Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial

Abstract

Context: Prolonged calorie restriction increases life span in rodents. Whether prolonged calorie restriction affects biomarkers of longevity or markers of oxidative stress, or reduces metabolic rate beyond that expected from reduced metabolic mass, has not been investigated in humans.

Objective: To examine the effects of 6 months of calorie restriction, with or without exercise, in overweight, nonobese (body mass index, 25 to <30) men and women.

Design, setting, and participants: Randomized controlled trial of healthy, sedentary men and women (N = 48) conducted between March 2002 and August 2004 at a research center in Baton Rouge, La.

Intervention: Participants were randomized to 1 of 4 groups for 6 months: control (weight maintenance diet); calorie restriction (25% calorie restriction of baseline energy requirements); calorie restriction with exercise (12.5% calorie restriction plus 12.5% increase in energy expenditure by structured exercise); very low-calorie diet (890 kcal/d until 15% weight reduction, followed by a weight maintenance diet).

Main outcome measures: Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature.

Results: Mean (SEM) weight change at 6 months in the 4 groups was as follows: controls, -1.0% (1.1%); calorie restriction, -10.4% (0.9%); calorie restriction with exercise, -10.0% (0.8%); and very low-calorie diet, -13.9% (0.7%). At 6 months, fasting insulin levels were significantly reduced from baseline in the intervention groups (all P<.01), whereas DHEAS and glucose levels were unchanged. Core body temperature was reduced in the calorie restriction and calorie restriction with exercise groups (both P<.05). After adjustment for changes in body composition, sedentary 24-hour energy expenditure was unchanged in controls, but decreased in the calorie restriction (-135 kcal/d [42 kcal/d]), calorie restriction with exercise (-117 kcal/d [52 kcal/d]), and very low-calorie diet (-125 kcal/d [35 kcal/d]) groups (all P<.008). These "metabolic adaptations" (~ 6% more than expected based on loss of metabolic mass) were statistically different from controls (P<.05). Protein carbonyl concentrations were not changed from baseline to month 6 in any group, whereas DNA damage was also reduced from baseline in all intervention groups (P <.005).

Conclusions: Our findings suggest that 2 biomarkers of longevity (fasting insulin level and body temperature) are decreased by prolonged calorie restriction in humans and support the theory that metabolic rate is reduced beyond the level expected from reduced metabolic body mass. Studies of longer duration are required to determine if calorie restriction attenuates the aging process in humans.

Trial registration: ClinicalTrials.gov Identifier: NCT00099151.

Figure 1

Participant Flow in the Trial.

Figure 2

Percentage weight loss by group. Initial weight was recorded as the mean of 5 weights measured weekly during the baseline phase. The change in weight over time was significantly different between the control group and the three intervention groups (p<0.001) and between LCD and CR, CREX groups (p<0.001), but percent weight loss at Week 24 was not significantly different between LCD, CR and CREX groups. Footnote: CR = calorie restriction, CREX = calorie restriction plus exercise, LCD = liquid calorie diet.

Figure 3

Fasting plasma glucose, insulin, dehydroepiandrosterone sulphate (DHEAS), and triiodo-thyronine (T3) at baseline, Month 3 and Month 6. Footnote: CR = calorie restriction, CREX = calorie restriction plus exercise, LCD = liquid calorie diet. SI conversion factors: to convert glucose to mmol/L, multiply by 0.0555: insulin to pmol/L, multiply by 6.945; DHEAS to nmol/L, multply by 3.47; and T3 to nmol/L, multiply by 0.0154. * Statistically different from baseline p<0.05.

Figure 4

Change in core body temperature from baseline to M6 measured over 23h inside a metabolic chamber set to 22.2 (0.2)°C. Footnote: Values are in 7/11 controls, 11/12 CR subjects, 8/12 CREX subjects and 9/11 LCD subjects. Mean total temperature, mean day temperature (8am – 10:30pm), and night temperature (2am – 5am). * Statistically different from baseline p< 0.05.

Figure 5

Correlation between: Top panel: measured 24h-EE and fat-free mass. [24h-EE (kcal/d) = 596 + 26.8 * FFM, r² = 0.86, p<0.001]; Bottom panel: measured sleep-EE and fat-free mass. EE [sleeping EE = 501 + 20.2 * FFM, r² = 0.76, p<0.001]. Fat Free mass was the major determinant of sleep-EE. Footnote: EE = energy expenditure, CR = calorie restriction, CREX = calorie restriction plus exercise, LCD = liquid calorie diet. Regression lines are drawn at baseline in all subjects (n=48) with individual’s values at M6 in CR, CREX and LCD groups.

Figure 6

Fasting plasma protein carbonyls and DNA Damage measured by the Comet assay. *Statistically different from baseline p<0.005.