By Roger McCarter and Liam Jackson, Penn State
With the holiday season well on its way, research showing reduction of calories may increase life spans is not the most welcome of news. But if you ask Penn State researcher Roger McCarter how to live longer, he’ll tell you just that — consume fewer calories. McCarter has shown this in rat and mouse models (a 40 percent reduced-calorie diet leads to an approximately 40 percent longer life), and other researchers have duplicated this in spiders, yeast, flies, worms, rodents and humans. To fully take advantage of caloric restriction, McCarter, a professor of biobehavioral health in the College of Health and Human Development, and several other researchers around the world are trying to understand why eating less can lengthen a life span.
Health span, not life span
Most of McCarter’s research in this area has drawn upon rodent models. He has shown that rats and mice that ate 40 percent less calories daily lived approximately 40 percent longer than their counterparts that ate without restrictions. Not only that, but the calorie-restricted rats also exercised much more than their counterparts, if running wheels were provided in their cages. At the time that genetically similar noncalorie-restricted rats had all died of natural causes, the rats eating 40 percent less calories were running more than three miles daily on their exercise wheels. Typically, the strain of rat McCarter was studying run anywhere between one-half and one mile per day.
A long life can be good, but only when health is maintained into old age. “We don’t want to end up just increasing the number of old people who are sick,” said McCarter. “Ultimately, we hope to improve the quality of life in old age, and calorie restriction does this.”
Calorie restriction improves an organism’s “health span,” as McCarter refers to it (i.e., quality of life throughout a life span) in several ways.
First, it slows the deterioration of several bodily processes that occur naturally with increased age. Simply by being alive, the body is subject to numerous damaging factors — including X-rays and other types of electromagnetic radiation, which can sever strands of DNA; invasion by micro organisms like bacteria and viruses, which lead to tissue inflammation; and also cell death, which occurs naturally. To protect itself, the body has developed its own defense mechanisms, which can be thought of as healing processes at the cellular and microscopic levels. For example, the body has what are called “chaperone proteins,” which are activated when our cells are subjected to stress and repair damaged proteins. Calorie restriction stimulates this healing process, as well as others that help strengthen the body at the molecular level.
McCarter has found that rodents live longer — and run more — when eating a reduced calorie diet. Pictured are results of one study, which compares mice with no diets, mice on a 40 percent reduced calorie diet, and mice on a 10 percent reduced calorie diet.
Caloric restriction also inhibits or slows the progress of many diseases associate with age. It does this with a number of diseases: cancer; glaucoma; cataracts; and autoimmune, kidney, cardiovascular, and neurodegenerative diseases. “Not only does caloric restriction inhibit the growth of some forms of cancer, but it can totally eliminate others,” sids McCarter.
The benefits of calorie restriction are clear, but researchers still have not pinpointed an exact mechanism through which it helps. A number of other hypotheses have been created over the years: the increased insulin sensitivity theory, the metabolic rate theory, the reduced body fat hypothesis, and the growth retardation hypothesis, to name a few. None of these have held up to scientific scrutiny. McCarter has been one of the main scrutinizers, working to test these hypotheses. “It’s not just one mechanism that is the main player in caloric restriction, but the combination of many,” he said.
By testing and disproving these hypotheses, he is helping the scientific community understand how mechanisms of the body interact with each other to promote health. “It’s important to knock out the individual mechanisms as key players, because, for example, only a few years ago, 80 percent of the scientific community firmly believed that reduction in metabolic rate was the ultimate reason why calorie restriction worked.”
Harnessing the power of calorie restriction
A practical thinker, McCarter knows that convincing people to eat less is not likely.
“We’ve evolved in such a way that we’re programmed to eat what’s available to us, for survival,” he said. An alternative, and one of his main goals, is finding other ways to invoke the same benefits calorie restriction has — a “backdoor” or “cutting out the middle man” approach — without actually cutting calories. Right now, he is looking at a few different ways to accomplish this.
“I’m convinced that activating stress response is the name of the game,” he said. The stress to which McCarter refers is not the stress we experience in everyday life. Instead, he noted, “The cells of the body ready themselves for a stress by increasing the activity of defense mechanisms and by increasing anti-cell death processes.” These processes are regulated by a protein in the body known as the mammalian target of rapamycin (mTOR). As its name might suggest, mTOR is in turn regulated by an antibiotic drug known as rapamycin; rapamycin inhibits mTOR’s function. If mTOR can shackle the anti-cell-death processes, then consuming synthetically produced rapamycin can partially remove those shackles, which in turn increases the body’s stress response without there being an actual stressor. The body can jump start its natural anti-aging processes without being physiologically provoked.
McCarter said that similar effects have been found with sirtuins, which are substances found in red wine. He’s currently looking into several possibilities that may be involved in these actions.
To each his/her own genome
As of now, no researcher has found a definitive way to induce the same effects of caloric restriction consistently without eating less. McCarter noted not everyone is able to benefit from eating less. Part of what helps trigger the effects is a person’s genome — their genetic makeup.
McCarter knows this because in his research, he draws upon one of the largest and oldest heterogeneous mouse colonies in the country, which is housed at Penn State. This invaluable resource was brought to Penn State by Gerald McClearn, Evan Pugh professor of biobehavioral health, and is maintained in a “barrier” facility by Tobey Stout, a senior research associate in the Department of Biobehavioral Health. McCarter is currently conducting collaborative research with both of these investigators. The colony is in its 83rd generation.
These mice, because they are not inbred through generations, are “more like the human population in its genetic variability,” he said. “The problem with inbred populations is that anything you find will only apply to that population. In fact, some of what has been found helpful in one strain of mice has had the exact opposite effects in other strains.” For example, researchers recently found that calorie restriction works to increase longevity in only one-third of 42 inbred strains of mouse tested and was actually detrimental in another third of the strains tested.
It is these heterogeneous stock mice, McCarter hopes, that will eventually help him and his colleagues understand how calorie restriction works and how the body’s natural processes can be leveraged to increase the health span of people.