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

摘要 美国正面临着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压力，除非 可以在短期内减少与年龄有关的疾病。衰老的过程与 所有与年龄有关的疾病的发展;端粒长度，成人干细胞频率和 功能，都随着年龄的增长而下降。FOXO 3基因的SNP rs 2802292变异体与 在许多人群中长寿。这种FOXO 3变体特别赋予基本上 降低死于冠状动脉疾病的风险（>26%），与常见的 心血管危险因素，如高血压、糖尿病、吸烟。FOXO 3还影响其他 与年龄有关的疾病，身体和可能的认知功能。 成体造血干细胞和神经干细胞的维持依赖于FOXO 3。 尽管存在这些关联，但FOXO 3通过何种细胞和分子机制尚不清楚。 影响人类寿命和健康衰老。目前对潜在机制的研究 大多数仅限于细胞和动物模型;因此，拟议的项目将利用 大型纵向临床队列，试图填补我们理解中的这一空白。 提出的具体目标是评估FOXO 3的作用机制， 人类寿命是：1 -测试的假设，最强大的保护FOXO 3变异 (SNP rs 2802292）影响端粒动力学， 几十年的随访和男女后代的横断面研究; 2 - 检验保护性FOXO 3变体影响造血干细胞数量的假设， 3：-检验长寿相关FOXO 3变体影响功能的假设， 维持大脑中的干细胞和神经系统健康作为年龄的函数。 端粒随年龄的消耗在个体之间是可变的，并且消耗率与年龄相关。 心血管疾病风险和死亡率。如果FOXO 3通过影响基因组稳定性， 端粒磨损率，或通过端粒酶水平维持端粒的变化， 表达，这将是显而易见的，在拟议的纵向和横截面分析， 端粒动态跨越几十年的生活。干细胞群体作为一种储备， 整个成年期的组织补充，这些人口的数量下降， 功能随着年龄的增长。如果FOXO 3寿命变体有助于改善这些 细胞，它应该反映在频率和功能的干细胞从外周血 和大脑，以及大脑老化的更健康的表型，如更高的神经干细胞计数， 减少衰老细胞的积累，减少斑块/缠结，更强健的树突/棘 分支和/或更好的认知功能。 拟议的研究将对以下因素之间的关系进行首次临床评估： 纵向端粒动力学与FOXO 3的关系，并首次临床分析 人类FOXO 3长寿变异体与干细胞频率和功能变化之间的关系， 年龄从更深入地了解一个主要的人类 长寿基因影响衰老将为更多有针对性的研究提供信息， 改善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.