Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE™ a multicentre, phase 2, randomised controlled trial

Kim M. Huffman, Divisions of Rheumatology and Immunology, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Daniel C. Parker, Geriatrics, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Manjushri Bhapkar, Duke Clinical Research Institute, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Susan B. Racette, Program in Physical Therapy and Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Corby K. Martin, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
Leanne M. Redman, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
Sai Krupa Das, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA.
Margery A. Connelly, Laboratory Corporation of America Holdings (Labcorp), Morrisville, NC, USA.
Carl F. Pieper, Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, USA.
Melissa Orenduff, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Leanna M. Ross, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
Megan E. Ramaker, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
James L. Dorling, Human Nutrition, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Clifford J. Rosen, Maine Medical Center Research Institute 81 Research Drive Scarborough, Maine 04074 USA.
Irina Shalaurova, Laboratory Corporation of America Holdings (Labcorp), Morrisville, NC, USA.
James D. Otvos, Laboratory Corporation of America Holdings (Labcorp), Morrisville, NC, USA.
Virginia B. Kraus, Divisions of Rheumatology and Immunology, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.
William E. Kraus, Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, USA.

Document Type

Article

Publication Date

1-3-2022

Institution/Department

MaineHealth Institute for Research

Journal Title

EClinicalMedicine

Abstract

BACKGROUND: For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values within ranges considered normal for 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 (21-50 years), 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, multicenter, randomized controlled trial (May 2007-November 2012) in healthy, adults without obesity to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9 ± 7.2 years and body mass index (BMI) 25.1 ± 1.7 kg/m, 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. FINDINGS: 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 ≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and low-density lipoprotein particles, a shift to larger high-density lipoprotein particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all ≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women. INTERPRETATION: In normal to slightly overweight adults without overt risk factors or disease, 12 months of ∼12% CR improved newly identified risk markers for atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These markers suggest that CR improves risks by reducing inflammation and BCAAs and shifting lipoproteins from atherogenic to cholesterol transporting. Additionally, these improvements are greater for men and for those with greater BMIs indicating sex and BMI-influences merit attention in future investigations of lifestyle-mediated improvements in disease risk factors. FUNDING: The CALERIE™ trial design and implementation were supported by a National Institutes of Health (NIH) U-grant provided to four institutions, the three intervention sites and a coordinating center (U01 AG022132, U01 AG020478, U01 AG020487 U01 AG020480). For this secondary analysis including sample acquisition and processing, data analysis and interpretation, additional funding was provided by the NIH to authors as follows: 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).

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