Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans

Simin N Meydani, Sai K Das, Carl F Pieper, Michael R Lewis, Sam Klein, Vishwa D Dixit, Alok K Gupta, Dennis T Villareal, Manjushri Bhapkar, Megan Huang, Paul J Fuss, Susan B Roberts, John O Holloszy, Luigi Fontana, Simin N Meydani, Sai K Das, Carl F Pieper, Michael R Lewis, Sam Klein, Vishwa D Dixit, Alok K Gupta, Dennis T Villareal, Manjushri Bhapkar, Megan Huang, Paul J Fuss, Susan B Roberts, John O Holloszy, Luigi Fontana

Abstract

Calorie restriction (CR) inhibits inflammation and slows aging in many animal species, but in rodents housed in pathogen-free facilities, CR impairs immunity against certain pathogens. However, little is known about the effects of long-term moderate CR on immune function in humans. In this multi-center, randomized clinical trial to determine CR's effect on inflammation and cell-mediated immunity, 218 healthy non-obese adults (20-50 y), were assigned 25% CR (n=143) or an ad-libitum (AL) diet (n=75), and outcomes tested at baseline, 12, and 24 months of CR. CR induced a 10.4% weight loss over the 2-y period. Relative to AL group, CR reduced circulating inflammatory markers, including total WBC and lymphocyte counts, ICAM-1 and leptin. Serum CRP and TNF-α concentrations were about 40% and 50% lower in CR group, respectively. CR had no effect on the delayed-type hypersensitivity skin response or antibody response to vaccines, nor did it cause difference in clinically significant infections. In conclusion, long-term moderate CR without malnutrition induces a significant and persistent inhibition of inflammation without impairing key in vivo indicators of cell-mediated immunity. Given the established role of these pro-inflammatory molecules in the pathogenesis of multiple chronic diseases, these CR-induced adaptations suggest a shift toward a healthy phenotype.

Trial registration: ClinicalTrials.gov NCT00427193.

Keywords: calorie restriction; cell-mediated immunity; familial longevity; human; inflammation; vaccine response.

Conflict of interest statement

Conflict of Interests Statement None of the authors have conflict of interest.

Figures

Figure 1. CONSORT diagram
Figure 1. CONSORT diagram
Two hundred and thirty eight individuals were eligible and 220 individuals were randomized. Two individuals, both assigned to the calorie-restricted (CR) group, dropped out prior to starting the intervention, resulting in an intention-to-treat cohort of 218 participants; 75 in the ad libitum (AL) control and 143 in the CR group (Table 1). Thirty participants were withdrawn or dropped from the intervention prior to completion including 4 (5.3%) in the AL control group and 26 (18.2%) in the CR group (p=0.01).
Figure 2. Change in the number of…
Figure 2. Change in the number of white blood cells and lymphocytes following 2 years of calorie restriction in humans
Panel (A) baseline values of white blood cells for ad libitum (AL) and calorie-restricted (CR) groups were 5.9 × 103/μl and 6.0 × 103/μl, respectively. Panel (B) baseline values of lymphocytes for both AL and CR groups were 1.8 × 103/μl. Data are mean (SE). The P value comparisons are for AL and CR groups at indicated time points.
Figure 3. Change in plasma concentrations of…
Figure 3. Change in plasma concentrations of inflammation markers following 2 years of calorie restriction in humans
Panel (A) baseline values of C-reactive protein (hs-CRP) for ad libitum (AL) and calorie-restricted (CR) groups were 1.1 and 1.5 μg/mL, respectively. Panel (B) baseline values of tumor necrosis factor-alpha (TNF-α) for AL and CR groups were 3.1 and 3.5 pg/ml, respectively. Panel (C) baseline values of intercellular adhesion molecule-1 (ICAM-1) for AL and CR groups were 165.4 and 165.0 ng/ml, respectively. Panel (D) baseline values of leptin for AL and CR groups were 17.7 and 16.9 ng/ml, respectively. Data are mean (SE). The P value comparisons are for AL and CR groups at indicated time points.

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