Dataset Information

DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment.

ABSTRACT: The current study investigates DNA methylation as a possible epigenetic regulator of transcription associated with aging and cognitive function. Young and aged male Fischer 344 rats were behaviorally characterized on a set shifting task, and whole genome bisulfite sequencing was employed to profile the DNA methylome of the medial prefrontal cortex (mPFC). DNA methylation was also compared to RNA expression in the mPFC from the same animals. Variability in methylation was mainly observed for CpG sites as opposed to CHG and CHH sites. Gene bodies, specifically introns, contain the highest levels of methylation. During aging, hypermethylation was observed for genes linked to synaptic function and GTPase activity. Furthermore, impaired cognitive flexibility during aging was associated with hypermethylation of genes linked to postsynaptic density, dendrites, the axon terminus, and Ca2+ channels. Finally, comparison with RNA expression confirmed that hypermethylation was correlated with decreased expression of synaptic genes. The results indicate that DNA methylation over the lifespan contributes to synaptic modification observed in brain aging and age-related cognitive impairment.

SUBMITTER: Ianov L

PROVIDER: S-EPMC5539085 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment.

Ianov Lara L Riva Alberto A Kumar Ashok A Foster Thomas C TC

Frontiers in aging neuroscience 20170802

The current study investigates DNA methylation as a possible epigenetic regulator of transcription associated with aging and cognitive function. Young and aged male Fischer 344 rats were behaviorally characterized on a set shifting task, and whole genome bisulfite sequencing was employed to profile the DNA methylome of the medial prefrontal cortex (mPFC). DNA methylation was also compared to RNA expression in the mPFC from the same animals. Variability in methylation was mainly observed for CpG ...[more]

PMID: 28824413

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Project description:Background and objectivesDNA methylation algorithms are increasingly used to estimate biological aging; however, how these proposed measures of whole-organism biological aging relate to aging in the brain is not known. We used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Framingham Heart Study (FHS) Offspring Cohort to test the association between blood-based DNA methylation measures of biological aging and cognitive impairment and dementia in older adults.MethodsWe tested 3 "generations" of DNA methylation age algorithms (first generation: Horvath and Hannum clocks; second generation: PhenoAge and GrimAge; and third generation: DunedinPACE, Dunedin Pace of Aging Calculated from the Epigenome) against the following measures of cognitive impairment in ADNI: clinical diagnosis of dementia and mild cognitive impairment, scores on Alzheimer disease (AD) / Alzheimer disease and related dementias (ADRD) screening tests (Alzheimer's Disease Assessment Scale, Mini-Mental State Examination, and Montreal Cognitive Assessment), and scores on cognitive tests (Rey Auditory Verbal Learning Test, Logical Memory test, and Trail Making Test). In an independent replication in the FHS Offspring Cohort, we further tested the longitudinal association between the DNA methylation algorithms and the risk of developing dementia.ResultsIn ADNI (N = 649 individuals), the first-generation (Horvath and Hannum DNA methylation age clocks) and the second-generation (PhenoAge and GrimAge) DNA methylation measures of aging were not consistently associated with measures of cognitive impairment in older adults. By contrast, a third-generation measure of biological aging, DunedinPACE, was associated with clinical diagnosis of Alzheimer disease (beta [95% CI] = 0.28 [0.08-0.47]), poorer scores on Alzheimer disease/ADRD screening tests (beta [Robust SE] = -0.10 [0.04] to 0.08[0.04]), and cognitive tests (beta [Robust SE] = -0.12 [0.04] to 0.10 [0.03]). The association between faster pace of aging, as measured by DunedinPACE, and risk of developing dementia was confirmed in a longitudinal analysis of the FHS Offspring Cohort (N = 2,264 individuals, hazard ratio [95% CI] = 1.27 [1.07-1.49]).DiscussionThird-generation blood-based DNA methylation measures of aging could prove valuable for measuring differences between individuals in the rate at which they age and in their risk for cognitive decline, and for evaluating interventions to slow aging.

Dataset Information

DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment.

Publications

DNA Methylation of Synaptic Genes in the Prefrontal Cortex Is Associated with Aging and Age-Related Cognitive Impairment.

Similar Datasets

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