Caloric restriction (CR) is a general strategy for improving wellbeing and lifespan. It is more than a simple limitation of calories for maintenance of body weight; CR is the dramatic reduction of caloric intake to levels that may be significantly (up to 50% in some cases) below that for maximum growth and fertility, but nutritionally sufficient for maintaining overall health (“undernutrition without malnutrition.”1). It remains one of the most researched and successful approaches to life extension in laboratory settings. Although the effects of CR on health are diverse, its mechanisms are not fully understood, and are thought to involve the activation of survival mechanisms that have been evolutionarily conserved to protect organisms from stress.
The idea of extending healthspan (the period of healthy living before the onset of age-related disease) and lifespan by lowering food intake is not a new one. Louis Caranaro’s 16th century best-selling anti-aging book suggested that longevity would come to those who ate only enough to sustain life; Benjamin Franklin supported the concept of abstinence as a defense against disease two centuries later.2 But it was the work of McCay in the 1930’s that first demonstrated that reducing calories below the level required for maximum fertility, while avoiding malnutrition, could extend the mean and maximum lifespan of laboratory rats by 40% or more.3 In the years following that seminal work, the health and longevity effects of CR have been observed in a wide range of organisms, ranging from single-celled Saccharomyces, to primates and man.
The practical challenge of long-term or lifetime CR has recently generated interest in caloric restriction mimetics (CRMs), an alternative to CR which may provide the pro-longevity benefits without an actual reduction in caloric intake.4 CRMs are a broad class of compounds and interventions that may promote life- and health-span by a diversity of mechanisms, ranging from induction of genes that protect against stress, to antioxidation and anti-inflammation.
CR in Animals and Non-human Primates
Seventy-five years of research have determined that the longevity and health effects of CR are a broad biological phenomenon that has been observed in species from three kingdoms of life (Animalia, Fungi, and Protoctista).5 Both the mean and maximum life spans of yeast (Saccharomyces cerevisiae), rotifers, nematodes (Caenorhabditis elegans), fruit flies (Drosophila melanogaster) and medflies, spiders, fish (guppies, zebrafish), rodents (hamsters, rats, mice), and dogs have been extended significantly by decreasing normal caloric consumption by 30 to 40 percent.6 Recently, the effects of CR on lifespan have been observed in non-human primates. The rhesus monkey (Macaca mulatta) is an excellent model for the study of human aging, exhibiting many physiological and biochemical similarities to humans.7 Unlike other animal aging models, the rhesus monkey also allows the study of brain atrophy, a characteristic of human aging that does not occur in smaller mammals8. With an average lifespan of about 27 years in captivity9, the rhesus also is suitable for determining the effects of CR on maximal lifespan.
Studies of the effects of CR on three separate rhesus colonies are currently underway; results from two have been published. A 20-year study conducted at the Wisconsin National Primate Research Center suggests that CR of baseline diet by 30 percent may slow aging in the rhesus, as gauged by two indicators of aging retardation: delays in mortality, and in the onset of age-associated diseases (particularly diabetes, cancer, cardiovascular disease, and neurological impairment; the most prevalent age-related diseases in humans).10 At study entry, the animals (46 males and 30 females) were at adult age (7-14 years); at the time the study was published (twenty years later), nearly three times as many control monkeys had died of age-related causes than CR monkeys (37% vs. 13%). The CR monkeys appeared to be biologically younger than their normal-fed counterparts, and not surprisingly, had lower body and fat mass. Sarcopenia (age-related muscle loss) was attenuated in the CR group. CR monkeys were also free of diabetes (compared to 5/38 of control animals) or glucose intolerance (compared to 11/38 of control animals). Incidence of cardiovascular disease, all cancers, and adenocarcinoma of the GI tract (the most common cancer in rhesus monkeys11) was reduced by half in the CR group. Calorie restriction resulted in preservation of brain volume in the caudate, putamen and insula, areas that are classically involved in regulation of motor and executive function. The effects of CR on maximum lifespan have yet to be determined for this colony, as animals in both groups are still living.
A smaller study at the University of Maryland tracked 8 CR rhesus monkeys and 109 ad-libitum (free-fed) controls over a period of 25 years, and produced many of the same observations.12,13 Ad libitum fed animals died at 25 years of age compared to a median survival of 32 years in the CR group. Calorie restriction also reduced hyperinsulinemia (elevated circulating insulin) and the frequency of age-associated diseases.
