Notice of Special Interest (NOSI): Analyses of CALERIE Datasets and Biospecimens to Elucidate the Biological Effects and the Behavioral and Psychological Aspects of Sustained Caloric Restriction in Humans
Notice Number:

Key Dates

Release Date:

January 11, 2022

First Available Due Date:
February 16, 2022
Expiration Date:
May 08, 2023

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

NOT-AG-23-024 - Notice of Special Interest (NOSI): Analyses of CALERIE Datasets and Biospecimens to Elucidate the Biological Effects and the Behavioral and Psychological Aspects of Sustained Caloric Restriction in Humans

Issued by

National Institute on Aging (NIA)


The National Institute on Aging (NIA) is issuing this Notice of Special Interest (NOSI) to encourage analyses of the unique research resources generated by the CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trial to improve our understanding of the effects of sustained caloric restriction (CR) in humans and its underlying mechanisms. NIA invites applications for innovative research (R01) projects and exploratory research (R21) projects which leverage the CALERIE Phase 2: 1) biological datasets and biospecimens and/or 2) the CALERIE Tracking System (CTS) behavioral database to address novel hypotheses on the following areas:

  • Biological, phenotypic, and functional aging, and their related pathways;
  • Risk factors for chronic diseases and the underlying cellular and molecular mechanisms; and
  • Behavioral and psychological aspects of sustained CR.

The CALERIE research resources are broadly accessible to investigators through the NIA Aging Research Biobank. Prior to any submission of an application for the analysis of CALERIE biospecimens, a request to access the CALERIE biospecimens must be submitted to the NIA Aging Research Biobank and approved by the NIA Biobank Scientific Review Committee. Prospective applicants are strongly advised to seek the necessary permissions well in advance of the anticipated submission date for their applications.


Caloric restriction (CR), defined here as a reduction in caloric intake with preserved optimal nutrition, is the only non-pharmacological intervention that has been shown to extend both mean and maximal lifespan across a variety of species, and to delay, or slow, the progression of a wide variety of aging changes and age-related pathologies. The CALERIE trial was the first study to specifically focus on the effects of sustained CR in humans. CALERIE demonstrated the feasibility of sustained CR (for at least two years) and its favorable effects on predictors of longevity and cardiometabolic risk factors.

The CALERIE trial was conducted in two phases. Phase 1 supported pilot/feasibility studies, the results of which informed the design of the full-scale CALERIE Phase 2 trial. The CALERIE Phase 2 trial was a two-year, three-site, randomized controlled trial in young and middle-aged (age range 21-50 years) non-obese (BMI between 22 and 28 kg/m2) healthy men and women. It compared outcomes in a group assigned a target of 25% CR (i.e., a 25% reduction in energy intake below baseline levels) to an ad libitum diet control group. A unique feature of the CALERIE Phase 2 trial design was the objective measurement of caloric intake through the intake-balance method. This was used to calculate energy intake from the difference between changes in energy stores (assessed by dual-energy X-ray absorptiometry (DXA)) and total energy expenditure (TEE) assessed by the doubly labeled water method (DLW). The CALERIE datasets include these measures made at baseline and intervals after the start of the study.

Noteworthy features of the CALERIE trial are the substantial size of the study; the sustained weight loss achieved (not previously attained in any clinical study in non-obese individuals); the comprehensive physiologic, psychologic, quality-of-life, and cognitive assessments conducted; and the extensive collection of biological samples. In addition, to enhance adherence to CR, the CALERIE trial used a Computerized Tracking System (CTS) that included intensive behavioral strategies combined with dietary modifications (i.e., toolbox methodology). Further details on the CALERIE trial can be found on the CALERIE Research Network website. The CALERIE Research Network was established to facilitate outreach to and engagement of the broader scientific community to analyze the CALERIE research resources. Access to the CALERIE datasets and biospecimens is available through the NIA Aging Research Biobank.

