Analysis of Cell and Molecular Phenotypes of the Longevity Associated FOXO3 Variant

长寿相关 FOXO3 变体的细胞和分子表型分析

• 批准号: 10263958
• 负责人: Philip M C Davy
• 金额: $ 26.83万
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10263958
• 关键词: Ablation; Adult; Affect; Age; Age of Onset; Age-Years; Aging; Alleles; Animal Model; Autopsy; Biological Assay; Blood; Blood Banks; Blood specimen; Brain; CD34 gene; Caenorhabditis elegans; Cell Aging; Cell Count; Cell Maintenance; Cell Proliferation; Cell model; Cell physiology; Cells; Center for Translational Science Activities; Cessation of life; Chronic stress; Clinical; Clinical assessments; Collaborations; Coronary Arteriosclerosis; Cross-Sectional Studies; DNA analysis; Data; Dendritic Spines; Development; Diabetes Mellitus; Disease; Elderly; FOXO3A gene; Female; Flow Cytometry; Fluorescence-Activated Cell Sorting; Frequencies; Genes; Genome Stability; Genomic DNA; Genotype; Goals; Golgi Apparatus; Guidelines; Health; Healthcare Systems; Heart; Heart Diseases; Hematopoietic; Hematopoietic stem cells; Hippocampus (Brain); Homologous Gene; Human; Hypertension; In Vitro; Individual; Length; Leukocytes; Life; Link; Longevity; Longitudinal Studies; Maintenance; Medical; Medical center; Mesenchymal Stem Cells; Methods; Minor; Molecular; Morphology; Mus; Mutation; Neurofibrillary Tangles; Neurologic; Participant; Peripheral Blood Stem Cell; Phenotype; Population; Process; Quality of life; Regulation; Research Personnel; Reserve Stem Cell; Reverse Transcriptase Polymerase Chain Reaction; Risk; Sampling; Senile Plaques; Silver Staining; Smoking; Somatic Cell; Stains; Targeted Research; Telomerase; Telomere Maintenance; Testing; Time; Tissues; Umbilical Cord Blood; United States; Variant; Vertebral column; Woman; adult stem cell; age related; aging brain; brain tissue; cardiovascular disorder risk; cardiovascular risk factor; cell behavior; cognitive function; cohort; follow-up; gene therapy; genetic variant; germline stem cells; healthy aging; human old age (65+); improved; innovation; insight; interest; longevity gene; longitudinal analysis; male; men; molecular phenotype; mortality; nerve stem cell; nervous system disorder; nestin protein; novel therapeutics; offspring; peripheral blood; preservation; prevent; primary endpoint; programs; protective effect; secondary endpoint; self-renewal; senescence; stem cell function; stem cell population; stem cells; telomere; transcription factor

ABSTRACT The United States is facing a boom in the proportion of its population over the age of 65. This will put enormous strain on the health care system for decades to come unless the impact of age-related diseases can be reduced in the short term. The process of aging is associated with the development of all age-related diseases; telomere length, adult stem cell frequency and function, all decline with age. A variant of the FOXO3 gene at SNP rs2802292 associates with longevity in many human populations. This FOXO3 variant specifically confers a substantially reduced risk of dying of coronary artery disease (>26%), similar in magnitude to common cardiovascular risk factors, such as hypertension, diabetes, smoking. FOXO3 also impacts other age-related diseases, physical and possibly cognitive function. The maintenance of adult hematopoietic- and neural- stem cells is dependent on FOXO3. Despite these associations it is unknown by what cellular and molecular mechanisms FOXO3 influences human longevity and healthy aging. Current studies of potential mechanisms have mostly been limited to cell and animal models; thus, the proposed project will make use of a large, longitudinal clinical cohort to attempt to fill this gap in our understanding. The specific aims proposed to assess the mechanisms which FOXO3 operates via to impact human longevity are: 1 - Test the hypothesis that the most robust protective FOXO3 variant (SNP rs 2802292) affects telomere dynamics in a longitudinal study of a human cohort with several decades of follow up and in cross-sectional studies of male and female offspring; 2 - Test the hypothesis that the protective FOXO3 variant affects blood stem cell numbers and function; and 3: - Test the hypothesis that the longevity-associated FOXO3 variant affects the maintenance of stem cells in the brain and neurological health as a function of age. Telomere attrition with age is variable between individuals, and the rate of attrition is associated with cardiovascular disease risks and mortality. If FOXO3 affects genome stability via an impact on the rate of telomere attrition, or changes in telomere maintenance via telomerase levels or expression, it will be evident in the proposed longitudinal and cross-sectional analyses of telomere dynamics spanning several decades of life. Stem cell populations act as a reserve for replenishment of tissues throughout adulthood, and these populations decline in number and function with age. If the FOXO3 longevity variant contributes to improved maintenance of these cells it should be reflected in the frequency and function of stem cells from the peripheral blood and brain, and with healthier phenotypes of brain aging, such as higher neural stem cell count, reduced accumulation of senescent cells, fewer plaques/tangles, more robust dendrite/spine branching, and/or better cognitive function. The proposed study will perform the first clinical assessment of the relationship between longitudinal telomere dynamics and FOXO3, and the first clinical analysis of the relationship between human FOXO3 longevity variants and changes in stem cell frequency and function with age. The insights gained from greater understanding of the mechanism by which a major human longevity gene affect aging will inform more targeted research that could result in medical innovations that improve quality of life among older adults.

