Project Summary This is a supplement to the parent R01 award 5R01AG027060-12: FOXO3 Genotype, InflammAging, Cardiovascular Disease, and Dementia. Kuakini Hawaii Lifespan Study III. The parent R01 study proposed to utilize the Kuakini Honolulu Heart Program/Kuakini Honolulu-Asia Aging Study (Kuakini HHP/Kuakini HAAS) cohort. The Kuakini HHP study began in 1965. AIM 1. CONDUCT a prospective study of FOXO3 genotype on incident disease and mortality utilizing 47 years of follow-up data. 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 and dementia. 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. The parent award was in response to PA-16-160: Research Project Grant (Parent R01). As such, the focus was not on new data collection. Due to COVID-19 we had a number of delays in completing the primary Aims. For example, we had limited access to our medical center, which was in lock-down, we had supply chain disruptions, including delays in obtaining replacements for broken equipment, and inability to receive cytokine assay supplies in a timely manner. The AIM of this supplement is to complete the work that was disrupted due to COVID-19 issues and to measure an additional 600 study subjects (stored blood) for blood cytokine levels. The additional 600 study subjects will provide greater power to detect potentially statistically significant relations from currently underpowered borderline results. This supplement addresses the need to urgently examine scientific challenges surrounding healthy human aging, particularly with regard to inflammaging, a major driver of aging-related disease and disability.