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Development of an epigenetic clock that predicts age-impaired or age-unimpaired cognitive performance

开发表观遗传时钟来预测年龄受损或年龄未受损的认知表现

基本信息

批准号：
10510390
负责人：
Timothy Lamont Downing
金额：
$ 39.46万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10510390
关键词：
Aberrant DNA Methylation Affect Age Age-associated memory impairment Aging Agreement Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Animals Biological Biological Process Brain Brain region C57BL/6 Mouse Carbon Censuses Characteristics Chronology Cognition Cognitive Collection Cytosine DNA Methylation Data Development Disease Epigenetic Process Exhibits Female Foundations Gene Expression Gene Expression Regulation Genetic Transcription Genome Genomics Heritability Hippocampus (Brain)Human Impaired cognition Impairment Individual Lead Learning Liver Longevity Malignant Neoplasms Mammals Memory Methylation Modeling Modification Molecular Mus Pattern Play Population Positioning Attribute Predisposition Publishing Repetitive Sequence Reporting Resistance Role Site Testing Tissue Sample Tissues Update age related aged bioinformatics pipeline bisulfite sequencing cognitive function cognitive performance cognitive testing data analysis pipeline effective therapy epigenome epigenome-wide association studies epigenomics genome-wide improved innovation insight male methylation pattern mouse model normal aging novel strategies resilience sex

项目摘要

Project Summary/Abstract The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk factor for Alzheimer’s Disease (AD) and dementia. The 2012 National Projections report by the U.S. Census Bureau indicates that in 2050 the population in the U.S. aged 65+ will be approximately 84 million, which will reflect 21% of the predicted U.S. total population. Also in the U.S., 16-20% of current 65+ individuals are predicted to be cognitively impaired. Understanding mechanisms of age-related cognitive decline may inform AD-related dementia and lead to the discovery of effective treatments for improving cognitive function in AD. Genomic and epigenomic studies, as well as cognitive neuroepigenetic studies, have demonstrated that alterations of the epigenome may be critically important to age- and AD-associated cognitive decline. Recent studies have also demonstrated that the epigenome, and DNA methylation in particular, may be used to distinguish chronological age from biological age. That is, the exact age of an individual (chronological age) versus the apparent age of an individual (biological age). The precise collection of patterns of DNA methylation that are used to make these distinctions in different tissue types are called ‘epigenetic clocks’. Although several epigenetic clocks have been published from mixed tissues and whole brain regions, there are no studies identifying an epigenetic clock in a brain region necessary for memory, and determining the ability of that clock to predict age-impaired or age-unimpaired cognitive performance, which would represent a major conceptual and technical innovation. In this proposal, we aim to identify an epigenetic clock in the hippocampus, a major brain region involved in learning and memory, and one that begins to decline with age and becomes even further impaired with AD pathology. Our preliminary data demonstrates our ability to develop a DNA methylation data analysis pipeline (using reduced representation bisulfite sequencing) from the hippocampus of 2 and 20 month old male and female C57BL/6 mice, which established a foundation for arriving at an epigenetic clock. In Aim 1 we proposed to identify a hippocampus epigenetic clock in wildtype male and female mice across the lifespan, and to determine how that epigenetic clock is altered in the context of AD using the 5xFAD mouse model. In Aim 2, we propose to determine the epigenetic clock can predict age-impaired versus age-unimpaired cognitive performance in wild type animals, and whether the clock may distinguish resilience versus susceptibility to cognitive decline in 5xFAD animals.

项目总结/文摘