抽象的 美国正面临 65 岁以上人口比例激增的问题。 未来几十年将给医疗保健系统带来巨大压力，除非 与年龄相关的疾病可以在短期内减少。衰老的过程与 所有与年龄相关的疾病的发展；端粒长度、成体干细胞频率和 机能，都会随着年龄的增长而衰退。 FOXO3 基因 SNP rs2802292 的变体与 许多人群的长寿。该 FOXO3 变体特别赋予了显着的 死于冠状动脉疾病的风险降低 (>26%)，程度与常见疾病相似 心血管危险因素，如高血压、糖尿病、吸烟。 FOXO3 还会影响其他 与年龄相关的疾病、身体功能和可能的认知功能。 成体造血干细胞和神经干细胞的维持依赖于 FOXO3。 尽管存在这些关联，但尚不清楚 FOXO3 通过什么细胞和分子机制 影响人类的长寿和健康老龄化。目前对潜在机制的研究已经 大多局限于细胞和动物模型；因此，拟议项目将利用 大型纵向临床队列试图填补我们理解上的这一空白。 提出的具体目标是评估 FOXO3 运作影响的机制 人类长寿的因素是： 1 - 检验最强大的保护性 FOXO3 变体的假设 (SNP rs 2802292) 在一项针对人类队列的纵向研究中影响端粒动态 对男性和女性后代进行了数十年的跟踪和横断面研究； 2 - 检验保护性 FOXO3 变体影响造血干细胞数量的假设 功能; 3： - 检验与长寿相关的 FOXO3 变体影响寿命的假设 维持大脑中的干细胞和神经系统健康作为年龄的函数。 端粒随年龄的磨损在个体之间存在差异，并且磨损率与 与心血管疾病风险和死亡率。如果 FOXO3 通过影响影响基因组稳定性 端粒磨损率，或通过端粒酶水平改变端粒维持，或 表达式，这将在拟议的纵向和横截面分析中显而易见 跨越数十年生命的端粒动态。干细胞群充当储备 整个成年期组织的补充，这些种群的数量和数量下降 功能随年龄增长。如果 FOXO3 长寿变体有助于改善这些的维护 细胞 应该体现在来自外周血的干细胞的频率和功能上 和大脑，并且具有更健康的大脑老化表型，例如更高的神经干细胞数量， 减少衰老细胞的积累，减少斑块/缠结，更坚固的树突/脊柱 分支和/或更好的认知功能。 拟议的研究将对两者之间的关系进行首次临床评估 纵向端粒动力学和FOXO3，以及关系的首次临床分析 人类 FOXO3 长寿变异与干细胞频率和功能的变化之间的关系 年龄。从对主要人类的机制的更深入了解中获得的见解 长寿基因影响衰老将为更有针对性的研究提供信息，这些研究可能会导致医学结果 改善老年人生活质量的创新。