StemCell Therapy

Evidence-Based Gerontology

One of the most important things about the Okinawa Centenarian Study is the fact that it is based on solid evidence. The most important evidence needed for any centenarian study is reliable age-verification data. Throughout Japan (including Okinawa prefecture), every city, town, and village records birth, marriage and death data (among other data) in a koseki (family register). This system was instituted throughout Japan in the 1870's. The koseki is supplemented by a regular census undertaken every five years. Life tables calculated from this database show one of the world's longest life expectancies and prevalence data show the world's highest known concentration of centenarians for any country or state.

After examining over 900 Okinawan centenarians and numerous other elderly in their seventies, eighties, and nineties, some fascinating findings have emerged. One, genetic factors appear important to human longevity, including Okinawan longevity. Two, it has also become clear that the Okinawan lifestyle provides many reasons why older Okinawans are so remarkably healthy so far into their senior years. Discovering the reasons for the apparent genetic and environmental advantages could have an important impact on our health and well-being in the West. Below appear some of the key findings and what they mean in terms of healthy aging -- for the Okinawans, and the rest of us.

Identifying factors that help us remain healthy, vigorous and disability-free at older ages is one of our major research priorities. Since the completion of the Human Genome Project and the HapMap Project (a project to identify common variations in human genes), a promising novel strategy by some human longevity researchers is to try to identify genes (and variations of those genes) that impact human aging and longevity. If such genes and their genetic pathways can be identified then novel therapies might be created that affect the biology of these pathways. This may help prevent or treat age-associated diseases and perhaps even slow aging itself. Such therapies might include interventions as simple as diet and focused exercise, specific food compounds, neutraceuticals or pharmaceuticals.

How much of human longevity is due to genes? Estimates of the heritability of human lifespan vary from 10-50% with the most common finding being that about a third of human lifespan may be heritable. Phenotypes that suggest slower aging, such as survival to 90+ years, may have an even stronger genetic basis, which explains why centenarians and near-centenarians tend to cluster in families. But until the discovery of the apolipoprotein E (ApoE) gene, there was little evidence for a single gene effect large enough to impact human longevity. This discovery has been replicated in many populations, suggests that associations with some genes are large.

Studies of long-lived humans, such as American centenarians, have helped identify other promising genetic loci for longevity and healthy aging. However, these studies are often limited in scope due to small sample sizes, genetic admixture, and inappropriate selection of controls. Some success has been achieved through use of genetically homogeneous populations with smaller gene pools.

Our research group was the first to identify so called "human longevity genes" using centenarians as a study model when we published a study showing that Okinawan centenarians have HLA (human leukocyte antigen) genetic polymorphisms that place them at lower risk for inflammatory and autoimmune diseases (see figure below: Takata et al., Lancet 1987).

We also studied the mortality patterns of centenarian siblings. Past family studies in other populations have shown that there are familial (genetic) components to longevity. That is, longevity tends to run in families. In support of this, we found that a mortality advantage exists for centenarian siblings versus their age-matched birth cohorts. This advantage appears sustained over the course of the siblings' lives. At each 5-year age interval until age 90 years, siblings of Okinawan centenarians maintained approximately a 50% lower mortality risk. This resulted in an average of 11.8 years extra lifespan compared to their age-matched birth cohort. The sustained mortality advantage over the life course provides further evidence that human longevity has an important genetic component since most environmental mortality advantages, such as education, diminish or disappear completely in older age groups (see figure below from Willcox BJ et al. Siblings of Okinawan centenarians exhibit lifelong mortality advantages. J Gerontol A Biol Sci Med Sci. 2006;61:345-54).

In order to quantify the genetic contribution to Okinawan longevity, we studied the sibling recurrence risk ratio or "lambda of sib (ls)" in siblings of Okinawan centenarians. This is a calculation that has been shown to give a rough idea of how important genes might be to a given phenotype, such as a disease, or even to something more complex like human longevity.

