Caloric Restriction 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).22-25 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 breast,27 prostate,28 and colon cancers.29 COX-2, in addition to its role in inflammation, can promote the growth and spread of tumors.30-32
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 two years of CR in non-obese but overweight healthy individuals. Researchers of the Pennington CALERIE group have followed 48 overweight (average body mass index [BMI] 27.5) middle-aged (average age 37) individuals for six months adopting one of four 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 one year of either CR (three months of 16% CR followed by nine 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 (intertrochanter) than either the exercise-only or control groups, which was observable by month three 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 six.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 six months, followed by self-monitored restriction for an additional six months. Clinical indicators (fasting serum triglycerides, cholesterol, insulin) were significantly reduced in both groups at six 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 six 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 post-meal 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