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.

项目摘要/摘要 端粒损耗是关键的老化标志。端粒是重复的序列 ttaggg在染色体的末端，随着年龄的增长而缩短，细胞进入 端粒何时达到较短的长度。观察和 遗传研究表明，血液中的端粒长度短（TL）与 阿尔茨海默氏病（AD）的风险增加。但是，研究样本量是 相关的小，2016年荟萃分析仅包括860名AD患者和2,022例 来自13项研究的控制。有越来越多的证据表明发生大脑发生变化 诊断出阿尔茨海默氏病或​​其相关痴呆症（AD/ADRD）的几年。 尽管TL和AD/ADRD之间的关系是可能的，但关联 在TL和认知功能或下降之间是不一致的，并且研​​究TL 与大脑成像特征的关联在很大程度上缺少。为了填补这些空白，我们 提出使用已经可用的大脑磁共振成像（MRI）数据的提案 我们的父母赠款（R21NR018963-- 01a1）。我们旨在测试和表征TL和AD/ADRD之间的关系 相关措施的样本量要比任何先前的研究都要大得多。我们 将在TL和认知功能以及 使用横截面和纵向数据进行大脑成像测量。父母 格兰特不专注于广告/ADRD，主要旨在划定可修改的暴露 直接影响或中等的TL，以及关系如何影响健康和 疾病的风险。申请人团体具有丰富的经验。 英国生物银行（UKB）的定向分析，包括大脑MRI数据。另外，我们 包括Drs。大卫·斯特芬斯（David Steffens）和王王（Lihong Wang）支持这种补充的目标。 Steffens博士是一名精神科医生，他的专业知识是情绪的特征 以及晚期抑郁症的认知结果以及神经基础和 AD/ADRD的结果。 Wang博士是一名神经科医生，她进行了神经影像学 对晚期抑郁症和认知能力下降的患者的研究。两者都熟悉 UKB痴呆和成像数据。我们希望能深入了解这种关系 通过中间认知功能和大脑成像在TL和AD/ADRD之间 措施。我们的发现将暗示大脑区域以降低进展的目标 走向广告/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

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

• 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

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