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Scientists Weigh Mechanisms, Effects of Calorie Restriction

apple on a scaleBack in 1934, dust storms rolled across the Great Plains, Anything Goes premiered on Broadway, the New Deal was still new, and Bonnie and Clyde met their demise. During that year, too, scientists at Cornell University 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 lifespans 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 cholesterol, serum glucose, and blood pressure levels.

Still open to debate, though, are the reasons why calorie restriction (CR) boosts longevity in some animals and lower organisms, and the effects of this less-is-more approach to energy consumption in humans. Confirming CR’s effects and pinpointing the mechanism—or mechanisms—through which CR promotes longevity remain scientific goals, and NIA investigators and grantees working in this niche of aging research are actively searching for answers.

“Calorie restriction remained a black box for many years, and only in the past 5 years have we begun to get a handle on the box’s contents,” says Felipe Sierra, Ph.D., director of NIA’s Biology of Aging Program. “NIA is very interested in calorie restriction and is funding a wide variety of research in this area. Our goal is to examine the relationship of CR to healthy aging and disease. We’re not necessarily trying to find ways for people to live very long lives, but to find ways to improve health so they can live better in their later years.”

Deciphering the mechanisms behind CR

Although scientists have been studying CR for years, only recently have they begun to decipher the cellular and molecular mechanisms that may mediate its positive effects. Elucidation of these mechanisms, many believe, offers hope for advancing understanding of aging processes. Ultimately, it also could 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.

“We need to study the mechanisms and the relationships among them so we can learn more about the process of aging. This may help us identify interventions that act like calorie restriction without actually restricting diet,” Sierra says.

Dr. Rafael de Cabo
Dr. Rafael de Cabo, NIA Laboratory of Experimental Gerontology

A review of recently published CR-related research illustrates the wide range of mechanisms—from expression of genes known as sirtuins to involvement of insulin signaling pathways—that are currently under investigation, notes Rafael de Cabo, Ph.D., head of the Aging, Metabolism, and Nutrition Unit in NIA’s Laboratory of Experimental Gerontology (LEG). His unit’s bench and rodent experiments focus on identifying potentially protective mechanisms invoked by CR and on evaluating the consequences of dietary interventions on lifespan, pathology, and behavioral function. The lab team also works closely with NIA grantees on CR-related studies.

Recently, for example, a research team including de Cabo and David Sinclair, Ph.D., of Harvard Medical School, discovered in mice that two sirtuin genes, SIRT3 and SIRT4, influence the stability of mitochondria, structures within cells that convert nutrients into energy-yielding molecules and play a role in cell survival. They observed that a gene called NAMPT is activated in calorically restricted cells, resulting in accumulation of NAD+ molecules, which are needed for many metabolic processes. This accumulation, in turn, causes enzymes created by the SIRT3 and SIRT4 genes in the mitochondria to increase, slowing the cell’s aging process.

The findings (PDF, 1.1M), reported September 21, 2007, in Cell, provide clues to cell survival in mammals following the stress brought on by CR, and have potential implications for longevity and aging-associated diseases such as cancer, diabetes, and neurodegenerative diseases such as Alzheimer’s disease.

With each bit of knowledge gained, de Cabo says, investigators are edging closer to understanding at the most basic level why CR may protect against disease and increase longevity. Complementing these efforts, NIA investigators and grantees are searching for mimetics—compounds that mimic the protective cellular effects that appear to occur with restricted energy 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 is now underway in monkeys in a recently launched, 2-year controlled trial at NIA.

Studies in nonhuman primates ongoing

While NIA investigators and grantees continue to probe the mechanisms behind CR, for the past two decades NIA LEG researchers and colleagues at the University of Wisconsin have been studying CR’s effects on mortality, morbidity, and function in nonhuman primates.

NIA's Intramural Primate Aging Study, begun in 1987, currently includes 80 healthy rhesus monkeys that ranged in age from 1 to 23 years when they entered the study, as well as a smaller group of squirrel monkeys. The experimental CR and control groups are fed the same mix of nutrient-rich foods, but the CR group is given 30 percent fewer calories than the age- and weight-matched controls.

Dr. Julie Mattison
Dr. Julie A. Mattison, NIA Primate Aging Study

“Monkey studies are incredibly valuable because they’re the closest we can come to human studies,” says Julie Mattison, Ph.D., facility head of NIA’s nonhuman primate program. “Rhesus monkeys are a great model for studying calorie restriction and the mechanisms of aging because they age at a rate about three times that of humans, are genetically close to humans, and get many of the age-related diseases seen in humans.”

Thus far, the physiological effects of CR seen in these primate studies are generally 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.

Although it is not yet known if CR extends the lifespan of nonhuman primates, the findings emerging from these studies are encouraging, showing that calorie-restricted monkeys have a lower incidence and less severe effects of age-related diseases, particularly cardiovascular disease and diabetes. Recently launched studies also are examining the effects of CR on the monkeys’ behavior, motor skills, learning and memory, macular degeneration, reproductive health, hearing, and osteoarthritis.

“As the monkeys approach older age, we’ll learn more about the long-term effects of CR and possible mechanisms that regulate these effects,” Mattison says.

Human trial begins

Recently, NIA extended its CR research one step further when the Institute 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. Before the CALERIE pilot studies began, all well-controlled investigations into CR’s effects had been in lower organisms and animals other than humans.

Studying this dietary practice in humans is different from studying it in animals, points out Sergei Romashkan, M.D., Ph.D, chief of the Clinical Trials Branch in NIA’s Geriatrics and Clinical Gerontology Program. “Unlike animals kept in a lab, humans can choose to eat when and what they want,” Romashkan says. “The CALERIE study will help us to understand the adaptive physiologic and metabolic changes that have been observed in animal studies and to learn whether humans can sustain a nutrient-rich, calorie-restricted diet over time. It also will help us to learn about the safety of calorie restriction.”

CALERIE began in 2002 with pilot studies at three sites: Pennington Biomedical Research Center in Baton Rouge, Tufts University in Boston, and Washington University in St. Louis. This small-scale research compared 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 1 year, depending on the protocol, volunteers in the CR or exercise arms had lower 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 and reduced DNA damage.

The full-scale, 5-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 2-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 will let us look at 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 and how CR may affect markers of diseases associated with aging,” Romashkan says. Because the study timeframe is 2 years, the analyses will not show whether CR can extend human lifespan, he notes.

Whether they are studying 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 believe that progress is being made. “This field is extremely exciting, and many of us are coming to the same conclusions about the pathways that are being activated,” says NIA’s de Cabo. “In the next 5 to 10 years, we may make important strides toward designing compounds to emulate CR’s effects.”