Issue 20.4: August/September 2017
Department

The Long Game

Males of Okinawan descent live the longest and healthiest lives of any men, anywhere. Brad Wilcox set out to discover why.
Story by Rosemary Camozzi. Photos by Dana Edmunds.

Ninety-seven-year-old Osamu Kasashima laughs easily. He’s hard of hearing but his mind is razor-sharp, and he finds questions about his life pretty amusing. Ask him about his education and he’ll tell you about McKinley High School’s class of 1938 and his favorite teacher, Mr. Jackson.

Ask him about Pearl Harbor and he’ll tell you about the shrapnel raining down upon the tin roof he was working on when the bombs began to fall. Ask about the war years and he’ll tell you about the time he spent as a conscripted laborer working under the eyes of armed guards on horseback. He’s not one to hold grudges, though.“That was their duty,” he says.

When you ask him how he’s stayed so healthy over the years, he laughs again and jokes that it’s all due to “the program.” Kasashima has been participating in the Kuakini Honolulu Heart Program—a continuing study designed to track the incidence of coronary heart disease and stroke in Hawai‘i men of Japanese and Okinawan descent. Many of the eight thousand participants in the program, which was launched in 1965, lived to be a hundred years old or older. All of the remaining participants—about a hundred of them are left—are either centenarians or close to it. One of the largest, longest and most comprehensive medical studies of men in the world, the heart program has led to key discoveries in many areas of health. It has also spawned several other studies that seek to crack the secrets of long life and healthy senescence.

With the greatest life expectancy in the country, Hawai‘i has become a living laboratory for some of the world’s leading gerontological researchers. One ongoing study, the Kuakini Honolulu Heart Program, has tracked heart disease and stroke in men of Okinawan descent since 1965. Ninety-seven-year-old Osamu Kasashima, seen here with his wife, Frances, is one of the study’s participants.

With the greatest life expectancy in the country, Hawai‘i has become a living laboratory for some of the world’s leading gerontological researchers. Thanks to volunteers such as Kasashima, these scientists are advancing our understanding of how and why people can live to ripe old ages while maintaining good health.

“With the longest-lived people and the highest concentration of centenarians in the United States, Hawai‘i is a hotbed for discovery of the keys to healthy aging,” says Dr. Brad Willcox, a professor of geriatrics at the University of Hawai‘i’s medical school and a researcher with the Kuakini Health System.

Willcox has been at the forefront of much of this research. He is the principal investigator for the Kuakini Hawaii Life-span Study, which looks at the role of diet, exercise and other lifestyle factors to determine why Japanese and Okinawan men in Hawai‘i live so much longer than the national average. In the Kuakini Hawaii Healthspan Study, he’s leading an ongoing investigation into the genetic factors involved with living long and in good health. He is a co-investigator for the Kuakini Honolulu-Asia Aging Study, in which about a thousand men to date have donated their brains to help with research into dementia. He is also a co-investigator with the Kuakini Honolulu Heart Program Offspring Study, which is following the children and grandchildren of the original Honolulu Heart Program participants. The offspring participants include Kasashima’s daughter, Iris Kasashima-Pepper, as well as David Ige, Hawai‘i’s governor.

Willcox became fascinated with healthy aging while still in medical school, when he interviewed an extremely healthy 105-year-old Okinawan-Canadian. The man was a participant in a study that Willcox set up with his twin brother, Craig, who was working to become a medical anthropologist. When they asked the man the secret of his long and healthy life, his 95-year-old wife piped up and said, “It’s me! I’ve fed him healthy Okinawan food ever since I married him.” That meeting became the impetus for Willcox’s life’s work. “I was already hooked on nutrition and health,” says Willcox. “Once I met the centenarian, I got really interested in aging and Okinawa.”

“Hawai‘i is a hotbed for discovery of the keys to healthy aging,” says Brad Willcox, seen here. Wilcox is a professor of geriatrics at the University of Hawai‘i’s medical school and a researcher with the Kuakini Health System.

The Willcox brothers went to Okinawa in the mid-1990s and teamed up with Dr. Makoto Suzuki, principal investigator for the groundbreaking Okinawa Centenarian Study, which had been under way since 1975. Over the course of forty-plus years, this study looked at nine hundred centenarians, and many more people in their seventies, eighties and nineties, testing their genetic makeup and recording their lifestyle choices, including diet, exercise and spiritual practices. The study sought to identify the factors responsible for the remarkable longevity of Okinawans, who have not just the longest life expectancy but also the longest health expectancy (meaning that they maintain good health as they age) of any people in the world. The Willcoxes and Suzuki ended up writing two New York Times best sellers on the Okinawan diet and lifestyle.

Much of Willcox’s research revolves around a gene called FOXO3. To understand how this gene works, think of living in a big apartment building with lots of complex interior systems. When something goes wrong—say the air-conditioning stops working—you call the superintendent, trusting that he’ll call the appropriate contractor and someone will show up and fix the problem. FOXO3 is the super for the building that is your body. “When there’s trouble, it gets on the phone,” Willcox says.

Found in all humans (as well as a wide range of other organisms, including yeast, worms, flies and mice), the gene plays the role of first responder to the body’s mild stressors, such as a deficiency of energy or nutrients. “We think it acts like a thermostat,” Willcox says, “so that when something is perturbed—when homeostasis is out of balance—it activates and communicates with two or three hundred genes down the line. It might say, ‘There’s not enough food! Get us some more food! In the meantime, decrease the amount of calories we’re burning and increase the efficiency over here!’”

