Identifying potentially modifiable exposures to improve telomere health and disease outcomes

识别潜在可改变的暴露以改善端粒健康和疾病结果

• 批准号: 10288463
• 负责人: Chia-Ling Kuo
• 金额: $ 14.02万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288463
• 关键词: Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Biological; Blood; Brain; Brain imaging; Brain region; Cell division; Cells; Chromosomes; Cognitive; Communities; Data; Dementia; Diagnosis; Disease; Disease Outcome; Early Intervention; Etiology; Exposure to; Frontotemporal Dementia; Genetic; Genetic study; Genotype; Health; Image; Impaired cognition; Intervention; Length; Lewy Body Dementia; Link; Magnetic Resonance Imaging; Measures; Mendelian randomization; Meta-Analysis; Moods; Neurodegenerative Disorders; Neurologist; Observational Study; Onset of illness; Outcome; Participant; Patients; Phenotype; Population Study; Psychiatrist; Repetitive Sequence; Reporting; Research; Risk; Sample Size; Sampling Studies; Telomerase; Telomere Shortening; Testing; Vascular Dementia; base; biobank; case control; cognitive function; cohort; disorder risk; experience; genetic variant; genome integrity; geriatric depression; imaging modality; improved; insight; mild cognitive impairment; mixed dementia; mortality; neuroimaging; parent grant; preservation; prevent; relating to nervous system; senescence; telomere

Project Summary/Abstract Telomere attrition is a key aging hallmark. Telomeres are repetitive sequences of TTAGGG at the ends of chromosomes, shortening with age, and cells enter senescence states when telomeres reach a critically short length. Observational and genetic studies have shown that shorter telomere length (TL) in blood is associated with increased risk of Alzheimer’s disease (AD). However, the study sample sizes have been relatively small, with a 2016 meta-analysis including only 860 AD patients and 2,022 controls from 13 studies. There is increasing evidence that brain changes take place years before Alzheimer’s disease or its related dementias (AD/ADRD) are diagnosed. While the relationship between TL and AD/ADRD is possibly causal, associations between TL and cognitive function or decline are inconsistent and studies to test TL associations with brain imaging features are largely missing. To fill these gaps, we propose to use already available brain Magnetic Resonance Imaging (MRI) data from 100,000 participants in the UK Biobank building on our parent grant (R21NR018963- 01A1). We aim to test and characterize the relationship between TL and AD/ADRD and related measures with a much larger sample size than that of any previous study. We will conduct association and causation analyses on TL and cognitive function as well as brain imaging measures, using both cross-sectional and longitudinal data. The parent grant is not focused on AD/ADRD and aims mainly to delineate modifiable exposures that directly influence or moderate TL, and how the relationships influence health and risk of disease. The applicant group have extensive experience undertaking aging oriented analyses in UK Biobank (UKB), including the brain MRI data. Additionally, we include Drs. David Steffens and Lihong Wang to support the aims of this supplement. Dr. Steffens is a psychiatrist and his expertise has been the characterization of mood and cognitive outcomes in late life depression, as well as the neural basis and outcomes of AD/ADRD. Dr. Wang is a neurologist and she has conducted neuroimaging research in patients with late-life depression and cognitive decline. Both are familiar with UKB dementia and imaging data. We expect to gain insight into the relationship between TL and AD/ADRD via intermediate cognitive function and brain imaging measures. Our findings will suggest brain regions to target to slow the progression towards AD/ADRD.

项目总结/摘要 端粒磨损是一个关键的衰老标志。端粒是一种重复序列， TTAGGG在染色体末端，随着年龄的增长而缩短，细胞进入 当端粒达到一个临界的短长度时，衰老状态。观测和 遗传学研究表明，血液中较短的端粒长度（TL）与 阿尔茨海默病（AD）的风险增加。然而，研究样本量已经 相对较小，2016年的荟萃分析仅包括860名AD患者和2，022名 13项研究的对照组。越来越多的证据表明大脑的变化 在阿尔茨海默病或其相关痴呆症（AD/ADRD）被诊断之前数年。 虽然TL和AD/ADRD之间的关系可能是因果关系， TL与认知功能或衰退之间的关系不一致， 与脑成像特征的关联在很大程度上缺失。为了填补这些空白，我们 建议使用现有的脑部磁共振成像（MRI）数据， 100，000名参与者在英国生物银行建设我们的母基金（R21 NR 018963- 01A1）。我们的目的是测试和表征TL和AD/ADRD之间的关系， 相关措施，样本量比以往任何研究都要大得多。我们 将对目标语和认知功能进行关联和因果分析， 脑成像测量，使用横截面和纵向数据。母 补助金的重点不是AD/ADRD，主要目的是描述可改变的暴露 直接影响或缓和TL，以及这些关系如何影响健康和 疾病的风险。申请人群体具有丰富的老龄化工作经验 英国生物库（UKB）中的定向分析，包括大脑MRI数据。另外我们 包括大卫斯蒂芬斯博士和王丽红博士，以支持本增刊的目标。 博士斯蒂芬斯是一名精神病学家，他的专长是对情绪的描述 和认知结果，以及神经基础， AD/ADRD的结果。王医生是一名神经科医生， 对老年抑郁症和认知能力下降患者的研究。两人都熟悉 UKB痴呆和成像数据。我们希望深入了解 通过中间认知功能和脑成像确定TL和AD/ADRD之间的关系 措施我们的研究结果将提示大脑区域的目标，以减缓进展 AD/ADRD。

项目成果

Mid-life leukocyte telomere length and dementia risk: An observational and mendelian randomization study of 435,046 UK Biobank participants.

• DOI: 10.1111/acel.13808
• 发表时间: 2023-07
• 期刊: Aging cell
• 影响因子: 7.8

Association between Residential Exposure to Air Pollution and Incident Coronary Heart Disease Is Not Mediated by Leukocyte Telomere Length: A UK Biobank Study.

• DOI: 10.3390/toxics11060489
• 发表时间: 2023-05-28
• 期刊: Toxics
• 影响因子: 4.6
• 作者: Kuo CL;Liu R;Godoy LDC;Pilling LC;Fortinsky RH;Brugge D
• 通讯作者: Brugge D

Does physical activity moderate the association between shorter leukocyte telomere length and incident coronary heart disease? Data from 54,180 UK Biobank participants.

• DOI: 10.1007/s11357-023-00890-7
• 发表时间: 2024-02
• 期刊: GEROSCIENCE
• 影响因子: 5.6
• 作者: Xiang, Meiruo;Pilling, Luke C.;Melzer, David;Kirk, Ben;Duque, Gustavo;Liu, Rui;Kuchel, George A.;Wood, Andrew R.;Metcalf, Brad;Diniz, Breno S.;Hillsdon, Melvyn;Kuo, Chia-Ling
• 通讯作者: Kuo, Chia-Ling

Very Low and High Levels of Vitamin D Are Associated with Shorter Leukocyte Telomere Length in 148,321 UK Biobank Participants.

148,321名英国生物库参与者的白细胞端粒长度较短和高水平的维生素D与较短的白细胞端粒长度有关。

• DOI: 10.3390/nu15061474
• 发表时间: 2023-03-19
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Kuo CL;Kirk B;Xiang M;Pilling LC;Kuchel GA;Kremer R;Duque G
• 通讯作者: Duque G