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

老龄化是导致重大慢性病和残疾的最重要的风险因素。在之前的工作中，我们在Kuakini檀香山心脏计划(Kuakini HHP)队列中发现FOX03基因(人类与秀丽线虫daf-16基因的同源物)的变异与健康衰老和长寿密切相关。自那以后，这种对长寿的保护作用在许多人群中得到了复制，FOX03现在是为数不多的在人类长寿的人群中具有一致复制的两个基因之一。 然而，这种机制在疾病特异性基础上或分子基础上尚不清楚。在初步工作中，我们发现FOXO_3对心血管疾病(CVD)、血管认知障碍和痴呆(VCID)--老年人死亡和残疾的重要原因--具有很强的预防作用。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-特别是血管相关疾病-的重要细胞和分子机制。 这项更新建议评估了炎症(衰老相关炎症)是否受FOXO_3基因的调节，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： 目的1.进行一项FOXO_3基因对大多数成年人群发病和死亡率的前瞻性研究。 假设：FOXO_3主要通过预防血管疾病来延长成人寿命。 目的2.检测与长寿相关的FOX03等位基因携带者是否具有保护性抗炎血清图谱。 假设：FOXO_3通过细胞因子介导的抗炎途径降低死亡率。 目的3.检测FOXO_3基因对认知衰老、AD和VCID的影响。 假设：促进长寿的基因变异也可能促进健康的大脑老化，包括更好的认知功能，更少的尸检大脑病理，以及更低的AD和VCID发生率。炎症可能是一个中介因素。

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.