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.

Public Health Relevance

The renewal of the Kuakini Medical Center (Kuakini) Hawaii Lifespan Study will investigate how people's genes may affect their ability to achieve healthy old age. This study focuses on functional characteristics of healthy aging over the lifespan and identifies genetic factors that enable people to survive to exceptional ages in good health. Research on the genetics of healthy aging may help identify potential targets for therapies resulting in less age-related disease and disability.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG027060-09A1
Application #
9522783
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Raghavachari, Nalini
Project Start
2005-09-30
Project End
2022-05-31
Budget Start
2018-06-15
Budget End
2019-05-31
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Kuakini Medical Center
Department
Type
DUNS #
077701613
City
Honolulu
State
HI
Country
United States
Zip Code
96817
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Morris, Brian J; Willcox, Donald Craig; Donlon, Timothy A et al. (2015) FOXO3: A Major Gene for Human Longevity--A Mini-Review. Gerontology 61:515-25
Zeng, Yi; Chen, Huashuai; Ni, Ting et al. (2015) GxE interactions between FOXO genotypes and drinking tea are significantly associated with prevention of cognitive decline in advanced age in China. J Gerontol A Biol Sci Med Sci 70:426-33
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Huh, Ji Young; Ross, George Webster; Chen, Randi et al. (2015) Total and differential white blood cell counts in late life predict 8-year incident stroke: the Honolulu Heart Program. J Am Geriatr Soc 63:439-46

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