The researchers also found that calorie restriction (CR) decreases the circulating concentration of a powerful inflammatory molecule called tumor necrosis factor alpha (TNF). They say the combination of lower T3 levels and reduced inflammation may slow the aging process by reducing the body's metabolic rate as well as oxidative damage to cells and tissues.

ncentration of a powerful inflammatory molecule called tumor necrosis factor alpha (TNF). They say the combination of lower T3 levels and reduced inflammation may slow the aging process by reducing the body's metabolic rate as well as oxidative damage to cells and tissues.

Previous research on mice and rats has shown that both calorie restriction and endurance exercise protect them against many chronic diseases including obesity, diabetes, cardiovascular disease and some types of cancer. However, the research has shown that only CR increases the animals' maximum lifespan by up to 50 percent. These animal studies suggest that leanness is a key factor in the prevention of age-associated disease, but reducing caloric intake is needed to slow down aging.

For the new study, researchers examined 28 members of the Calorie Restriction Society who had been eating a CR diet for an average of six years. Although the CR group consumed fewer calories -- averaging only about 1,800 per day -- they consumed at least 100 percent of the recommended daily amounts of protein and micronutrients. A second group of 28 study subjects was sedentary, and they ate a standard Western diet. A third group in the study ate a standard Western diet -- approximately 2,700 calories per day -- but also did endurance training. The researchers found reduced T3 levels -- similar to those seen in animals whose rate of aging is reduced by CR -- only in the people on CR diets.

But their serum concentrations of two other hormones -- thyroxin (T4) and thyroid stimulating hormone (TSH) -- were normal, indicating that those on CR were not suffering from the thyroid disease of clinical hypothyroidism. The findings are published online in the Journal of Clinical Endocrinology and Metabolism.

Interestingly, body fat levels did not affect serum T3 concentrations. The people in the CR group and the endurance athletes had similar amounts and composition of body fat. But although the CR group had lower T3 levels, the exercise group had T3 levels closer to those seen in the sedentary people who ate a standard Western diet.

"The difference in T3 levels between the CR group and the exercise group is exciting because it suggests that CR has some specific anti-aging effects that are due to lower energy intake, rather than to leanness," says first author Luigi Fontana, M.D., Ph.D., assistant professor of medicine at Washington University in St. Louis and an investigator at the Istituto Superiore di Sanita, Rome, Italy. "These findings suggest that although exercise helps prevent problems that can cut life short -- such as obesity, diabetes and cardiovascular disease -- only CR appears also to have an impact on primary aging."

Primary aging determines maximal length of life. Secondary aging, on the other hand, refers to diseases that can keep a person or an animal from reaching that expected lifespan. Eliminating factors related to secondary aging allows more people to reach their projected length of life. By slowing primary aging, CR may increase maximal lifespan.

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In a related study in 1997, co-investigator John O. Holloszy, M.D., professor of medicine at Washington University School of Medicine, reported in the Journal of Applied Physiology that in rats, CR extended life longer than exercise.

"Sedentary rats who ate a standard diet had the shortest average life-spans," Holloszy says. "Those who exercised by running on a wheel lived longer, but animals on calorie restriction lived even longer."

Earlier this year, Fontana's group reported that CR seemed to prevent or delay primary aging in the heart. Ultrasound examinations showed that the hearts of people on calorie restriction were more elastic than those of age- and gender-matched control subjects. Their hearts were able to relax between beats in a way similar to the hearts of younger people.

This latest study targeted another marker of primary aging. The thyroid gland produces critical hormones that play an indispensable role in cell growth and development as well as in lipid and carbohydrate metabolism. T4 is the main product secreted by the cells of the thyroid gland, but most actions of thyroid hormone are initiated by T3. Fontana says T3 controls body temperature, cellular metabolism and to some extent, it also appears to be involved with production of free radicals, unstable molecules that can damage cells. All are important aspects of aging and longevity. In fact, a 2002 study in Science magazine from researchers at the National Institute on Aging observed that men with lower body temperatures tended to live longer those with higher body temperatures.

Fontana says lower levels of T3, cholesterol and the inflammatory molecules TNF and C-reactive protein, combined with evidence of "younger" hearts in people on calorie restriction, suggest that humans on CR have the same adaptive responses as did animals whose rates of aging were slowed by CR.

Holloszy and Fontana are getting ready to launch a 2-year study to look at the effects of calorie restriction. Later this year, they will begin recruiting volunteers between the ages of 25 and 45 who are willing to go on a CR diet for 24 months.

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Called the Comprehensive Assessment of the Long Term effects of Reducing Intake of Energy (CALERIE) study, the goal is to get some clues about whether putting a normal weight person on calorie restriction will lower their levels of inflammation and their serum concentrations of T3, improve their heart function and change other markers of aging, as Fontana and Holloszy have observed in members of the Calorie Restriction Society.

"We want to learn whether calorie restriction can reverse some of these markers of aging in healthy people," Holloszy says. "It's going to be many years before we know whether calorie restriction really lengthens life, but if we can demonstrate that it changes these markers of aging, such as oxidative damage and inflammation, we'll have a pretty good idea that it's influencing aging in the same way that CR slows aging in experimental animals."

Reference: Fontana L, Keline S, Holloszy JO, Premachandra BN. Effect of long-term calorie restriction with adequate protein and micronutrients on thyroid hormones. Journal of Clinical Endocrinology and Metabolism, first published ahead of print May 23, 2006 as doi: 10.1210/jc 2006-0328.

This research was supported by was supported by the National Institutes of Health.