COURTESY PHOTO / 2004 "Most people my age would get into the starting block and never be able to get up," says Chuck Yogi, 89. A lifelong runner of Okinawan decent, Yogi's mother lived to 102 and his father to 98. "If worrying made you live longer, I would do it, but it doesn't help so I never do," he says. Here, Yogi runs on a high school track in Hilo.

Gene raises odds of long life

Hawaii scientists' discovery is the latest related to an aging study started in 1965

Hawaii scientists say they have identified a human "longevity" gene prevalent in men who have led long, healthy lives.

The gene, labeled FOXO3A, was identified by Kuakini Medical Center and Pacific Health Research Institute investigators. They studied biological specimens and clinical data collected and maintained at Kuakini since 1965 on 8,006 Japanese-American men recruited for the Honolulu Heart Program and Honolulu-Asia Aging study.

Discovery of the FOXO3A gene is part of a Hawaii Lifespan Study that is continuing to mine information from the cohort to increase understanding of diseases and aging.

Findings of the team, led by Dr. Bradley Willcox, were published yesterday in the National Academy of Sciences' journal.

"Some humans are just built stronger, built to last, and other humans are more frail. That's our genetic endowment," Willcox said.

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The discovery by Drs. Bradley Willcox, J. David Curb, Tim Donlon and colleagues at the Kuakini Medical Center and Pacific Health Research Institute was published in yesterday's issue of the Proceedings of the National Academy of Sciences.

Invertebrates have one FOXO gene and mammals have four: FOXO1, 3, 4 and 6. FOXO proteins have been shown to prolong life span in less complicated species, such as earthworms, yeast and mice, but the Hawaii study is the first to show a connection to human longevity, the researchers said.

This is the latest of many significant findings on health, disease and aging by Hawaii researchers related to a group of 8,006 local Japanese-American men recruited in 1965 for the Honolulu Heart Program and Honolulu-Asia Aging Study at Kuakini. The men were born between 1900 and 1919 and identified through the World War II Selective Service registration file.

No other study has been done so long or in such detail on such a large group of men, Willcox said. About 1,000 are still living, ranging from 89 to 107 years old, he said.

Research has continued through a Hawaii Lifespan Study funded by the National Institute on Aging at Kuakini with Willcox and Curb as co-investigators.

Willcox is principal investigator of the latest study. Co-authors from the PHRI and University of Hawaii include Qimei He, Randi Chen, John S. Grove, Katsuhiko Yano, Kamal H. Masaki and Beatriz Rodriguez. Biostatistician D. Craig Willcox of Okinawa International University, Bradley Willcox's brother, also participated.

The group studied specimens from biological samples and clinical data on the men stored at Kuakini since the heart program and periodic physical exams began.

"The bottom line is we found a gene, if it works efficiently and works well or is made to operate well by medications or food or some other means - drinking red wine, eating soy foods or certain compounds - we think the gene makes more of a protein that can affect many, many things that affect how long you're going to live and how healthy you're going to be," Bradley Willcox said in an interview.

"This particular gene works in the insulin energy metabolism," he explained. "It affects insulin levels and blood glucose. Glucose is the energy product, the gasoline, that drives the body, and insulin is the hormone that decides how to distribute the gasoline.

"All kinds of genes are within this biological energy mechanism, like the engine on a car with a lot of working parts."

He said the group screened the DNA of 213 of the long-lived participants in the cohort and 402 of those with average life spans, focusing on five genes in the insulin pathway.

"We then calculated how the DNA bases found at three locations on each gene were correlated with a comprehensive set of health criteria, including chronic diseases, disability and insulin levels."

The results were "very surprising and exciting," he said.

One location on the FOXO3A gene stood out, he said. Of the four chemical bases in the DNA code - adenine (A), guanine (G), cytosine (C) and thymine (T) - most participants had the base T on both chromosomes at that location, he said.

But those who had the G base instead of T when they were originally examined had better health, he said. And 15 years later the G base was more prominent in men who averaged 98 years old than those who reached only an average age of 78, suggesting it was a factor in survival, Willcox said.

The researchers also found those who were carriers of the G allele (an alternative form of a gene) doubled their chances of living an average 98 years and some as long as 106 years. Men who had two G copies almost tripled their odds of living nearly a century and were healthier at older ages, according to the study.

Nongenetic factors affect the health and length of a person's life, said Willcox, a geriatrics scientist who found diet and exercise were the keys to long, disease-free lives of Okinawan centenarians.

But genetic differences could explain up to half of the variations in human life span, he said. "Some humans are just built stronger, built to last, and other humans are more frail. That's our genetic endowment."

However, there might be a way to make the gene work better, he said, noting millions of dollars are being spent on drug studies to try to influence how the FOXO3 gene works and the proteins it makes in animals.