# Mitochondrial NAD+ Metabolism in Cardiac Aging

> **NIH NIH R01** · OKLAHOMA MEDICAL RESEARCH FOUNDATION · 2024 · $635,248

## Abstract

Project Summary/Abstract
Nicotinamide adenine dinucleotide (NAD+) is a redox cofactor for energy metabolism and a co-substrate of
sirtuins for protein deacetylation. Cellular NAD+ levels decline with age in the heart and other organs. Previous
studies have shown that cellular NAD+ repletion or boosting is protective against aging and age-related
diseases. NAD+ is compartmentalized at subcellular levels and the proper distribution of NAD+ into
mitochondria is crucial for NAD+-dependent metabolic and signaling function in mitochondria. SLC25A51 was
recently identified as the primary mammalian mitochondrial NAD+ (mtNAD+) transporter that imports NAD+ from
cytosol into mitochondria. Unlike the established roles of NAD+ synthesis and consumption, there is a critical
knowledge gap in the role of mtNAD+ transport by SLC25A51 in aging and heart function. Despite the
important roles of mtNAD+ in mitochondrial energy metabolism and protein deacetylation, how mtNAD+ levels
change with age and impact cardiac aging remain unknown. Our preliminary study discovered that old murine
hearts had reduced mtNAD+ levels and lower SLC25A51 expression compared to young hearts. The objective
of this study is to determine the mechanistic role of SLC25A51 in cardiac aging using our newly
developed genetic tools to overexpress or knockdown SLC25A51 in the heart. Multiple preclinical studies
and clinical trials have examined or are investigating the therapeutic potential of various NAD+ boosting
strategies in different diseases. Importantly, the existing NAD+ boosting strategies do not directly boost
mtNAD+ levels, which may limit their efficacy. Our preliminary data showed that supplementation with an NAD+
precursor NMN significantly elevated total NAD+ levels in old murine hearts but did not effectively increase
mtNAD+ levels. This highlights the potential of enhancing mtNAD+ transport as a novel approach to improve
the benefits of NAD+ boosting strategies.
 We hypothesize that an age-related decline in SLC25A51 function reduces mtNAD+ levels, leading to
compromised mitochondrial metabolism and cardiac dysfunction. We also propose that enhancing
SLC25A51-mediated mtNAD+ transport will improve the protective effects of NAD+ boosting strategy in
the old heart. In this study, we will 1) determine if SLC25A51 deficiency lowers mtNAD+ levels and
accelerates cardiac aging; 2) determine if cardiac-specific SLC25A51 overexpression enhances mtNAD+ levels
and cardiac function in old mice; and 3) test the hypothesis that levels of SLC25A51 expression regulate the
efficacy of NAD+ precursor to improve cardiac function. The findings of this study will establish the roles of
SLC25A51 in cardiac aging and open new avenues towards developing new interventions to enhance mtNAD+
metabolism or to maximize the efficacy of NAD+ boosting strategies.

## Key facts

- **NIH application ID:** 10882362
- **Project number:** 1R01AG081855-01A1
- **Recipient organization:** OKLAHOMA MEDICAL RESEARCH FOUNDATION
- **Principal Investigator:** Ying Ann Chiao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $635,248
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882362

## Citation

> US National Institutes of Health, RePORTER application 10882362, Mitochondrial NAD+ Metabolism in Cardiac Aging (1R01AG081855-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882362. Licensed CC0.

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