FOXO3, Telemere Dynamics and Healthy Brain Aging

FOXO3、端粒动力学和健康的大脑老化

• 批准号: 10493191
• 负责人: Kalpana Juliet Kallianpur
• 金额: $ 16.36万
• 依托单位: KUAKINI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-10 至 2023-02-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10493191
• 关键词: Affect; Age; Aging; Anti-Inflammatory Agents; Attention; Biological; Biological Assay; Blood; Brain; Brain region; Cell Aging; Cell Death; Center for Translational Science Activities; Cognitive; Cognitive deficits; Corpus Callosum; Cross-Sectional Studies; DNA; DNA Repair; Data; Deoxyguanosine; Elderly; Exhibits; Female; Frequencies; Future; Genes; Genetic; Genetic Polymorphism; Genomic DNA; Genotype; Goals; Hawaii; Heart; Hippocampus; Human; Impairment; Inflammatory; Intervention; Japanese American; Lead; Length; Leukocytes; Link; Longevity; Magnetic Resonance Imaging; Measures; Memory; Methods; Mitochondria; Mitochondrial DNA; Neurocognitive Deficit; Nucleus Accumbens; Oxidative Stress; Participant; Peripheral; Play; Population; Prefrontal Cortex; Process; Proteins; Research; Rest; Role; Sampling Studies; Serum; Structure; Telomerase; Telomere Shortening; Thick; Thinness; Variant; Work; aging brain; brain health; brain volume; cerebral atrophy; cognitive process; cytokine; depressed patient; forkhead protein; genetic variant; gray matter; indexing; insight; interest; male; men; nerve stem cell; normal aging; offspring; oxidative damage; peripheral blood; programs; protective effect; telomere; white matter

Project Summary/Abstract Longevity appears to be strongly affected by genetic and cellular factors. The FOXO3 gene that encodes the transcription factor forkhead box O-3 (FOXO3) has been consistently linked to increased human lifespan. Aging is typically accompanied by gradual brain atrophy and neurocognitive decline, but the cellular mechanisms underlying the aging process are still unclear. The proposed study seeks to understand how aging at the cellular level, as characterized by telomere shortening and altered telomerase activity, is related to longevity and brain aging. We hypothesize that the protective FOXO3 gene variant is associated with decelerated brain aging, and suggest that a slower rate of brain aging is also linked to greater telomerase activity and telomere length in peripheral blood leukocytes (PBL). Brain volume and function will be cross-sectionally assessed by structural magnetic resonance imaging (MRI) and resting-state functional connectivity (RSFC) MRI, respectively, in 100 male and female Kuakini Honolulu Heart Program (Kuakini HHP) Offspring study participants. Regional brain atrophy and disrupted RSFC will serve as indices of brain aging and will be examined for associations with FOXO3 genotype and PBL telomerase activity and telomere length. Additionally, we will investigate whether differences in RSFC associated with FOXO3 genotype, telomerase activity or telomere length, 8-oxo-dG (a measure of DNA break frequency), or anti-inflammatory cytokine levels in the blood relate to cognitive processes impaired in normal aging. Results from this study may provide insight into effects of the protective FOXO3 variant on the rate of brain aging, and may elucidate biological mechanisms of aging and eventually identify interventions to increase the number of years of healthy living.

项目总结/摘要 长寿似乎受到遗传和细胞因素的强烈影响。FOXO 3基因编码 转录因子叉头盒O-3（FOXO 3）一直与人类寿命的延长有关。 衰老通常伴随着逐渐的脑萎缩和神经认知能力下降，但细胞 衰老过程的潜在机制仍不清楚。 这项拟议中的研究旨在了解细胞水平上的衰老是如何以端粒为特征的 缩短和改变端粒酶活性，与长寿和大脑老化有关。我们假设 保护性FOXO 3基因变异与大脑衰老的减缓有关，并表明， 脑老化还与外周血白细胞中更高的端粒酶活性和端粒长度有关 （PBL）。脑容量和功能将通过结构磁共振成像进行横断面评估 (MRI)和静息态功能连接（RSFC）MRI，分别在100名男性和女性Kuakini 檀香山心脏计划（Kuakini HHP）后代研究参与者。区域性脑萎缩， RSFC将作为脑老化的指标，并将检查与FOXO 3基因型的关联， PBL端粒酶活性和端粒长度。此外，我们将研究RSFC的差异是否 与FOXO 3基因型、端粒酶活性或端粒长度、8-oxo-dG（DNA断裂的量度） 频率），或血液中的抗炎细胞因子水平与正常人中受损的认知过程有关。 衰老这项研究的结果可以提供对保护性FOXO 3变异体对肿瘤发生率的影响的见解。 大脑老化，并可能阐明衰老的生物学机制，并最终确定干预措施，以增加 健康生活的年数。