The Kuakini Medical Center (Kuakini) Hawaii Lifespan Study II will focus a multidisciplinary team of genetic, epidemiological, and geriatric scientists on the use of innovative approaches for secondary data analysis. We will use existing human data and specimens from the 45-year Kuakini Honolulu Heart Program/Honolulu Asia Aging Study (longitudinal studies of aging and chronic diseases), in Japanese-American men. Our work will focus on identifying the mechanism(s) of action of FOXO3A on healthy aging and longevity. We will attempt to identify novel genetic mechanisms by which people survive to older ages in good health. While terms such as """"""""successful"""""""", """"""""healthy"""""""" or """"""""effective"""""""" aging describe a paradigm of aging with minimal chronic disease, the genetic mechanisms of such aging are poorly understood. In recent work we have: 1) operationalized phenotypes of healthy aging that use performance-based measures of function 2) identified environmental predictors of healthy aging and longevity in a longitudinal study, (3) replicated a previous association of the CETP gene on longevity and extended the finding to include a role in healthy aging 4) and discovered a novel gene (FOXO3A) variation that is strongly associated with healthy aging and longevity. For the current study, a renewal proposal of our original parent R01-the Kuakini Hawaii Lifespan Study-we propose the following aims: 1) High density sequencing of the FOXO3A gene;2) Repeat the original case-control study with 184 additional Kuakini HHP cases (n=397 longevity cases;402 average-lived controls) in order to identify the strongest association with longevity;3) Conduct a longitudinal study for incident diseases, functional loss and mortality with 3,569 Kuakini HHP subjects;4) Conduct tests of association between genotypes and gene expression/protein function using cell lines from 287 Kuakini HHP subjects. Discovery of biologic pathways that affect vulnerability to age-related diseases and disability could have a dramatic impact on our ability to achieve healthy old age by identifying biological targets for new therapies. Our study directly supports NIA's mission to improve the health and well-being of older Americans.
The Kuakini Medical Center (Kuakini) Hawaii Lifespan Study II will investigate how people's genes affect their ability to achieve healthy old age. This study focuses on understanding physical and cognitive function over the lifespan and identifies genetic and environmental factors that enable people to survive to exceptional ages in good health. Research on factors that lead to healthy aging may help us develop therapies that result in less age-related disease and disability, and increase quality of life at older ages.
|Donlon, Timothy A; Morris, Brian J; Chen, Randi et al. (2017) FOXO3 longevity interactome on chromosome 6. Aging Cell 16:1016-1025|
|Willcox, Bradley J; Willcox, Donald Craig; Suzuki, Makoto (2017) Demographic, phenotypic, and genetic characteristics of centenarians in Okinawa and Japan: Part 1-centenarians in Okinawa. Mech Ageing Dev 165:75-79|
|Willcox, Bradley J; Tranah, Gregory J; Chen, Randi et al. (2016) The FoxO3 gene and cause-specific mortality. Aging Cell 15:617-24|
|White, Lon R; Edland, Steven D; Hemmy, Laura S et al. (2016) Neuropathologic comorbidity and cognitive impairment in the Nun and Honolulu-Asia Aging Studies. Neurology 86:1000-8|
|Morris, Brian J; Chen, Randi; Donlon, Timothy A et al. (2016) Association Analysis of FOXO3 Longevity Variants With Blood Pressure and Essential Hypertension. Am J Hypertens 29:1292-1300|
|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|
|Morris, Brian J; Carnes, Bruce A; Chen, Randi et al. (2015) Genetic variation in the raptor gene is associated with overweight but not hypertension in American men of Japanese ancestry. Am J Hypertens 28:508-17|
|Karino, Shigehiko; Willcox, Bradley J; Fong, Kaon et al. (2015) Total and differential white blood cell counts predict eight-year incident coronary heart disease in elderly Japanese-American men: the Honolulu Heart Program. Atherosclerosis 238:153-8|
|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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