Data and Biospecimens:

Several outcome measures related to the following broad categories were assessed at different time points in the CALERIE Phase 2 trial:

  • Energy metabolism (i.e., total energy expenditure and energy intake, core body temperature, and resting metabolic rate (RMR))
  • Cardiovascular risk factors (i.e., blood pressure, serum lipids, and lipoproteins)
  • Markers of inflammation (i.e., plasma C-reactive protein (CRP), MCP-1, IL-6, IL-1, IL-8, TNF-a, and ICAM-1)
  • Glucose tolerance and insulin (i.e., serum glucose, insulin, and C-peptide levels in the fasting state and during oral 75g glucose tolerance test)
  • Immune function (i.e., dihydrotestosterone (DTH), white blood cell differential, and antibody responses to vaccines)
  • Endocrine responses (i.e., thyroid hormones (TSH and T3), adiponectin, leptin, cortisol, angiotensin, GH, IGF-1, IGFBP-1, IGFBP-3, PDGF-AB, and TGF- 1)
  • Sex hormones (in men only) (i.e., total and free testosterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone (DHEA))
  • Physical activity measures (i.e., cardiorespiratory fitness using peak VO2 via expired gas analysis, energy expenditure using the Stanford 7-day Physical Activity Recall (PAR), and muscular strength and endurance (e.g., knee flexors and knee extensors, grip strength))
  • Body weight, height, and body composition (i.e., waist circumference, bone density, fat mass (FM) and fat-free mass (FFM), by DXA))
  • Bone mineral density and markers of bone turnover
  • Nutrient intake (i.e., calories, micro- and macro-nutrient composition, fiber, and variety of food intake)
  • Quality-of-life measures (i.e., Rand SF-36, Profile of Mood States, and Perceived Stress Scale)
  • Psychological assessments (i.e., Pittsburgh Sleep Quality Index (PSQI), food craving questionnaire, food craving inventory, eating inventory or Three-Factor Eating Questionnaire (TFEQ), weight self-efficacy, Multiaxial Assessment of Eating Disorder Symptoms (MAEDS), and body shape questionnaire)
  • Tests for cognitive biases

In addition, the CALERIE biorepository contains serum, plasma, urine, skeletal muscle (vastus lateralis), and adipose tissue (subcutaneous abdominal) biopsies collected during the course of the trial.

Computerized Tracking System (CTS) adherence strategies and dataset:

The CALERIE intervention employed a Computerized Tracking System (CTS), an intensive behavioral approach coupled with dietary modifications (i.e., toolbox methodology see below) anticipated to enhance adherence to CR. Specifically, the CALERIE trial used a combination of individualized and group counseling sessions to enhance CR adherence. Individual counseling sessions were used as the primary means of promoting CR adherence, and the group counseling sessions were used to disseminate information to complement the individualized sessions and to provide social support. The CTS was established to track adherence to CR (change in body weight was used as a proxy measure) and to guide individualized counseling sessions in the form of toolbox options (based on an individual's needs and preferences). The toolbox methodology included a series of intervention options and behavioral strategies specifically designed to increase adherence to the intervention; toolbox algorithms allowed tailoring of the treatment to address the unique needs of each participant. Examples of toolbox options included cognitive behavioral strategies, problem-solving strategies, increased training in portion size and caloric estimation skills, and use of structured meal plans. Examples of CTS data include information on the use of toolbox options (e.g., cognitive behavioral strategies, modification of meal patterns), appetite ratings, and individual energy intake targets.

Public Availability of Research Resources generated by the CALERIE Phase 2 trial:

The CALERIE Research Network has instituted two multi-institutional collaborative CALERIE working groups, namely, the Behavioral Working Group and the Molecular Physiology Working Group. The main role of these Working Groups is to promote topic-specific ancillary projects that make use of the CALERIE biospecimens and datasets. Broad participation in the CALERIE Working Groups is welcomed and encouraged. Individuals interested in participating in the CALERIE Working Groups may contact Dr. Kim Huffman ( and/or Dr. Cliff Rosen ( While involvement in the CALERIE Working Groups is welcomed to further and synergize novel research ideas and create new scientific collaborations, participating in the CALERIE Working Groups is not a pre-requisite for applying to the related Funding Opportunity Announcements (FOAs).

