Calorie Restriction Improves Lipid-Related Emerging Cardiometabolic Risk Factors in Healthy Non-Obese Adults: Distinct Influences of BMI and Sex From CALERIE™ - A Multicentre, Phase 2, Randomised Controlled Trial

Background: For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values extending ranges of normal healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young, normal weight healthy population undergoing calorie restriction for two years. Methods: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, randomized controlled trial in healthy, non-obese adults to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9±7.19 years and BMI 25.1±1.73 kg/m2, mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy.­­­­­­­­­ Results: Averaging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes—Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all PCRvsAL ≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and LDL particles, a shift to larger HDL particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all PCRvsAL ≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women. Conclusions: In normal to slightly overweight adults without overt risk factors or disease, 12 months of ~12% CR improved risks of atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These CR-mediated benefits accrued via reduced inflammation and branched chain amino acids, and a shift from atherogenic to cholesterol transporting lipoproteins. Additionally, CR benefits were influenced by sex and BMI, factors meriting close attention in future investigations of lifestyle-mediated improvements in disease risk factors. Clinical Trial Registration Details: NCT00427193. Funding Information: CALERIETM was conducted as a National Institutes of Health (NIH) U-grant (U01 AG022132, U01 AG020478, U01 AG020487 U01 AG020480 ). As defined by this mechanism, the study design and conduct was a collaborative effort between internal NIH and external study investigators. Additional project funding was provided by NIH R01 AG054840 (MO, VBK); R33 AG070455 (KMH, DCP, MB, SBR, CKM, LMR, SKD, CFP, CJR, WEK); P30 DK072476 (CKM, LMR); and U54 GM104940 (CKM, LMR) and without any additional scientific contribution or other role in this report. Declaration of Interests: MAC, IS, and JDO are employees of Labcorp. All other authors have no conflicts interests. Ethics Approval Statement: The study protocol (NCT00427193) was approved by the institutional review boards at all participating clinical centers (Washington University School of Medicine, St Louis, MO; Pennington Biomedical Research Center, Baton Rouge, LA; Tufts University, Boston, MA), and the coordinating center (Duke University, Durham, NC). All study participants provided written informed consent and study oversight was provided by a Data and Safety Monitoring Board.