Partridge, 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rapamycin and metformin can mimic effects of exercise and diet changes.

    “There are also drugs, such as rapamycin and metformin, that are able to mimic the effects of exercise and diet changes (Mercken et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mercken et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise and dietary changes including caloric restriction and intermittent fasting can slow and even reverse aging progression.

    “Exercise and dietary changes, including caloric restriction and intermittent fasting, can slow and even reverse the progression of aging (Brandhorst et al., 2015; Fontana and Partridge, 2015; Garatachea et al., 2015; Mercken et al., 2012)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Brandhorst et al., 2015 source

      Not checked in the free run.

    • cites Fontana and Partridge, 2015 source

      Not checked in the free run.

    • cites Garatachea et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Diet and exercise changes affect insulin/IGF signaling and AMPK and alter expression of many genes.

    “Changes in diet and exercise impact the activity of various longevity regulatory mechanisms, including insulin/IGF signaling and the nutrient-sensing kinase AMPK, and can alter the expression of many genes (Fontana and Partridge, 2015; Garatachea et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fontana and Partridge, 2015 source

      Not checked in the free run.

    • cites Garatachea et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Aging is the result of dysfunction of a complex network maintaining organismal health, tissue homeostasis, and stress resistance.

    “aging is the result of dysfunction of a complex network that maintains organismal health, tissue homeostasis, and stress resistance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Epigenomic regulation is highly connected to other hallmarks, and dysregulation of gene expression and epigenome promotes aging.

    “epigenomic regulation is highly connected to the other hallmarks of aging, and dysregulation of gene expression and the epigenome promote the progression of aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Age-associated gene expression changes have been identified at single-cell level in hematopoietic stem and progenitor cells, suggesting that for some tissues, cellular composition changes cannot fully explain age-associated epigenomic dysregulation.

    “age-associated gene expression changes have recently been identified at the single-cell level in hematopoietic stem and progenitor cells (Kowalczyk et al., 2015), suggesting that at least for some tissues, changes in the cellular composition of a tissue with age cannot fully explain age-associated epigenomic dysregulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kowalczyk et al., 2015 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Exceptionally long or short natural lifespans may have distinct molecular causes.

    “suggests that unique molecular mechanisms may underlie the exceptionally long or short lifespans found in nature”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Lifespans differ among species, including closely related species.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Changes in transcription regulatory networks during evolution contribute substantially to phenotypic diversity.

    “Interestingly, the evolution of transcription regulatory networks is a rich source of phenotypic diversity (Carroll, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Carroll, 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Age-associated changes in gene regulation could trigger other hallmarks of aging in a snowball effect.

    “age-associated changes in gene regulation could in turn trigger the emergence of other hallmarks of aging in a snowball effect (Figure 4).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Two mechanisms could underlie observed age-associated epigenomic changes: tissue cellular composition changes with age and/or cell-intrinsic gene expression/chromatin changes.

    “two mechanisms could underlie the observed, age-associated epigenomic changes: (1) the exact cellular composition of a tissue or organism may change with age (even within highly purified populations of cells), and/or (2) the gene expression and chromatin state within the cells that normally reside in a particular tissue may change.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Changes in one generation could influence gametes and perhaps be passed to next generations.

    “changes in one generation could even influence the gametes and perhaps be passed on to next generations (Lim and Brunet, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lim and Brunet, 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    More chromatin marks and transcription factor families are still being discovered.

    “many more chromatin marks and even transcription factor families are still being discovered (Lohse et al., 2010; Luo et al., 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Lohse et al., 2010 source

      Not checked in the free run.

    • cites Luo et al., 2015 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Aging and longevity evolve.

    “The diversity of lifespans between species, even closely related species, illustrates that aging and longevity evolve”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Lifespans differ among species, including closely related species.
110 of 110

  • The paper relies on this without support.

    Aging involves progressive functional decline across molecular, cellular, tissue, and organismal levels.

    “Aging is characterized by progressive functional decline at the molecular, cellular, tissue, and organismal levels.”

