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

摘要 美国正面临65岁以上人口比例的激增。这 将在未来几十年给医疗保健系统带来巨大的压力，除非 与年龄相关的疾病可以在短期内减少。衰老的过程与 所有年龄相关疾病的发展；端粒长度，成体干细胞频率和 功能，都随着年龄的增长而衰退。位于SNP rs2802292的FOX03基因变异与 在许多人类群体中的长寿。这款FOX03变种特别赋予了一种实质上 降低死于冠状动脉疾病的风险(&gt；26%)，幅度与普通相似 心血管危险因素，如高血压、糖尿病、吸烟。FOX03也影响了其他 与年龄有关的疾病，身体功能，可能还有认知功能。 成人造血干细胞和神经干细胞的维持依赖于FOX03。 尽管存在这些联系，但FOXO_3的细胞和分子机制尚不清楚 影响人类长寿和健康衰老。目前对潜在机制的研究已经 主要局限于细胞和动物模型；因此，拟议的项目将利用 大规模的纵向临床队列，试图填补我们理解中的这一空白。 为评估FOXO_3的作用机制而提出的具体目标 人类的长寿是：1-检验假设，最强大的保护性FOX3变体 (SNP Rs 2802292)在一项人类队列的纵向研究中影响端粒动力学 数十年的随访和对男性和女性后代的横断面研究；2- 验证保护性FOXO_3变体影响血液干细胞数量和 功能；以及3：-测试与长寿相关的FOXO_3变体影响 大脑中干细胞的维持和神经健康是年龄的函数。 端粒磨损随年龄的变化在不同的个体之间是不同的，并且端粒磨损的比率是相关的 有心血管疾病的风险和死亡率。如果FOXO_3通过影响基因组稳定性 端粒磨损率，或通过端粒酶水平或端粒维持的变化 表达，这将在拟议的纵向和横截面分析中显而易见 端粒动力学跨越了几十年的生命。干细胞群体作为储备 整个成年期组织的补充，这些种群的数量和 随着年龄的增长而发挥作用。如果FOX03长寿变种有助于改善这些 它应该反映在外周血干细胞的频率和功能上 和大脑，以及大脑老化的更健康的表型，例如更高的神经干细胞数量， 减少衰老细胞的堆积，减少斑块/缠结，更强壮的树突/棘突 分支和/或更好的认知功能。 这项拟议的研究将进行第一次临床评估 端粒纵向动力学与FOXO_3的关系及首次临床分析 人类FOXO_3长寿变异与干细胞频率和功能变化之间的关系 年龄。通过更好地理解一个主要的人类 影响衰老的长寿基因将为更有针对性的研究提供信息，这可能导致医学上的 提高老年人生活质量的创新。

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.