The gene’s function is an example of a biological phenomenon called hormesis, which means that a beneficial effect can come from the body’s reaction to low amounts of stress or even toxins. “Basically, the gene makes you more metabolically efficient,” Willcox says. “It also controls how quickly your cells divide, and controls cell surveillance. If you have an aberrant cell, it makes the immune system more active to find the cancer cells and kill them.”

FOXO3 has also been studied by cancer researchers, who have shown that it is an important player in warding off the disease. But the studies conducted by Willcox and his partners are the first to show that it affects human longevity in a multitude of other ways, including reducing one’s risk of dying from a heart attack.

The good news is that we all have the FOXO3 gene. The bad news is that only some of us have what Willcox calls the “longevity version.” If you have the FOXO3 G variant, rather than the more common FOXO3 TT, you have almost three times the chance of living a long life, and you are far less likely to have cancer or cardiovascular disease. And you’re more likely to have better physical and cognitive function into your nineties and beyond.

If you’re not a “G,” don’t panic. Consuming foods containing certain plant compounds and getting plenty of exercise have been shown to activate the FOXO3 gene and ward off illness, decline and death. As an example, only about 30 percent of Okinawans have the gene, yet they are the longest-lived group of people in the world. “Eat like an Okinawan!” Wilcox says.

The traditional Okinawan diet—the one established before the introduction of white rice and white bread—is heavily weighted toward foods that contain bioactive nutrients that “upregulate,” or turn on, the FOXO3 gene. The Okinawans eat large quantities of green and yellow vegetables, and their diet is dominated by purple sweet potatoes. Another major player is turmeric, which contains a compound called curcumin that has powerful antioxidant, anti-cancer and anti-inflammatory properties. Other dietary stars include jasmine green tea, hot peppers, seaweed, tofu and lots of phytoactive spices and herbs.

Caloric intake consists of about 80 percent carbohydrates—mostly from sweet potatoes—10 percent protein and 10 percent fat, resulting in a low-calorie diet that is high in nutrient intensity. Miso soup, tofu, bitter melon and a small amount of fish are eaten daily, but no matter what the main course is, there is always a side of sweet potatoes. As it turns out, the purple sweet potato contains an amazing array of micronutrients and is especially high in anthocyanin, which is known to help prevent certain cancers and protect against cardiovascular disease, and which re-searchers think might also activate the FOXO3 gene.

Ginger, turmeric, purple sweet potatoes and astaxanthin, an antioxidant found in seaweed, are key ingredients in Okinawan dishes and have all been linked to healthy aging.

Researchers have long known that caloric restriction is associated with long life. One study found that mice, for example, lived 30 percent longer when their intake of calories was reduced by 30 percent. Of course, cutting 30 percent of the calories from your own diet is easier said than done. But again the Okinawan diet brings good news: Some of its potent bioactive nutrients—such as those found in turmeric—essentially trick the body into thinking it’s consuming fewer calories than it actually is. This causes the FOXO3 gene to take action to protect the body’s cells against famine. “People don’t want to restrict their calories,” Willcox says, “but if they can eat certain foods or take certain supplements that mimic the effects, then they can upregulate the gene network that results in longevity.”

Another important compound is a red marine carotenoid called astaxanthin, which is produced by a microalgae and found in seaweed, salmon and shrimp. Astaxanthin has turned out to be a more potent antioxidant than any other yet discovered, scavenging free radicals and protecting your body from oxidative damage. The Okinawans consume it primarily in seaweed, an important part of their diet.

Tofu has also played a major role. Contrary to popular understanding, the weak phytoestrogens in soy not only activate the FOXO3 gene but also block stronger, more powerful estrogens in the body that stimulate cancer cells, Willcox says. The Okinawans, not surprisingly, have a low incidence of hormone-related cancers such as breast, colon, ovarian and prostate.

All in all, data from the Okinawa study has shown that Okinawans eating a traditional diet gained almost a decade of additional disability-free life expectancy as compared with Americans.

There are other factors. Willcox notes that while few of the centenarians they met had a low-stress life, they had what he calls stress-resistant personalities. “They are never in a hurry, they worry less, have a positive outlook, have good social support and are always busy with work, hobbies, family or friends,” he says. “In Okinawa they call it ikigai, having a purpose.”

A traditional Okinawan diet is low-calorie and high in nutrient intensity. A meal may include daikon, taro, stewed pork and seaweed. It almost always includes purple sweet potatoes.

Being physically active is also important. “Most centenarians we studied both in Okinawa and in Hawai‘i were lean or normal weight in their youth, and they walked a lot, gardened and liked to dance,” he says.

Kasashima is a good example. Active through his work in heavy construction, he didn’t slow down after he retired—swimming at Ala Moana Beach Park every day and climbing steep Diamond Head trail both morning and evening. Well into his nineties he still does the laundry, pays the bills and files his own taxes.

FOXO3 has proved to be a major player in a long, healthy life span, but it’s not the only gene that matters, Willcox say “FOXO3 is a very big gene that has 120,000 active pairs of DNA letters. We know it talks to other genes, and we’re doing studies to try to figure out which ones it communicates with. Maybe there are different genes that we can target simultaneously with nutraceuticals or pharmaceuticals that would help activate this whole anti-aging network.” The ultimate goal is to develop therapies to help people age in good health.

Willcox says it is technologically possible to insert the FOXO3 gene variant into humans, but the ensuing ethical questions mean that probably won’t happen anytime soon. Instead, the first approach should be to upregulate your own system naturally, through lifestyle and diet, he says. So take to heart the old Okinawan proverb, hara hachi bu (eat until you are 80 percent full), and give careful thought to what’s on your plate. Nuchi gusui, the Okinawans say. Food is medicine. HH