We analyzed a population-based sample of 348 Okinawan centenarians (born between 1874 and 1902) and 969 of their siblings (507 females and 462 males) to explore the feasibility of a genome-wide study of Okinawan longevity. The ls for Okinawan centenarians was 6.5 (95% confidence interval: 3.9-10.7) for females and 5.1 (95% confidence interval: 1.8-14.2) for males, respectively. The weighted sex-combined ls was 6.3. These estimates in Okinawans appear to be higher than those obtained in past work on U.S. Caucasians. For example, a study of the familial component of longevity in Utah families estimated the ls to be 2.3. This suggests an important genetic component to Okinawan longevity and supports further work on the genetics of healthy aging and longevity in this population (see Willcox BJ et al., Substantial advantage for longevity in siblings of Okinawan centenarians. Genetic Epidemiology). 2005;29:286.

Does this mean that Okinawan longevity is all genetic? Not at all. We believe the Okinawans have both genetic and non-genetic longevity advantages -- the best combination. In fact, we have written extensively that the Okinawan traditional way of life -- the dietary habits, the physical activity, the psychological and social aspects, all play an important role in Okinawan longevity.

While most studies of humans have suggested that about a third of human longevity is due to genetics, this depends on the age, sex, ethnicity and environment of the study population. For example, studies of "model organisms" of aging, such as rodents, who share many of the same genes as humans, have shown that single genes can influence lifespan by 50% or more. On the other hand, studies of lifestyle interventions, such as eating fewer calories (a.k.a. "caloric restriction") have shown that this dietary intervention can also yield increases in lifespan of a similar magnitude (see Willcox DC et al., Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology. 2006;7:173-77). The key is to study both genetic and non-genetic (environmental) factors and ultimately "gene-environment" interactions that lead to healthy longevity.

One of the most durable theories of aging is the free radical theory. This theory postulates that damage from free radicals (unstable molecules), generated mainly from metabolizing food into energy, ultimately damages vital body molecules (tissue, DNA, etc.). This damage accumulates with time until, like an old car, we fall apart. In support of this theory, one of the most important findings in free-radical research has been that eating fewer calories increases life span (Sohal RS, et al. Science 1996;273:59-63; Heilbronn LK, et al. Am J Clin Nutr 2003;78:361-9). The initial evidence that this may work in humans has been indirect and based on observation of the low caloric intake of the Okinawans and their long life expectancy (Willcox DC, et al. Biogerontology 2006). More direct evidence suggests that Okinawans following the traditional ways have low blood levels of free radicals. The elders had significantly lower levels of lipid peroxide-compelling evidence that they suffer less free-radical-induced damage. This may indicate healthier lifestyles but may also be due to gene variants that result in lower blood levels of free radicals. This is currently under investigation.

Levels of Lipid Peroxides in Okinawan Centenarians and Septuagenarians

Elderly Okinawans were found to have impressively young, clean arteries, low cholesterol, and low homocysteine levels when compared to Westerners. These factors help reduce their risk for coronary heart disease by up to 80% and keep stroke levels low.

Their healthy arteries appear to be in large part due to their lifestyle: diet, regular exercise, moderate alcohol use, avoidance of smoking, blood pressure control, and a stress-minimizing psychospiritual outlook. However, there are also potential genetic aspects such as lower fibrinogen levels possibly due to differences in fibrinogen-related genes. A recent autopsy study that we conducted on a centenarian demonstrated that her coronary arteries were virtually free of atherosclerotic plague (Bernstein, Willcox et al. JGMS 2004).

The chart to the right indicates that the higher the plasma homocysteine (a new risk factor) level is, the more people suffer from cardiovascular disease. Homocysteine is an amino acid that causes damage to arterial walls. It is higher in people who don't get enough folate (e.g. green leafy vegetables) and vitamins B6, B12 but low in Okinawans.

Okinawans are at extremely low risk for hormone-dependent cancers including cancers of the breast, prostate, ovaries, and colon. Compared to North Americans, they have 80% less breast cancer and prostate cancer, and less than half the ovarian and colon cancers. Some of the most important factors that may protect against those cancers include low caloric intake, high vegetables/fruits consumption, higher intake of good fats (omega-3, mono-unsaturated fat), high fiber diet, high flavonoid intake, low body fat level, and high level of physical activity.

