Genetic determinants of exceptional human longevity …

Age (Dordr). 2006 Dec; 28(4): 313332.

1College of Nursing, Okinawa Prefectural University, 1-24-1 Yogi, Naha City, Okinawa Japan 902-0076

2Pacific Health Research Institute, 846 South Hotel Street, Suite 301, Honolulu, HI 96813 USA

3Departments of Geriatric Medicine and Medicine, John A. Burns School of Medicine, University of Hawaii, 1356 Lusitana Street, 7F, Honolulu, HI 96813 USA

4School of Medicine, University of California San Francisco, 74 New Montgomery Street, Suite 600, San Francisco, CA 94105 USA

52200 Post Street, C433, San Francisco, CA 94143-1640 USA

6Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, Japan

Received 2006 Jun 6; Revised 2006 Sep 30; Accepted 2006 Oct 1.

Centenarians represent a rare phenotype appearing in roughly 1020 per 100,000 persons in most industrialized countries but as high as 4050 per 100,000 persons in Okinawa, Japan. Siblings of centenarians in Okinawa have been found to have cumulative survival advantages such that female centenarian siblings have a 2.58-fold likelihood and male siblings a 5.43-fold likelihood (versus their birth cohorts) of reaching the age of 90years. This is indicative of a strong familial component to longevity. Centenarians may live such extraordinarily long lives in large part due to genetic variations that either affect the rate of aging and/or have genes that result in decreased susceptibility to age-associated diseases. Some of the most promising candidate genes appear to be those involved in regulatory pathways such as insulin signaling, immunoinflammatory response, stress resistance or cardiovascular function. Although gene variants with large beneficial effects have been suggested to exist, only APOE, an important regulator of lipoproteins has been consistently associated with a longer human lifespan across numerous populations. As longevity is a very complex trait, several issues challenge our ability to identify its genetic influences, such as control for environmental confounders across time, the lack of precise phenotypes of aging and longevity, statistical power, study design and availability of appropriate study populations. Genetic studies on the Okinawan population suggest that Okinawans are a genetically distinct group that has several characteristics of a founder population, including less genetic diversity, and clustering of specific gene variants, some of which may be related to longevity. Further work on this population and other genetic isolates would be of significant interest to the genetics of human longevity.

Key words: longevity, genetics, centenarians, Okinawa, longevity genes

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