Metabolic Slowing and Reduced Oxidative Damage with Sustained Caloric Restriction Support the Rate of Living and Oxidative Damage Theories of Aging

Abstract

Calorie restriction (CR) is a dietary intervention with potential benefits for healthspan improvement and lifespan extension. In 53 (34 CR and 19 control) non-obese adults, we tested the hypothesis that energy expenditure (EE) and its endocrine mediators are reduced with a CR diet over 2 years. Approximately 15% CR was achieved over 2 years, resulting in an average 8.7 kg weight loss, whereas controls gained 1.8 kg. In the CR group, EE measured over 24 hr or during sleep was approximately 80-120 kcal/day lower than expected on the basis of weight loss, indicating sustained metabolic adaptation over 2 years. This metabolic adaptation was accompanied by significantly reduced thyroid axis activity and reactive oxygen species (F2-isoprostane) production. Findings from this 2-year CR trial in healthy, non-obese humans provide new evidence of persistent metabolic slowing accompanied by reduced oxidative stress, which supports the rate of living and oxidative damage theories of mammalian aging.

Trial registration: ClinicalTrials.gov NCT00427193 NCT02695511.

Keywords: aging; energy expenditure; intervention; nutrition.

Figure 1

Subject throughput from enrolment (N=71) to data analysis (N=53). Analyses were performed on 53 men and women who on the basis of an objective pre-analytical criterion (weight change) were determined to be adherent to their assigned treatment groups.

Figure 2

Percent of calorie restriction (A) achieved after 1 and 2 years of calorie restriction and the resulting change in fat mass (FM) and fat free mass (FFM), panel B. N=53; 34 CR, 19 Control. P-value for statistically significant treatment group effects, adjusted for multiple comparisons is shown. The change in weight, FM and FFM were all significantly different between the CR and control group (p<.0001 for all, treatment main effect).

Figure 3

A comparison of metabolic adaptation in sleep energy expenditure (panel A) and 24-hour energy expenditure (panel B) between the AL (control, n=19 ■) and CR (n=34, □) groups, after 1 and 2 years of calorie restriction. Metabolic adaptation was considered to represent the change in energy expenditure after adjusting for the changes in fat-free mass, fat mass, age and sex and the metabolic adaptation at baseline (see methods, Sedentary 24-hour Energy Expenditure, for calculation). P-values for statistically significant treatment group effects, adjusted for multiple comparisons are shown.

Figure 4

A comparison of changes in the potential mediators of metabolic adaptation; leptin (panel A) and thyroxine (T4, panel B), and the association between metabolic adaptation in Sleep EE with percent change from baseline in leptin concentrations at year 1 (Y1) (panel C) and percent change from baseline in thyroxine concentrations (T4) at year 2 (Y2), panel D. AL (control, ■) and CR groups (□). P-values for statistically significant treatment group effects, adjusted for multiple comparisons are shown. Scatterplots show the linear regression model with 95% confidence interval. N=53; 34 CR, 19 Control.