Hormone-Dependent Cancer Risk

Yearly Cancer Deaths (per 100,000 people)

Adapted from World Health Organization 1996; Japan Ministry of Health and Welfare 1996

NK, a typical healthy centenarian was reported to be in particularly good health, completely independent, and still farming. He is shown here getting his bone density tested by heel bone ultrasound.

Okinawans have about 20% fewer hip fractures than do mainland Japanese, and Japanese have about 40% fewer hip fractures than Americans (Ross PD, et al. Am J Epidemiol 1991;133:801-9). Our research on Okinawan elders showed that their bone density, when adjusted for body size, is similar to Americans, and like the rest of us they continue to lose bone mass as they get older, but possibly at a slower rate. We compared bone mineral density in a group of Okinawans to two groups from mainland Japan and found that by age forty for women and age fifty for men the groups began to diverge. The Japanese began to lose significantly more calcium from their bones than the Okinawans, suggesting the Okinawans preserve their bone density at healthy levels for longer periods of time than other Japanese (Suzuki M, et al. Japanese J Bone Res 1995;63:166-72). Protective lifestyle factors that may play a role here include high calcium intake by Okinawans in both food and their natural drinking water, high vitamin D levels from exposure to sunlight, increased physical activity, especially at older ages, and high intake of dietary flavonoids (estrogenic compounds from plant foods).

Prevalence surveys suggest that the dementia rate is fairly low among the Okinawan elderly, compared to other elderly populations. Even into their late 90s Okinawans suffered lower dementia rates than reported for comparable populations in the United States and elsewhere.

Photo: 97 year old karate master Seikichi Uehara

Okinawan centenarians have been lean throughout their extraordinarily long lives, with an average body mass index (BMI) that ranged from 18 to 22 (lean is less than 23). The Okinawans have traditionally kept eating a low-calorie, low glycemic load diet, practicing calorie control in a cultural habit known as hara hachi bu (only eating until they are 80% full), and keeping physically active the natural way. Particular exercise interventions are under study for their role in healthy aging.

Women's health and aging is one of our research interests. For example, women in Okinawa tend to experience menopause naturally and nonpharmacologically with fewer complications such as hot flashes, hip fractures, or coronary heart disease. Lifestyle determinants include diet, avoidance of smoking and exercise in the form of dance, soft martial arts, walking and gardening. Okinawan women also have a very high intake of natural estrogens through their diet, mainly from the large quantities of soy they consume. Soy contains phytoestrogens, or plant estrogens called flavonoids. The other important major phytoestrogens are lignans, which are derived from flax and other grains. All plants, especially legumes (beans, peas), onions, and broccoli, contain these natural estrogens, but not nearly in the same quantity as soy and flax. Recent double-blind placebo controlled studies support the ability of soy isoflavones to slow the bone loss (Alekel D, et al. Am J Clin Nutr 2001;72:844-52) and hot flashes (Albertazzi P, et al. Obstet Gynecol 1998;91:6-11) that occur with menopause.

Okinawan elders may have higher levels of sex hormones, including natural DHEA, estrogen, and testosterone than similarly aged Americans, suggesting that the Okinawans are physiologically younger. DHEA is a steroid produced in the human adrenal gland, and some studies suggest that it may help ameliorate the ravages of aging. However, taking DHEA supplements could increase risk for breast and other cancers so we do not recommend taking DHEA supplements. More supported by the scientific literature is that DHEA levels decline in direct ratio with age, so it may be a good marker of biological age. Okinawans appear to have higher DHEA levels than similarly aged Americans suggesting that Okinawans may age slower than Americans. As Okinawans age, both sexes maintain remarkably higher levels of estrogen which may help protect against heart disease and osteoporosis. Testosterone is the male equivalent of estrogen. Higher endogenous levels increase our muscle mass and our body hair, deepen our voices, and control our libidos, among other functions. This hormone also appears higher in older Okinawan men. Cross-national population studies are needed to confirm these differences and their biological significance.

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The Okinawa Centenarian Study : Evidence based gerontology

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