CALERIE trial molecular data summary: DNA methylation, mRNA, smRNA for blood, adipose, and muscle

Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from the CALERIE randomized, controlled trial of long-term CR in healthy, non-obese humans (NCT00427193) broadly support a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n=218 participants during the trial. These data constitute the first genomic data resource for a randomized controlled trial of an intervention targeting the biology of aging. Datasets include whole-genome SNP genotypes, and three-timepoint-longitudinal DNA methylation, mRNA, and small RNA datasets generated from blood, skeletal muscle, and adipose tissue samples (total sample n=2327). The CALERIE Genomic Data Resource described in this article is available from the Aging Research Biobank. This multi-tissue, multi-omic, longitudinal data resource has great potential to advance translational geroscience.

Methods
CALERIE Phase 2 was a multi-center, randomized controlled trial conducted at three clinical centers in the United States8 (ClinicalTrials.gov Identifier: NCT00427193). It aimed to evaluate the time-course effects of 25% CR (that is, intake 25% below the individual’s baseline level) over a 2-yr period in healthy adults (men aged 21–50 yr, premenopausal women aged 21–47 yr) with BMI in the normal weight or slightly overweight range (BMI 22.0–27.9 kg m−2). The study protocol was approved by Institutional Review Boards at three clinical centers (Washington University School of Medicine, St Louis, MO, USA; Pennington Biomedical Research Center, Baton Rouge, LA, USA; Tufts University, Boston, MA, USA) and the coordinating center at Duke University (Durham, NC, USA). All study participants provided written informed consent. Nongenomic data were obtained from the CALERIE Biorepository (https://calerie.duke.edu/apply-samples-and-data-analysis). Oversight of our study was performed by the Institutional Review Board of Columbia University Irving Medical Center AAAS2948.

Extending CALERIE phase I in both scale and duration, CALERIE recruited a total of 220 subjects and assigned them in a 2:1 allocation to a CR treatment group or ad libitum (AL) control arm. Subjects were randomly assigned to CR or AL groups stratified on study site, sex, and body mass index. Participants in the CR group were assigned to a protocol designed to result in a 25% reduction in caloric intake relative to estimated energy requirements at enrollment. CR participants received an intensive behavioral intervention that included individual and group sessions, a meal provision phase, digital assistants to monitor caloric intake, and training in portion estimation and other nutrition and behavioral topics. Adherence was assessed using measures of energy expenditure using the doubly-labeled water method as well as expected changes in body composition. The duration of the study for both CR and AL participants was 2 years.

Throughout the 2-year study duration, starting at baseline prior to randomization and recurring at months 1, 3, 6, 9, 12, 18, and 24, participants were evaluated for a range of pre-specified anthropometric, psychological, behavioral, and physiological outcomes. Blood samples were collected every six months. At baseline, 12-months, and 24-months, whole blood and samples were collected and banked. In addition, a subset of participants agreed to biopsies of adipose and muscle tissue at baseline, 12-months, and 24-months. From these samples, SNP-based genotypes, DNA methylation, mRNA, and small RNAs were assayed. Here, we describe these datasets and provide an overview of this data resource (Fig. 1).

More details about the CALERIE trial, including study protocols and ongoing and published research, are available at https://calerie.duke.edu. Data can be accessed through the Aging Research Biobank (https://agingresearchbiobank.nia.nih.gov/studies/calerie/). Data use is restricted to non-commercial use in studies to determine factors that affect age-related conditions. Biospecimens are available, but limited to research on the effects that caloric restriction may have on aging and aging-related diseases. Applications for data access include a brief summary of the research question and intended analysis and proof of IRB approval for the project.