Although the available data is limited, these two studies do implicate that the healthspan and lifespan benefits of CR that have been observed in rodents and lower animals may also extend to primates and possibly man.
CR in Humans and Increased Lifespan
Assessing the effects of dietary interventions on human lifespan is a difficult endeavor; with average life expectancies of 75 and 80 years for men and women, respectively14 , any prospective study would likely necessitate several generations of researchers to carry out. Therefore, human aging studies must rely on surrogate measures (biomarkers) of aging. Reduced body temperature and lowered fasting insulin levels are robust markers of CR and slowed aging in rodents and rhesus monkeys.15
Dehydroepiandrosterone sulfate (DHEA-S), which declines in both rhesus monkeys and humans during normal aging, may be important in health maintenance and may serve as another potential longevity marker.16 DHEA-S, a product of the adrenal glands and the most abundant circulating steroid hormone, serves as the precursor to the sex steroids (androgens and estrogens). Increased DHEA-S levels in monkeys on CR are associated with survival17. Similarly, data from the Baltimore Longitudinal Study of Aging (BLSA)18 suggests that long-lived humans exhibit some of the same physiological and biochemical changes that accompany caloric restriction in animals. In the study, human survival rates were highest in those with low body temperatures, low levels of circulating insulin; and high DHEA-S levels.19
While there is yet no direct evidence of human lifespan extension by CR, there has been limited observational and clinical data that suggests a connection. In the 1970s, the Japanese island of Okinawa was reported to contain up to 40 times as many centenarians as other Japanese communities, which was suggested to result from CR (The caloric intake of adults and children in Okinawa was 20- and 40 percent lower than their mainland counterparts, respectively)20 Two decades earlier, a small study revealed that 60 healthy seniors receiving an average of 1500 kcal/day for a period of 3 years had significantly lowered rates of hospital admissions and a numerically lowered death rate than an equal number of control volunteers.21
CR in Humans Mitigates Disease Risk
There is a growing body of evidence suggesting that CR may reduce disease risk factors, which may have a direct influence on healthspan (and indirectly increase lifespan). Several observational studies have tracked the effects of CR on lean, healthy individuals, and have demonstrated that moderate CR (22-30% decreases in caloric intake from normal levels) improves heart function, reduces markers of inflammation (C-reactive protein, tumor necrosis factor (TNF)), reduces risk factors for cardiovascular disease (elevated LDL cholesterol, triglycerides, blood pressure) and reduces diabetes risk factors (fasting blood glucose and insulin levels).22,23,24,25 CR in healthy individuals has also been associated with reductions in circulating insulin-like growth factor - 1 (IGF-1), and cyclooxygenase II (COX-2) 26, all of which may be indicative of a decreased risk of certain cancers. Epidemiological data shows an association between higher plasma IGF-1 concentrations and a greater risk of breast27, prostate28, and colon cancers.29 COX-2, in addition to its role in inflammation, can promote the growth and spread of tumors.30 31 32
Preliminary results from the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE)33 are reproducing many of the metabolic and physiologic responses to CR observed in rodents and monkeys.34 To better elucidate the effects of CR in humans, The National Institute on Aging (NIA) is sponsoring a multi-site randomized human clinical study to assess the safety and efficacy of 2 years of CR in non-obese but overweight healthy individuals. Researchers of the Pennington CALERIE group have followed 48 overweight (average BMI 27.5) middle-aged (average age 37) individuals for 6 months adopting one of 4 protocols: 1) 25% caloric restriction (CR group), 2) 12.5% CR with an additional 12.5% caloric expenditure from exercise (CREX group), 3) very low calorie diet (890 kcal/day) until 15% weight reduction, followed by a diet of sufficient calories to maintain this weight (VLCD group), or 4) control. Not surprisingly, all three intervention groups demonstrated reduced body weight, visceral (abdominal) fat, and fat cell size35,36, as well as reduced liver fat deposits.37 Fat loss was not significantly different between the CR and CREX groups (24% total fat, 27% visceral fat).38 All three intervention groups also demonstrated reductions in DNA damage.39 Only the CR and CREX groups, however, were able to improve two markers of longevity (reduced body temperature and reduced fasting plasma insulin), as well as reduce cardiovascular risk factors (LDL-C, triglycerides, and blood pressure. C-reactive protein was reduced only in the CREX group.40 Circulating thyroid hormone (T3) concentrations were lower in the CR and CREX groups. 41 Under conditions of CR, reduction in circulating thyroid hormone and body temperature suggests the normal adaptation of the body to lower energy intake and expenditure; similar reductions in T3 and metabolic rate have been observed in other human and animal CR studies.42 The CR groups also exhibited increases in the amount of mitochondria (the cellular sites of energy production), and increased expression of two genes (TFAM and PGC-1α) that are indicative of mitochondrial biogenesis, the formation of new mitochondria.43 Mitochondrial loss and dysfunction may be responsible for some of the most potent effects of the aging process.44
