Effect of 2-Year Caloric Restriction in the Absence of Malnutrition on Indicators of Anemia, Iron Status, and Hepcidin in Healthy Adults: A Randomized Clinical Trial

BACKGROUND: Caloric restriction (CR) is a promising nutritional intervention for improving metabolic and age-related health outcomes, but its long-term effects on hematologic health remain unclear. Clarifying how prolonged CR affects anemia risk and iron status is essential for evaluating its long-term safety and clinical relevance. OBJECTIVES: To determine the effects of a 2-y CR intervention on markers of anemia, iron status, and hepcidin in females and males enrolled in the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) Phase 2 trial. METHODS: Participants in CALERIE Phase 2 (n = 220) were randomly assigned to 25% CR or ad libitum (AL) control. AL continued their habitual diet, whereas CR received an intensive intervention to promote CR over 2 y. All participants received a multivitamin/mineral supplement containing 18 mg iron. Fasted blood was collected at baseline (BL) and 12 (M12) and 24 (M24) mo and indicators of iron status (ferritin, soluble transferrin receptor, and serum iron), anemia (hemoglobin and hematocrit), and regulators of iron status (hepcidin, C-reactive protein, and IL-6) were measured. Six-day diet diaries were collected twice at BL and once each at M12 and M24. An anemia surveillance protocol monitored hemoglobin, hematocrit, red blood cell (RBC) count, and serum iron throughout the intervention, with medical evaluation and temporary/permanent CR discontinuation as needed. Linear mixed-effects models were used to evaluate the effect of treatment (CR compared with AL), time (BL, M12, and M24), and their interaction (treatment × time). RESULTS: Participants (n = 218) were mostly female (70%) with an mean age (±SD) of 38.1 ± 7.2 y and a mean BMI of 25.2 ± 1.7 kg/m². At baseline, ferritin (105.5 ± 126.9 μg/L), hepcidin (8.6 ± 5.8 ng/mL), and dietary iron intake (16.1 ± 5.5 mg/d) were similar between groups (P > 0.05). There were no group × time interactions for markers of anemia, indicators of iron status, or hepcidin (P > 0.05). Despite the anemia surveillance protocol, anemia prevalence remained >5% in both groups across all timepoints. Low RBC count was the most common trigger, and participants who triggered the protocol had lower hematocrit at M12 (P < 0.001) and M24 (P < 0.001); however, dietary iron intake remained similar and there were no differences in any indicators of iron status or hepcidin between those who triggered the protocol and those who did not. CONCLUSIONS: These findings suggest that prolonged CR in the absence of malnutrition does not adversely affect iron status or hepcidin in healthy adults.