# Calorie Restriction, Mitochondrial DNA Heteroplasmy, Cardiometabolic Profiles, and Biological Aging

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2024 · $467,416

## Abstract

Project Summary
Calorie restriction (CR) has the potential to attenuate aging; however, the mechanisms by which CR enhances
longevity and reduces disease burden are not fully understood. Mitochondria have been in the limelight due to
their potential role in regulating the aging process. Mitochondrial DNA (mtDNA) integrity is of crucial
importance in mitochondrial function. Accumulation of mtDNA heteroplasmic mutations have been implicated in
cardiometabolic disease development and in aging. It is not clear whether CR promotes mtDNA integrity in
humans. CALERIE (the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), the
two-year randomized controlled clinical trial of CR in humans, demonstrated that, compared to the ad libitum
(AL) control group, sustained moderate CR reduced markers of biological aging and improved cardiometabolic
profiles. The data and samples from the CALERIE study provide an unprecedented opportunity to explore the
potential effects of CR on mtDNA heteroplasmies. Using the existing whole blood samples collected by
CALERIE, the proposed project will measure mtDNA heteroplasmies at three time points over the two years.
The overarching goal of the proposed study is to understand whether CR attenuates mtDNA heteroplasmic
mutations. Our central hypothesis is that CR promotes mitochondrial integrity by reducing the accumulation of
mtDNA heteroplasmies, and that these changes are associated with improved biological aging and
cardiometabolic health. We propose the following Aims: 1) Examining the effect of CR on the changes in
mtDNA heteroplasmies in CALERIE, 2) Examining whether mtDNA heteroplasmies are associated with
markers of biological aging, and 3) Examining whether the mtDNA heteroplasmies are associated with
cardiometabolic risk factors. We also propose an exploratory aim to test whether the mtDNA heteroplasmies
potentially mediate the effects of CR on biological aging and cardiometabolic measures. The proposed study is
directly relevant to the NIH FOA PA-20-195 that supports exploratory analyses utilizing CALERIE data and
biospecimens to evaluate the mechanisms of CR. The proposed project has the potential to provide insights
into the molecular basis of CR-mitigated effects on aging and role of mtDNA in cardiometabolic diseases. Data
generated by the proposed study will inform the design for a larger scale study to facilitate the identification of
preventive and therapeutic targets for aging and age-associated cardiometabolic diseases.

## Key facts

- **NIH application ID:** 10788975
- **Project number:** 1R21AG085086-01
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Jiantao Ma
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $467,416
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10788975

## Citation

> US National Institutes of Health, RePORTER application 10788975, Calorie Restriction, Mitochondrial DNA Heteroplasmy, Cardiometabolic Profiles, and Biological Aging (1R21AG085086-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10788975. Licensed CC0.

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