# Advances in the Synthesis and Physiological Metabolic Regulation of Nicotinamide Mononucleotide
###### Abstract  
Nicotinamide mononucleotide (NMN), the direct precursor of nicotinamide adenine dinucleotide (NAD\({}^{+}\)), is involved in the regulation of many physiological and metabolic reactions in the body. NMN can indirectly affect cellular metabolic pathways, DNA repair, and senescence, while also being essential for maintaining tissues and dynamic metabolic equilibria, promoting healthy aging. Therefore, NMN has found many applications in the food, pharmaceutical, and cosmetics industries. At present, NMN synthesis strategies mainly include chemical synthesis and biosynthesis. Despite its potential benefits, the commercial production of NMN by organic chemistry approaches faces environmental and safety problems. With the rapid development of synthetic biology, it has become possible to construct microbial cell factories to produce NMN in a cost-effective way. In this review, we summarize the chemical and biosynthetic strategies of NMN, offering an overview of the recent research progress on host selection, chassis cell optimization, mining of key enzymes, metabolic engineering, and adaptive fermentation strategies. In addition, we also review the advances in the role of NMN in aging, metabolic diseases, and neural function. This review provides comprehensive technical guidance for the efficient biosynthesis of NMN as well as a theoretical basis for its application in the fields of food, medicine, and cosmetics. N 20241623541 aging, scientists have attempted to obtain NMR with high purity, high yield, and low cost through chemical catalytic synthesis and biosynthesis methods to meet the increasing market demand. To enable biosynthetic approaches, the pathways of intracellular NMN synthesis have been extensively studied [10; 11; 12]. Among them, the production of NMN from intracellular nicotinamide (NAM) under the catalysis of nicotinamide phosphoribosyltransferase (NAMPT) is the most important pathway, but it has a tight bottleneck due to limited NAMPT enzyme activity [13; 14]. Nicotinamide N-methyltransferasearse (NNMT) does not directly participate in NMN synthesis, but it significantly impacts NMN homeostasis. By methylating nicotinamide to reduce its free content and affect the flux of NAM, an important precursor of the NMN salvage pathway, it regulates NAD\({}^{+}\) levels. Thus, developing NNMT inhibitors could be a promising strategy to increase nicotinamide and NMN precursor levels [15; 16]. In addition, nicotinamide nucleoside (NR) can also be converted into NMN under the catalysis of NR kinases NRK1 and NRK2 [17]. With the continuous clarification of the intracellular metabolic pathways of NMN, researchers have utilized synthetic biotechnology to transform key enzymes and metabolic pathways, producing NMN and related cellular proteins and providing sufficient raw materials for the application of NMN and its derivatives in fields such as nutrition, medicine, and animal husbandry. Studies have shown that oral supplementation of NMN can rapidly increase the level of NAD\({}^{+}\) in blood circulation, directly and indirectly affecting many key cellular functions, including metabolic pathways, DNA repair, chromatin remodeling, cellular aging, and immune cell function [1]. Importantly, NMN supplementation could also reverse the incidence of many aging-related diseases caused by the decline of NAD\({}^{+}\) levels, including cognitive decline, cancer, metabolic diseases, osteoporosis, and frailty [18]. Targeting NAD\({}^{+}\) metabolism by direct supplementation of NMN to ameliorate aging-related diseases and extend the healthy lifespan has become a potential approach for anti-aging and the regulation of metabolic imbalance [19]. This article reviews the main molecular strategies for promoting efficient NMN synthesis in chemical and biosynthetic processes from the perspectives of metabolic engineering, such as host screening and chassis cell optimization, as well as enzyme engineering approaches, such as gene mining and enzyme modification.