CALERIE biospecimens and related phenotypic and clinical data are available from the Aging Research Biobank. Applications requesting access to these biospecimens/data must follow the steps described in the NIA Biobank User's Guide . Applications will be reviewed by the Biobank Scientific Review Committee. For dates when reviews are conducted and further detailed instructions on requesting access to the biospecimens/data, please also refer to

Costs for archiving data that will be made publicly available should be included in the budget. Plans for the creation of a publicly archived database must include adequate dataset documentation and instructions for use by investigators not affiliated with the original study. Provision for easy accessibility of archived datasets is required. Applications requesting inclusion/archival of datasets in the Aging Research Biobank must follow the steps outlined at Failure to follow this guidance may negatively impact the funding potential of an application even if the application receives a scientifically meritorious score.

Research Objectives

The overarching objective of this NOSI is to incentivize the investigation of key aging biology questions that advance our understanding of the effects of CR on biological, phenotypic, and functional aging and on risk factors for chronic diseases, as well as itsunderlying cellular and molecular mechanisms. The use of transdisciplinary approaches and new methodologies, such as integrative system technologies, complex data modeling, and analyses of the dynamic pattern of genetic and environmental influences, is of particular relevance and is highly encouraged. Innovative methodologies and integrative analyses that explore multifaceted aspects of aging can ultimately lead to the development of novel therapeutic targets for intervention, CR mimetics, and/or pharmacological approaches that may help to promote healthy aging. Examples of potential research topics guiding analyses of the CALERIE resources that are relevant to this NOSI include the following:

    • Analyses of the complex effects of sustained CR on fundamental mechanisms of aging, including effects on protective and risk factors for aging processes and diseases associated with aging.
    • Blood-based bioenergetics profiling that integrates metabolism and bioenergetics with physiologic parameters.
    • Assessment of the degree of correlation between circulating markers and their levels of activity in target tissues.
    • Development of molecular predictors of aging through changes associated with CR and assessment of predictors of multiple aging outcomes in response to CR.
    • Development of dose-response causal modeling of the effects of CR on health and/or longevity parameters.
    • Elucidation of the physiologic, molecular, cellular, and genetic mechanisms underlying the effects of sustained CR. This includes the application of "omics" analyses of body fluids, organ tissues, and/or multiple systems to evaluate the effects of CR on aging processes.
    • Evaluation of the effects of CR on aging-related processes (e.g., mitochondrial function, proteostasis and autophagy, macromolecular damage, epigenetic regulation, inflammation, stem cell function) and dynamics such as adaptation to stress, and physiologic functions like metabolism, and tissue regeneration.
    • Influence of CR on cognitive performance and other variables relevant to well-being, such as emotion regulation and levels of stress.

In addition, this NOSIsupports secondary data analyses of the CALERIE Computerized Tracking System (CTS) adherence strategies and dataset to explore behavioral aspects of sustained CR in humans.

Examples of potential research topics to explore include but are not limited to:

    • Variations in adherence of the CALERIE study participants and underlying factors contributing to the variability including personal characteristics, mood, demographic factors, sex differences, emotion regulation, stress phenotypes, or other characteristics.
    • Behavioral and psychological factors that emerged during the early phases of CR that can be predictive of long-term CR adherence.
    • Association between specific adherence strategies in the form of toolbox options adopted during the trial and weight loss success or failure in CALERIE.
    • Comparison of characteristics including psychological, behavioral, and emotional characteristics, comprising self-regulation and stress phenotypes of CALERIE participants with those of self-selected, calorically restricted, individuals to potentially identify better screening tools.
    • Analyses to understand conceptual links among domains related to self-regulation and stress phenotypes and putative mechanisms underlying behaviors, such as adherence.

Applicants are required to include plans for sharing data and results, as well as innovative data analytics approaches (see Goal 3, NIH Strategic Plan For Data Science).

Application and Submission Information

This notice applies to due dates on or after February 16, 2022 and subsequent receipt dates through May 8, 2023.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include NOT-AG-21-028 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

We encourage inquiries concerning this Notice and welcome the opportunity to answer questions from potential applicants.

Scientific/Research Contact(s)

Chhanda Dutta, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-4161

Inquiries related to availability of CALERIE resources from the AgingResearchBiobank, the process to be followed to be granted access to these resources, or on inclusion/archival of datasets resultant from studies conducted under this NOSI should be directed to:

Rosaly Correa-de-Araujo, MD, M.Sc., Ph.D.
National Institute on Aging
Telephone 301-496-6762

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Lennin Greenwood
National Institute on Aging (NIA)
Telephone: 301-451-3569