FOXO3 Genotype, InflammAging, Cardiovascular Disease, and Dementia. Kuakini Hawaii Lifespan Study III

老龄化是主要慢性病和残疾的最重要危险因素。在先前的工作中，我们发现FOXO 3基因（C。在Kuakini檀香山心脏计划（Kuakini HHP）队列中，elegans daf-16基因）与健康衰老和长寿密切相关。对长寿的保护作用已经在许多人群中复制，FOXO 3现在是仅有的两个在人类长寿人群中具有一致复制的基因之一。 然而，该机制在疾病特异性基础或分子基础上尚不清楚。在初步工作中，我们发现FOXO 3可以有效预防心血管疾病（CVD），血管性认知障碍和痴呆症（VCID）-老年人死亡和残疾的重要原因。 我们的数据还表明，FOXO 3驱动的抗炎途径可能是预防年龄相关疾病和残疾的重要细胞和分子机制-特别是血管相关疾病。 这项更新提案评估了炎症老化（衰老相关的炎症）是否受FOXO 3基因型的调节，以及这是否会影响CVD，阿尔茨海默病（AD）和VCID的风险。为了验证这一假设，我们提出了以下具体目标： AIM 1.进行一项FOXO 3基因型对成年人大部分寿命期内的发病率和死亡率的前瞻性研究。 假设：FOXO 3主要通过保护免受血管疾病而延长成年人的寿命。 AIM 2.测试长寿相关FOXO 3等位基因携带者是否具有保护性抗炎血清特征。 假设：FOXO 3通过烟碱介导的抗炎途径降低死亡率。 AIM 3.测试FOXO 3基因型是否影响认知老化，AD和VCID。 假设：促进长寿的基因变异也可能促进健康的大脑衰老，包括更好的认知功能，尸检时更少的大脑病理学以及更低的AD和VCID发病率。炎症可能是一个介导因素。

Aging is the most important risk factor for major chronic diseases and disability. In prior work, we found that variation in the FOXO3 gene (the human homolog of the C. elegans daf-16 gene) was strongly associated with healthy aging and longevity in the Kuakini Honolulu Heart Program (Kuakini HHP) cohort. The protective effect on longevity has since been replicated in numerous populations and FOXO3 is now one of only two genes that have consistent replications across populations for human longevity. Yet, the mechanism is not known on a disease-specific basis or a molecular basis. In preliminary work, we found that FOXO3 strongly protects against Cardiovascular Disease (CVD), Vascular Cognitive Impairment and Dementia (VCID) - important causes of death and disability at older ages. Our data also suggest that a FOXO3-driven anti-inflammatory pathway may be an important cell and molecular mechanism for protection against age-related diseases and disability – particularly vascular-related diseases. This renewal proposal assesses whether InflammAging (aging-related inflammation) is modulated by FOXO3 genotype and whether this impacts risk for CVD, Alzheimer’s disease (AD), and VCID. To test this hypothesis, we propose the following Specific Aims: AIM 1. CONDUCT a prospective study of FOXO3 genotype on incident disease and mortality across most of the adult lifespan. Hypothesis: FOXO3 enhances longevity over the adult lifespan principally through protection against vascular disease. AIM 2. TEST whether carriers of the longevity-associated FOXO3 allele have a protective anti- inflammatory serum profile. Hypothesis: FOXO3 reduces mortality through a cytokine-mediated anti-inflammatory pathway. AIM 3. TEST whether FOXO3 genotype influences cognitive aging, AD and VCID. Hypothesis: Gene variants that promote longevity may also promote healthy brain aging, including better cognitive function, less brain pathology on autopsy and lower rates of incident AD and VCID. Inflammation may be a mediating factor.