Biology of Aging
Does how much you eat affect how long you live?
Your body needs food to survive. However, the very process of extracting energy from food—metabolizing food—creates stress on your body. Overeating creates even more stress on the body. That’s part of the reason why it can lead to a shorter lifespan and serious health problems common among older people, including cardiovascular disease and type 2 diabetes.
Calorie restriction, an approach primarily (but not exclusively) used in a research setting, is more tightly controlled than normal healthy eating or dieting. It is commonly defined by at least a 30 percent decrease in calorie consumption from the normal diet with a balanced amount of protein, fat, vitamins, and minerals. In the 1930s, investigators found that laboratory rats and mice lived up to 40 percent longer when fed a calorie-restricted diet, compared to mice fed a normal diet. Since that time, scientists observed that calorie restriction increased the lifespan of many other animal models, including yeast, worms, flies, some (but not all) strains of mice, and maybe even nonhuman primates. In addition, when started at an early age or as a young adult, calorie restriction was found to increase the health span of many animal models by delaying onset of age-related disease and delaying normal age-related decline.
Two studies of calorie restriction in non-human primates (the animals most closely related to humans) have had intriguing results. In a study conducted at NIA, monkeys fed a calorie-restricted diet had a notably decreased and/or delayed onset of age-related diseases, compared to the control group of “normal” eaters. In a University of Wisconsin study supported by NIA, calorie-restricted rhesus monkeys had three times fewer age-related diseases compared to the control group. The Wisconsin study also found that rhesus monkeys on a restricted diet had fewer age-related deaths compared to their normal fed controls. In 2007, when the findings from the study conducted at NIA were published, it was too early to determine whether calorie restriction had any effects on lifespan. Research in primates continues.
Despite its apparent widespread acceptance, calorie restriction does not increase lifespan in all animals. In studies of non-laboratory (wild) mice, researchers found that on average, calorie restriction did not have any effect on lifespan. Some of the calorie-restricted mice actually lived shorter than average lives. This may be due to differences in the genetics of the wild mice. A 2010 NIA-funded study provides further evidence that genetics may play a role in whether or not calorie restriction will have a positive effect on longevity. Looking at 42 closely related strains of laboratory mice, researchers found that only about a third of the strains on a calorie-restricted diet had an increase in longevity. One-third of the strains of mice on a calorie-restricted diet had a shortened lifespan, and the other third had no significant difference in lifespan compared to mice on a normal diet.
While animal studies are ongoing, researchers are also exploring calorie restriction in humans to test its safety and practicality, as well as to see if it will have positive effects on health. Participants in a 2002 pilot of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study had, after 1 year, lowered their fasting glucose, total cholesterol, core body temperature, body weight, and fat. At the cellular level, they had better functioning mitochondria and reduced DNA damage. However, in terms of practicality, scientists observed that adapting and adhering to the regimen could be difficult. A longer-term trial is underway.
Given that ample studies have demonstrated mostly positive effects of calorie restriction in many organisms, today’s scientific studies focus on finding the mechanisms and pathways by which calorie restriction works. Researchers are also studying compounds that might act the same way in the body, mimicking the benefits of calorie restriction.
A wide range of possible mechanisms for calorie restriction are being investigated. Some scientists are exploring the possibility that metabolizing fewer calories results in less oxidative damage to the cells. Other scientists are looking at how the relative scarcity of nutrients caused by calorie restriction might induce heat shock proteins and other defense mechanisms that allow the body to better withstand other stresses and health problems. Some researchers wonder if the effects of calorie restriction are controlled by the brain and nervous system. In one NIA-conducted study, calorie restriction increased the production of brain-derived neurotrophic factor, or BDNF, a protein that protects the brain from dysfunction and degeneration, and supports increased regulation of blood sugar and heart function in animal models. Still other studies indicate calorie restriction may influence hormonal balance, cell senescence, or gene expression. It is likely that calorie restriction works through a combination of these mechanisms, and others yet to be identified.
There is an intriguing overlap between the pathways that control normal aging and those that scientists think may be pertinent to calorie restriction. The most relevant are the sirtuins and mTOR (mammalian target of rapamycin) pathways discussed in "Pathways of Longevity Genes." In several, but not all cases, disrupting these pathways means the organism no longer responds positively to calorie restriction. These two pathways have been important for identifying at least two compounds that may mimic the effects of calorie restriction: resveratrol and rapamycin.
Resveratrol, found naturally in grapes, wine, and nuts, activates the sirtuin pathway. It has been shown to increase the lifespan of yeast, flies, worms, and fish. In 2006, NIA researchers, in collaboration with university scientists funded by NIA, reported on a study comparing mice fed a standard diet, a high fat-and-calorie diet, or a high fat-and-calorie diet supplemented with resveratrol beginning at middle age. Resveratrol appeared to lessen the negative effects of the high fat-and-calorie diet, both in terms of lifespan and disease. In a 2008 follow-up study, investigators found that resveratrol improved the health of aging mice fed a standard diet. It prevented age- and obesity-related decline in heart function. Mice on resveratrol had better bone health, reduced cataract formation, and enhanced balance and motor coordination compared to non-treated mice. In addition, resveratrol was found to partially mimic the effects of calorie restriction on gene expression profiles of liver, skeletal muscle, and adipose (fatty) tissue in the mice. However, the compound did not have an impact on the mice’s overall survival or maximum lifespan. These findings suggest that resveratrol does not affect all aspects of the basic aging process and that there may be different mechanisms for health versus lifespan. Research on resveratrol continues in mice, along with studies in nonhuman primates and people.
Rapamycin, another possible calorie restriction mimetic, acts on the mTOR pathway. This compound’s main clinical use is to help suppress the immune system of people who have had an organ transplant so that the transplant can succeed. A study by NIA’s Interventions Testing Program, as discussed in "Living long and well: Can we do both? Are they the same?", reported in 2009 that rapamycin extended the median and maximum lifespan of mice, likely by inhibiting the mTOR pathway. Rapamycin had these positive effects even when fed to the mice beginning at early-old age (20 months), suggesting that an intervention started later in life may still be able to increase longevity. Researchers are now looking at rapamycin’s effects on health span and if there are other compounds that may have similar effects as rapamycin on the mTOR pathway.
Scientists do not yet know how resveratrol, rapamycin, and other compounds that demonstrate effects similar to calorie restriction will influence human aging. Learning more about these calorie restriction mimetics, and the mechanisms and pathways underlying calorie restriction, may point the way to future healthy aging therapies.
Publication Date: November 2011
Page Last Updated: January 18, 2012