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

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.

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 Thirty participants were withdrawn or dropped from the intervention prior to completion including 4 (5.3%) in the AL control group and 26 (18.2%) in the CR group (p=0.01).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 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 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.