Aging in the Brain: New Roles of Epigenetics in Cognitive Decline

Barter, Jolie; Foster, Thomas C.

doi:10.1177/1073858418780971

Cited by 76 publications

(80 citation statements)

References 67 publications

(112 reference statements)

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“…During aging, biological, environmental, and lifestyle factors drive epigenetic modifications resulting in phenotypic differences. These changes alter almost all tissues and organs, although the brain is one of the most affected structures, leading to a progressive decline in the cognitive function (Barter & Foster, ; Fraga et al, ; Starnawska et al, ) and creating a context favorable for the development of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

“…Epigenetic mechanisms regulate a plethora of brain functions including activity‐dependent transcription, synaptic plasticity (Borrelli, Nestler, Allis, & Sassone‐Corsi, ; Day & Sweatt, ), learning and memory (Graff & Tsai, ; Guan et al, ; Lopez‐Atalaya & Barco, ; Sweatt, ; Zovkic, Guzman‐Karlsson, & Sweatt, ), and adult neurogenesis (Barrett & Wood, ; Jiang et al, ; Ma et al, ). In fact, several reports show that in some brain structures as hippocampus and prefrontal cortex (PFC), various genes linked to synaptic plasticity and synaptic structure are downregulated as a consequence of epigenetic alterations (Barter & Foster, ; Blalock et al, ; Ianov, De Both et al, ; Ianov, Rani, Beas, Kumar, & Foster, ; Palomer, Carretero, Benvegnu, Dotti, & Martin, ; Palomer, Martin‐Segura et al, ).…”

Section: Introductionmentioning

confidence: 99%

“…The epigenetic mechanisms altered in aging include DNA methylation, histone modifications, and nucleosome remodeling. In addition, non‐coding RNAs differentially expressed in the old can regulate not only mRNA stability or mRNA translation but also recruit chromatin modifying enzymes to specific sites in the DNA (Barter & Foster, ). Most of these epigenetic alterations contribute to cognitive decline during aging as we will see below.…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic mechanisms related to cognitive decline during aging

Harman

Martín

2019

J of Neuroscience Research

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Cognitive decline is a hallmark of the aging nervous system, characterized by increasing memory loss and a deterioration of mental capacity, which in turn creates a favorable context for the development of neurodegenerative diseases. One of the most detrimental alterations that occur at the molecular level in the brain during aging is the modification of the epigenetic mechanisms that control gene expression. As a result of these epigenetic‐driven changes in the transcriptome most of the functions of the brain including synaptic plasticity, learning, and memory decline with aging. The epigenetic mechanisms altered during aging include DNA methylation, histone modifications, nucleosome remodeling, and microRNA‐mediated gene regulation. In this review, we examine the current evidence concerning the changes of epigenetic modifications together with the molecular mechanisms underlying impaired neuronal gene transcription during aging. Herein, we discuss the alterations of DNA methylation pattern that occur in old neurons. We will also describe the most prominent age‐related histone posttranslational modifications in the brain since changes in acetylation and methylation of specific lysine residues on H3 and H4 are associated to functional decline in the old. In addition, we discuss the role that changes in the levels of certain miRNAs would play in cognitive decline with aging. Finally, we provide an overview about the mechanisms either extrinsic or intrinsic that would trigger epigenetic changes in the aging brain, and the consequences of these changes, i.e., altered transcriptional profile and reactivation of transposable elements in old brain.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic mechanisms related to cognitive decline during aging

Harman

Martín

2019

J of Neuroscience Research

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“…The epigenome is a complex regulatory code outside of the genetic nucleotide sequence. Through many molecular processes including electrostatic interactions, transcriptional machinery blockade, and RNA interference, the epigenetic code plays a role in determining what genes, and how much of a specific gene, is expressed [29]. Epigenetic processes can be dynamic and respond to social and environmental exposures.…”

