From Reproduction to Aging: Investigating the Physiological Roles of NAD+ Metabolism and Signaling
Research Poster Health & Life Sciences 2025 Graduate ExhibitionPresentation by Abdulkareem Alshaheeb
Exhibition Number 206
Abstract
Promoting healthy aging has been a key focus of research, with nicotinamide adenine dinucleotide (NAD+) playing a central role in cellular metabolism. NAD+ is involved in critical redox reactions like glycolysis, the TCA cycle, and oxidative phosphorylation, and also serves as a co-substrate for signaling enzymes such as PARPs, NADases, and Sirtuins. These functions regulate essential cellular processes, making NAD+ vital for aging and metabolic health. A decline in NAD+ levels with age is a hallmark of metabolic aging and is linked to various disorders. Traditionally, this decline was thought to result from reduced synthesis or increased degradation. However, recent studies in aged mice have shown that NAD+ synthesis remains stable, and the decline is not due to a lack of precursors. Instead, it appears to be driven by increased NAD+ consumption. This study aimed to explore the role of NAD+-consuming and signaling enzymes in age-related NAD+ decline. Using a combination of genetic and molecular biology approaches and HPLC-MS for precise metabolite quantification in C. elegans, we identified novel reproductive and aging phenotypes linked to the loss of these enzymes. Mutants with defective NAD+-consuming enzymes showed significantly reduced progeny numbers and lifespan. HPLC-MS analysis revealed dynamic shifts in metabolites, confirmed by quantitative PCR of NAD+ synthesis and consuming genes. These findings uncover a previously unrecognized connection between NAD+ degradation and reproductive aging, highlighting the importance of NAD+ metabolism in maintaining reproductive health and lifespan.
Importance
This study sheds new light on the role of NAD+, a crucial molecule involved in energy production and cellular processes, in aging. While previous research focused on NAD+ production or breakdown, this study finds that increased consumption of NAD+ is the main cause of its decline with age. By studying *C. elegans*, the research reveals how the loss of NAD+-consuming enzymes affects reproduction and lifespan. These findings suggest that targeting NAD+ metabolism could offer new approaches to slow aging, improve reproductive health, and promote healthier aging. This research is a step forward in understanding how molecular processes influence aging and how we might intervene to improve quality of life in later years.