Tissue-Specific Effects of Bacterial PncA Overexpression on NAD + Metabolism and Aging in Mice: Implications for Tissue-Specific Aging Interventions

Hailiang Liu^1*Shengyu Feng¹Liuling Guo¹Yue Liu¹Meili Zhao¹Qing Liu¹Taotao Mi¹Shuyao Lv¹Hao Wang¹Fengjiao Huo¹Jian-Kang Zhu²

• ¹Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
• ²Institute of Advanced Biotechnology and School of Medicine, Southern University of Science and Technology, Shenzhen, China

Background: As a critical molecule in biological systems, nicotinamide adenine dinucleotide (NAD+) influences the aging of mammals. Therefore, regulation of NAD+ synthesis and degradation may slow aging and mitigate related diseases.Results: This study investigated how mammalian tissues rely on different NAD+ synthesis pathways and prefer specific NAD+ precursors. Overexpressing the bacterial nicotinamidase PncA in mice increased NAD+ levels in the liver and kidneys but decreased levels in the heart and hippocampus. In aged mice (25 months old), this overexpression delayed aging indicators by boosting NAD+ levels in the liver and kidneys, indicating potential for PncA to improve age-related decline in these tissues. However, in younger mice (4 months old), PncA overexpression accelerates the senescence of cardiac cells, resulting in a reduction of NAD+ levels, increased aging markers, and cognitive decline. These disparate results underscore the necessity of a nuanced, tissue-specific perspective when contemplating the use of NAD+ precursor supplementation as a means of addressing aging. Conclusion: Our study highlights the complexity of NAD+ metabolism and its effects on aging in various tissues. It suggests personalized interventions for aging and age-related diseases by showing how different tissues respond to NAD+ precursor manipulation, emphasizing the importance of targeted strategies for optimal therapeutic results with minimal side effects.