Similar results have been observed from the CALERIE studies at Washington University on a separate group of 50-60 year old non-obese overweight (average BMI 27) volunteers after 1 year of either CR (3 months of 16% CR followed by 9 months of 20% CR) or exercise training of equivalent energy expenditure (ie. expending 20% of daily caloric intake).45 CR improved cardiovascular parameters (left ventricular diastolic function, diastolic and systolic blood pressure) 46, lowered C-reactive protein and insulin resistance 47, and lowered circulating thyroid hormone T348 and fasting plasma insulin.49
CR in this second, older volunteer population was not without some negative consequences: Compared to the exercise-only group, CR demonstrated decreases in muscle mass, strength, and aerobic capacity.50,51 The CR group also demonstrated significantly more loss of bone mineral density (BMD) at the spine, hip, and femur (interochanter) than either the exercise-only or control groups, which was observable by month 3 of the study.52 It should be noted that in the younger CALERIE study group, there was no significant differences in BMD in any of the groups at month 6.53 The potential of losses in aerobic capacity and BMD stress the importance of exercise in CR protocols.
The CALERIE group at the Jean Mayer-USDA Human Nutrition Center on Aging at Tufts University compared the effects of CR diet composition (high glycemic vs. low glycemic load) in 29 healthy overweight adults provided with 30% calorie restricted meals for 6 months, followed by self-monitored restriction for an additional 6 months. Clinical indicators (fasting serum triglycerides, cholesterol, insulin) were significantly reduced in both groups at 6 and 12 months, but were not different between groups.54 There was no significant difference in weight loss or energy expenditure between the high glycemic (HG; 60% of calories from carbohydrates) and low glycemic (LG; 40% of calories from carbohydrates) groups, but the LG group lost significantly more fat mass, and retained more fat-free mass.55 The LG group also demonstrated greater declines in CRP during the first 6 months of the CR protocol.56 While these data indicate that the overall reduction in energy intake, and not diet composition, may be a more important determinant of weight loss and its associated CR health benefits, it does suggest additional benefits of LG diets. By their very nature, LG diets can limit postprandial (“post-meal”) elevations in blood glucose; aiding in the maintenance of the target 2-hour postmeal level of <140 mg/dL, which the International Diabetes Federation suggests may lower the risk of several diseases, including cancer, cognitive impairment, cardiovascular disease, and retinopathy.57
A randomized clinical trial examined the effects of two years of calorie restriction on metabolism and oxidative stress. The 53 participants who completed the trial were healthy and either normal-weight or slightly overweight at the time of enrollment; 34 were in a calorie restriction group, given detailed instructions and support to help them achieve a 25% reduction in daily caloric intake while maintaining adequate nutritional intake; 19 were in a control group, instructed not to substantially change their diet.
At the end of two years, the calorie restriction group had achieved an average calorie reduction of 14.8% and sustained an average weight loss of 19.1 pounds, mostly due to loss of fat. In addition, a significant drop in resting energy output, particularly during sleep, was measured in tests done after one and two years of calorie restriction. While some of this reduction could be attributed to loss of metabolically active tissue due to weight loss, most of it—equivalent to 80–120 calories per day—exceeded this expected outcome. This phenomenon of decreased energy output in excess of what could be accounted for by weight loss alone has been noted in previous weight loss studies and is known as metabolic adaptation. Metabolic adaptation is thought to represent a shift toward more efficient energy use.
Importantly, measures of oxidative stress were improved in the calorie restriction group. This effect was noted after one year and was sustained at two years. The drop in oxidative stress correlated with the degree of calorie restriction and metabolic adaptation attained. It has been proposed that reduced production of harmful free radicals resulting from more efficient metabolic activity is the link between calorie restriction and extended lifespan. This theory is supported by the current findings.185