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Calorie restriction increases muscle mitochondrial biogenesis in healthy humans

Life expectancy (the average life span) greatly increased during the 20th century in most countries, largely due to improved hygiene, nutrition, and health care. One possible approach to further increase human life span is “caloric restriction.” A calorie-restricted diet provides all the nutrients necessary for a healthy life but minimizes the energy (calories) supplied in the diet. This type of diet increases the life span of mice and delays the onset of age-related chronic diseases such as heart disease and stroke. There are also hints that people who eat a calorie-restricted diet might live longer than those who overeat. People living in Okinawa, Japan, have a lower energy intake than the rest of the Japanese population and an extremely long life span. In addition, calorie-restricted diets beneficially affect several biomarkers of aging, including decreased insulin sensitivity (a precursor to diabetes). But how might caloric restriction slow aging? A major factor in the age-related decline of bodily functions is the accumulation of “oxidative damage” in the body’s proteins, fats, and DNA. Oxidants—in particular, chemicals called “free radicals”—are produced when food is converted to energy by cellular structures called mitochondria. One theory for how caloric restriction slows aging is that it lowers free-radical production by inducing the formation of efficient mitochondria.

Despite hints that caloric restriction might have similar effects in people as in rodents, there have been few well-controlled studies on the effect of good quality calorie-reduced diets in healthy people. It is also unknown whether an energy deficit produced by increasing physical activity while eating the same amount of food has the same effects as caloric restriction. Finally, it is unclear how caloric restriction alters mitochondrial function. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) organization is investigating the effect of caloric restriction interventions on physiology, body composition, and risk factors for age-related diseases. In this study, the researchers have tested the hypothesis that short-term caloric deficit (with or without exercise) increases the efficiency of mitochondria in human muscle.

The researchers enrolled 36 healthy overweight but non-obese young people into their study. One-third of them received 100% of their energy requirements in their diet; the caloric restriction (CR) group had their calorie intake reduced by 25%; and the caloric restriction plus exercise (CREX) group had their calorie intake reduced by 12.5% and their energy expenditure increased by 12.5%. The researchers found that a 25% caloric deficit for six months, achieved by diet alone or by diet plus exercise, decreased 24-hour whole body energy expenditure (i.e., overall calories burned for body function), which suggests improved mitochondrial function. Their analysis of genes involved in mitochondria formation indicated that CR and CREX both increased the number of mitochondria in skeletal muscle. Both interventions also reduced the amount of DNA damage—a marker of oxidative stress—in the participants’ muscles.

These results indicate that a short-term caloric deficit, whether achieved by diet or by diet plus exercise, induces the formation of “efficient mitochondria” in people just as in rodents. The induction of these efficient mitochondria in turn reduces oxidative damage in skeletal muscles. Consequently, this adaptive response to caloric restriction might have the potential to slow aging and increase longevity in humans as in other animals. However, this six-month study obviously provides no direct evidence for this, and, by analogy with studies in rodents, an increase in longevity might require lifelong caloric restriction. The results here suggest that even short-term caloric restriction can produce beneficial physiological changes, but more research is necessary before it becomes clear whether caloric restriction should be recommended to healthy individuals.

PLoS Medicine
March 20, 2007

Original web page at PLoS Medicine