In 1934, scientists observed that lab rats fed a calorie-restricted diet had twice the lifespan of other rats. Those observations, reported the following year, launched a line of inquiry that continues to intrigue scientists today.
Now, more than 70 years later, a large body of research shows that a calorie-restricted diet, coupled with adequate nutrition, extends the life spans of protozoa, yeast, worms, spiders, flies, and rodents. Research also suggests that calorie-restricted animals, including primates, tend to be more resistant to age-related chronic diseases, and that restricting calories while maintaining sufficient nutrient levels is associated with lower levels of cholesterol, serum glucose and blood pressure.
Only recently have scientists begun to look at the cellular and molecular mechanisms that might reflect the positive effects of calorie restriction (CR). Defining these mechanisms could possibly help scientists identify drug targets or one day develop gene therapies or other interventions to prevent and treat some of the most prevalent aging-related diseases.
Recent study findings have provided clues to cell survival in mammals, offering implications for longevity and for such aging-associated diseases as cancer, diabetes and Alzheimer’s disease. With each bit of knowledge gained, scientists are edging closer to understanding at the most basic level why CR might protect against disease and increase longevity. Complementing these efforts, scientists also are searching for compounds that mimic the protective cellular effects that appear to occur with restricted calorie intake. For example, resveratrol—a natural compound found in grapes, red wine and nuts—has been shown to improve health and survival in overweight, aged mice. Similar research now is underway in monkeys, in a recently launched, two-year controlled trial at the National Institute on Aging (NIA).
While ongoing research continues to probe the mechanisms behind CR, scientists for the past two decades have been studying CR’s effects on mortality, morbidity and function in nonhuman primates (monkeys).
Thus far, the physiological effects in these primate studies are comparable to those seen in rodent studies. For example, compared with free-feeding monkeys, the CR monkeys have lower body weight, less abdominal fat, lower fasting glucose levels, increased insulin sensitivity, lower systolic blood pressure, lower levels of serum triglycerides and higher HDL levels—all markers associated with reduced risk of age-associated diseases. The CR monkeys also show improved immune response and less severe response to induced inflammation.
Other studies are examining the effects of CR on the monkeys’ behavior, motor skills, learning and memory, macular degeneration, reproductive health, hearing and osteoarthritis.
Recently, the NIA awarded funding for the first randomized, controlled trial to assess the effects of CR in humans—the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study. CALERIE began in 2002 with pilot studies comparing the outcomes of varying levels of CR; exercise regimens designed to produce an energy deficit equivalent to that seen with CR; and a healthy lifestyle control intervention. Each of the pilot studies involved 48 volunteers.
The pilot studies showed that after one year, depending on the protocol, volunteers in the CR or exercise arms had lower levels of fasting glucose, total cholesterol, core body temperature, body weight and visceral fat. The CR and exercise groups also had increased expression of genes encoding proteins involved in mitochondrial function (converting nutrients into the energy-yielding molecule that fuels the cell’s activities) and reduced DNA damage.
A full-scale, five-year CALERIE study, launched in early 2007, involves 250 healthy volunteers ages 25 to 45, who are assigned to either a CR intervention or a control group. During a two-year period, participants in the intervention group will reduce their baseline calorie consumption by 25 percent, while the control group members will continue their usual diets.
The researchers will measure a range of outcomes, from insulin and glucose metabolism to oxidative cellular and DNA damage, muscle strength and cognition. They will also amass a repository of blood, urine and tissue samples that will be available to investigators studying oxidative damage in cells and molecular mechanisms associated with CR.
The CALERIE study is expected to help scientists determine the feasibility of such a diet and whether sustained calorie restriction in healthy men and women results in the same adaptive changes that occur in rodents subjected to CR. Also to be studied is how CR might affect markers of diseases associated with aging. (Because the study time frame is two years, the analyses will not show whether CR can extend human lifespan.)
Whether examining the cellular and molecular mechanisms behind CR’s effects or assessing the impact of CR on the health and longevity of lower organisms, animals or humans, many scientists are hopeful that compounds that mimic CR’s effects might one day be developed to prevent and treat some of the most prevalent aging-related diseases.