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.
Highlights
Calorie restriction (CR) without malnutrition is the most powerful intervention to increase lifespan in simple model organisms and rodents [1]
Research on rodents housed in pathogen-free facilities and data from undernourished children and adults living in third world countries suggest that a chronic reduction in energy intake may impair adaptive immunity against pathogens by lowering leptin and other nutrient-sensing pathways [17, 20] While data from animal and observational human studies show that CR without malnutrition inhibits inflammation [3, 2022], this randomized controlled trial (RCT) is the first to show a causal relationship in humans
The WBC count has been broadly used as a non-specific marker of systemic inflammation [23], with higher levels, even when within the clinical reference range, associated with an increased risk of developing insulin resistance, type 2 diabetes (T2D) [24], hypertension [25], cardiovascular disease (CVD) [26], and cancer [27]
Summary
Calorie restriction (CR) without malnutrition is the most powerful intervention to increase lifespan in simple model organisms and rodents [1]. Serum concentrations of Creactive protein (CRP, a highly specific systemic marker of inflammation) and TNF-α (a powerful proinflammatory cytokine) are both associated with an increased risk of developing insulin resistance, type 2 diabetes (T2D), cardiovascular disease (CVD) and cancer [5,6,7,8]. Concerns exist regarding the potential immunosuppressive effects of CR, because some studies have shown a detrimental effect on cell-mediated immune responses in monkeys [12] and increased susceptibility to infection in rodents [13, 14]. Other studies in aging mouse and monkeys show that CR can enhance the T cell receptor diversity suggesting improved immune –surveillance [15, 16]
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