  • The paper relies on this without support.

    In humans, age is the main risk factor for many diseases including neurodegeneration, cardiovascular disease, diabetes, osteoporosis, and cancer.

    “In humans, age is the primary risk factor for a panoply of diseases including neurodegeneration, cardiovascular disease, diabetes, osteoporosis, and cancer.”

  • The paper relies on this without support.

    Chromatin marks persist long and change progressively with age through cell divisions.

    “Chromatin marks are long lasting and show a progressive change with age that persists through cellular divisions.”

  • The paper relies on this without support.

    Recent evidence indicates epigenomic changes can occur very early in aging and be causative.

    “Recent evidence suggests that epigenomic changes can occur extremely early in the aging process and be causative.”

  • The paper relies on this without support.

    The order and molecular mechanism of youthful gene regulation can reveal the relationship and order of age-associated epigenomic and gene expression changes.

    “The order and molecular mechanism of youthful gene regulation can give clues about the relationship between and order of age-associated epigenomic and gene expression changes.”

  • The authors state this as an assumption.

    A model for normal DNA methylation patterning holds that H3K27 methylation repression occurs first and is then locked in by DNA methyltransferases.

    “One model for normal DNA methylation patterning is that repression by H3K27 methylation occurs first and is “locked in” by the subsequent action of DNA methyltransferases.”

  • The paper relies on this without support.

    Lifespans differ among species, including closely related species.

    “The diversity of lifespans between species, even closely related species”

  • The paper relies on this without support.

    Alterations in gene expression and regulation can strongly influence how well cells or organisms tolerate stress as environments change and as they age.

    “these changes can also profoundly impact the ability of a cell or organism to withstand stress in a changing environment and throughout an animal’s lifespan”

  • The paper relies on this without support.

    Individuals within a species vary in how long they live.

    “Lifespan differences also exist between individuals of the same species.”

  • The authors state this as an assumption.

    The molecular basis of lifespan differences between and within species is not fully understood.

    “we do not fully understand the molecular basis of interand intra-species lifespan differences”
10 of 10

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A consistent trend in aging is loss of heterochromatin and associated transcriptional de-repression at sites across the genome, observed from yeast to humans.

    “These changes are complex and generally cell-type specific, but a consistent trend is the loss of heterochromatin and an associated transcriptional de-repression at sites across the genome, which has been observed in species from yeast to humans55–57.”

    From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [55]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • The Nrf2-associated remodeler has two different names

    Minor

    The discussion names BRG2 as the Nrf2-associated protein, but the cited reference identifies BRG1. The protein name is inconsistent within the paper.

1 of 1

Cites

Flagged first, then by citations

1 of the 156 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Booth, L. N., & Brunet, A.
Affiliations
Stanford University (US)
Corresponding author
Brunet, Anne
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2016-06
Volume
62
Issue
5
Pages
728-744
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2016.05.013
PMC
PMC4917370
OpenAlex
W2415866521
Semantic Scholar
0ce183e944620e6c917b20635901d47ca5fc437f
Cited by
499
References
156
Citations by year
2026: 35 · 2025: 41 · 2024: 45 · 2023: 48 · 2022: 53 · 2021: 80 · 2020: 62 · 2019: 45 · 2018: 57 · 2017: 25 · 2016: 7
FWCI
3.99
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute on Aging (R56AG031198, DP1AG044848, P01AG036695)
  • National Human Genome Research Institute (T32HG000044)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
aging, epigenome, chromatin state, transcriptional regulatory networks, stress tolerance, frailty, age-related diseases, anti-aging therapeutics, epigenetic dysregulation
MeSH terms
Age Factors, Aging, Animals, DNA, Mitochondrial, Genotype, Histones, Humans, Mitochondria, Nutritional Status, Phenotype, Transcription Factors, Transcription, Genetic, Telomere, DNA Methylation, RNA, Untranslated, Chromatin Assembly and Disassembly, Genomic Instability, Epigenesis, Genetic, Epigenomics

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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