Section: Introductionmentioning

confidence: 99%

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

et al. 2019

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Individual differences in cognitive function are due to a combination of heritable and non-heritable factors. A large body of evidence from clinical, cognitive, and pharmacological neuroscience implicates dopaminergic gene variants as modulators of cognitive functions. Neuroepigenetic studies demonstrate environmental factors also influence complex phenotypes by affecting gene expression regulation. To evaluate the mechanism of environmental influence on cognitive abilities, we examined if epigenetic regulation of dopaminergic genes plays a role in cognition. Using a DNA methylation profiling microarray, we used a monozygotic (MZ) twin difference design to evaluate if co-twin differences in methylation of CpG sites near six dopaminergic genes predicted differences in response inhibition and memory performance. Studying MZ twins allows us to assess if environmentally driven differences in methylation affect differences in phenotype while controlling for the influence of genotype and shared family environment. Response inhibition was assessed with the flanker task and short-term and working memory were assessed with digit span recall. We found MZ co-twin differences in DRD4 gene methylation predicted differences in short-term memory. MZ differences in COMT, DBH, DAT1, DRD1, and DRD2 gene methylation predicted differences in response inhibition. Taken together, findings suggest methylation status of dopaminergic genes may influence cognitive functions in a dissociable manner. Our results highlight the importance of the epigenome and environment, over and above the influence of genotype, in supporting complex cognitive functions. ARTICLE HISTORYORCID Candace R. Lewis http://orcid.org/0000-0001-5253-9989 Reagan S. Breitenstein http://orcid.org/0000-0001-9998-166X

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“…Evidence of this "epigenetic clock" can be found in almost all tissues and organs, however the brain appears to be the most affected and these changes are thought to contribute to cognitive decline in aging (Fraga et al, 2005;Lardenoije et al, 2015;Starnawska et al, 2017;Barter and Foster, 2018). DNA methylation is known to play an important role in dynamic regulation of gene expression that is involved in synaptic plasticity and learning and memory in aging humans (Borrelli et al, 2008;Day and Sweatt, 2010;Graff and Tsai, 2013;Sweatt, 2013).…”

Section: Introductionmentioning

confidence: 99%

Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells

et al. 2020

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As the population ages, interest in identifying biomarkers of healthy aging and developing antiaging interventions has increased. DNA methylation has emerged as a potentially powerful molecular marker of aging. Methylation changes at specific sites in the human genome that have been identified in peripheral blood have been used as robust estimators of chronological age. Similar age-related DNA methylation signatures are also seen in various tissue types in rodents. However, whether these peripheral alterations in methylation status reflect changes that also occur in the central nervous system remains unknown. This study begins to address this issue by identifying age-related methylation patterns in the hippocampus and blood of young and old mice. Reducedrepresentation bisulfite sequencing (RBSS) was used to identify differentially methylated regions (DMRs) in the blood and hippocampus of 2-and 20-month-old C57/Bl6 mice. Of the thousands of DMRs identified genome-wide only five were both found in gene promoters and significantly changed in the same direction with age in both tissues. We analyzed the hippocampal expression of these five hypermethylated genes and found that three were expressed at significantly lower levels in aged mice [suppressor of fused homolog (Sufu), nitric oxide synthase 1 (Nos1) and tripartite motif containing 2 (Trim2)]. We also identified several transcription factor binding motifs common to both hippocampus and blood that were enriched in the DMRs. Overall, our findings suggest that some agerelated methylation changes that occur in the brain are also evident in the blood and could have significant translational relevance.

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Aging in the Brain: New Roles of Epigenetics in Cognitive Decline

Cited by 76 publications

References 67 publications

Epigenetic mechanisms related to cognitive decline during aging

Epigenetic mechanisms related to cognitive decline during aging

Dopaminergic gene methylation is associated with cognitive performance in a childhood monozygotic twin study

Age-Associated DNA Methylation Patterns Are Shared Between the Hippocampus and Peripheral Blood Cells

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