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

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.