CAREER: Tracing the coordinated control of NAD+ homeostasis

About This Grant

Cells age just as organisms do, but the mechanisms by which cell aging occurs are unknown. Metabolic imbalances and the inability to respond effectively to stress are key markers of cellular aging. At the heart of these processes is a vital molecule called NAD+, which plays a central role in cellular metabolism, repair of DNA, the ability of genes to direct protein formation, and chemical modification of those proteins. As cells age, NAD+ levels decline, which impairs cell ability to respond to stress. However, it remains unclear whether aging directly causes the decline in NAD+ levels, or whether disruptions in NAD+ metabolism accelerate aging. This project aims to uncover the biochemical mechanisms behind cellular aging by studying how NAD+ metabolism is maintained, regulated, and where it breaks down as cells age. There is still much to learn about metabolic dysfunction and aging, and this research seeks to fill those gaps by revealing how cellular stress influences the aging process. The project goal is to create a comprehensive database and metabolic map of NAD+ biology throughout the lifespan. The results could have implications for understanding the basis of aging and of many common diseases that affect aging animals, from worms to people. In addition to advancing scientific knowledge, this project will involve undergraduates in meaningful research, providing early, structured opportunities to train the next generation of scientists. It will also include an annual "Science in Action" workshop in rural Mississippi, designed to inspire curiosity and provide scientific exposure to students in that state. Nicotinamide adenine dinucleotide (NAD+) is a central metabolite that orchestrates cellular responses to environmental stimuli and plays a fundamental role in metabolism across all living organisms. Despite its essential and evolutionarily conserved role, significant gaps remain in our understanding of how NAD+ regulates homeostasis and participates in cellular stress responses, particularly over an organism’s lifespan. While much research focuses on NAD+ metabolism in health and disease, this proposal aims to explore the compensatory mechanisms that maintain NAD+ homeostasis and how these mechanisms fluctuate during cellular stress and aging. The central hypothesis posits that prolonged cellular stress leads to a decline in NAD+ levels, disrupting organismal homeostasis and driving physiological aging. To address this, the project will: (1) Determine how altering NAD+ metabolism affects redox balance; (2) Examine how cytoplasmic and mitochondrial [NAD+]/[NADH] ratios shift with stress and aging, and; (3) Create a research framework that enables undergraduates to explore the effects of NAD+ manipulation on behavior, phenotype, and lifespan. This research will integrate genetic manipulation with multi-omics profiling to establish a comprehensive baseline for understanding NAD+ dynamics. Quantitative isotope tracing coupled with metabolic flux analysis and spatially resolved redox imaging in C. elegans will reveal how NAD+ metabolism is maintained or disrupted. By addressing these objectives, the project seeks to elucidate how cells achieve and lose metabolic homeostasis, offering insights into physiological regulation over the lifespan. These findings will deepen our understanding of NAD+ biology and its broader implications for aging and stress resilience. This research is funded by the Cellular Dynamics and Function Program of the Division of Molecular and Cellular Biosciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.