Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial.
Journal: 2006/April - JAMA - Journal of the American Medical Association
ISSN: 1538-3598
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.
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.
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.
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).
Body composition; dehydroepiandrosterone sulfate (DHEAS), glucose, and insulin levels; protein carbonyls; DNA damage; 24-hour energy expenditure; and core body temperature.
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).
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.
ClinicalTrials.gov Identifier: NCT00099151.
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JAMA 295(13): 1539-1548

Effect of 6-mo. calorie restriction on biomarkers of longevity, metabolic adaptation and oxidative stress in overweight subjects

+7 authors
Pennington Biomedical Research Center, Baton Rouge, LA, 70808
Garvan Institute for Medical Research, Darlinghurst, NSW, AUSTRALIA, 2010
Please address correspondence to: Eric Ravussin, 6400 Perkins Rd, Baton Rouge, LA 70808, Ph: 225 763 3186, Fax: 225 763 3030, Email: ude.crbp@essuvar
See Pennington CALERIE team in acknowledgements.
Dr Ravussin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.



Prolonged calorie restriction (CR) increases lifespan in rodents. Whether prolonged CR affects biomarkers of longevity, markers of oxidative stress, and reduces metabolic rate, beyond that expected from reduced metabolic mass, has not previously been tested in humans.


To examine the effects of 6 months of calorie restriction, with or without exercise in nonobese (25≤BMI<30) humans.

Design, Setting, and Participants

Healthy, sedentary men and women (n=48) were randomized to one of four groups for 6-mo; Control=100% of energy requirements; CR=25% diet restriction; CREX=12.5%CR+12.5% increase in energy expenditure; LCD=low calorie diet until 15% weight reduction followed by weight maintenance.

Main Outcome Measures

Body composition, dehydroepiandrosterone sulfate (DHEAS), glucose, insulin, protein carbonyls, DNA damage, 24h energy expenditure (24h-EE, metabolic chamber) and core body temperature.


Weight change at M6 was -1.0(1.1)% (Control), -10.4(0.9)% (CR), -10.0(0.8)% (CREX), -13.9(0.7)% (LCD). At M6, fasting insulin was reduced from baseline in CR, CREX and LCD groups (all, p<0.01), whereas DHEAS and glucose were unchanged. Core temperature was reduced in CR by 0.2(0.05)°C and by 0.3(0.08)°C in CREX (both, p<0.05). After adjustment for changes in body composition, sedentary 24h-EE was unchanged in controls (-18(52) kcal/d; p>0.05), but decreased in CR (-135(42)kcal/d), CREX (-117(52)kcal/d) and LCD (-125(35)kcal/d, (all, p<0.008). These “metabolic adaptations” (~6% more than expected based on loss of metabolic mass) were statistically different from controls (p<0.05). DNA damage was also reduced from baseline in CR, CREX and LCD groups at M6 (p≤ 0.002).


These results show that two previously reported biomarkers of longevity (fasting insulin and body temperature) are reduced by prolonged CR in humans and support the theory that metabolic rate is reduced beyond the level expected for reduced metabolic body size. Studies of longer duration are now required to determine if CR attenuates the aging process in humans.

Keywords: aging, metabolic rate, oxidative damage, calorie restriction, core temperature, insulin

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