Introduction

Nicotinamide adenine dinucleotide (NAD+) is a crucial coenzyme involved in numerous cellular processes, including energy metabolism, DNA repair, and cell signaling. Declining NAD+ levels are associated with aging and various diseases, sparking intense research into strategies for boosting NAD+ levels. This mini-review summarizes recent advancements (2020-2024) in NAD+ precursor supplementation, enzymatic modulation, and production, focusing on their therapeutic potential and underlying mechanisms.

NAD+ Precursor Supplementation: Efficacy and Therapeutic Applications

A significant area of research focuses on the therapeutic potential of NAD+ precursors, particularly nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). Mihoko Yoshino's group at Washington University School of Medicine demonstrated in 2020 and 2021 that NMN increases muscle insulin sensitivity in prediabetic women (Mihoko Yoshino et al., 2020, Science, Mihoko Yoshino et al., 2021, Science). These findings suggest a potential role for NMN in managing metabolic disorders.

Further studies have explored the effects of NMN supplementation on various physiological parameters. Bagen Liao and colleagues at Guangzhou Sport University found that NMN supplementation enhances aerobic capacity in amateur runners (Bagen Liao et al., 2020, Journal of the International Society of Sports Nutrition, Bagen Liao et al., 2021, Journal of the International Society of Sports Nutrition). Masaki Igarashi's team at Tokyo Medical University showed that chronic NMN supplementation elevates blood NAD+ levels and alters muscle function in healthy older men (Masaki Igarashi et al., 2021, npj Aging, Masaki Igarashi et al., 2022, npj Aging). Lin Yi's research group at GeneHarbor (Hong Kong) Biotehnologies demonstrated the safety and efficacy of NMN supplementation in healthy middle-aged adults in a randomized, double-blind, placebo-controlled clinical trial (Lin Yi et al., 2021, GeroScience, Lin Yi et al., 2022, GeroScience). Mijin Kim and collaborators at Nikko Chemicals Co., Ltd. investigated the effect of NMN intake on sleep quality, fatigue, and physical performance in older Japanese adults (Mijin Kim et al., 2022, Nutrients).

Furthermore, studies have explored the therapeutic effects of NAD+ precursors in specific disease models. Vilhelm A. Bohr's group at the National Institute on Aging showed that NAD+ supplementation reduces neuroinflammation and cell senescence in a transgenic mouse model of Alzheimer's disease (Yujun Hou et al., 2020, Proceedings of the National Academy of Sciences, Yujun Hou et al., 2021, Proceedings of the National Academy of Sciences). Itaru Yasuda and his team at Jichi Medical University demonstrated the protective effects of NMN in a mouse model of diabetic nephropathy (Itaru Yasuda et al., 2020, Journal of the American Society of Nephrology, Itaru Yasuda et al., 2021, Journal of the American Society of Nephrology). Xiaodong Zhao's group at Shandong University found that NMN improves Alzheimer's disease by regulating intestinal microbiota (Xiaodong Zhao et al., 2023, Biochemical and Biophysical Research Communications). Xin Wu's team at Zhejiang University showed that NMN protects intestinal function in aging mice and d-galactose induced senescent cells (Meng Ru et al., 2022, Food & Function) and alleviates hepatic insulin resistance and steatosis in HFD mice (Yumeng Li et al., 2024, Biomedicine & Pharmacotherapy). Yan Chen's group at China Agricultural University found that NMN restores oxidative stress-related apoptosis of oocytes exposed to benzyl butyl phthalate in mice (Yi Jiang et al., 2023, Cell Proliferation). Hui-ru Li and Jiafeng Wang's team at Qingdao University found that NMN activates the NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice (Hui-ru Li et al., 2023, Redox Biology). Takeshi Katayoshi's group at Kobe University investigated the effect of long-term NMN supplementation on arterial stiffness (Takeshi Katayoshi et al., 2023, Sci. rep. (Nat. Publ. Group)).

Helena A. K. Lapatto's research group at the University of Helsinki demonstrated that NR improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study (Helena A. K. Lapatto et al., 2021, Science Advances, Helena A. K. Lapatto et al., 2022, Science Advances, Helena A. K. Lapatto et al., 2023, Science Advances). Charalampos Tzoulis and colleagues at the University of Bergen conducted the NADPARK study, a randomized phase I trial of NR supplementation in Parkinson's disease (Brage Brakedal et al., 2020, Cell Metabolism, Brage Brakedal et al., 2021, Cell Metabolism, Brage Brakedal et al., 2022, Cell Metabolism).

Bin Ye and Ning Ma's team at Shandong University found that NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis (Bin Ye et al., 2024, Journal of Cellular Biochemistry). Katalin Suszták's group at the University of Pennsylvania showed that NAD+ precursor supplementation prevents mtRNA/RIG-I-dependent inflammation during kidney injury (Tomohito Doke et al., 2023, Nature Metabolism). Jérôme N. Feige's team at Nestlé Research found that Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia (Mathieu Membrez et al., 2024, Nature Metabolism).

Enzymatic Modulation of NAD+ Metabolism

Another research area focuses on modulating enzymes involved in NAD+ metabolism. Gregory R. J. Thatcher's group at the University of Arizona has been actively involved in studying nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis. Their work includes investigating the mechanism of allosteric modulation of NAMPT (Kiira Ratia et al., 2023, Biochemistry), synthesizing and optimizing NAMPT positive allosteric modulators (N-PAMs) (Zhengnan Shen et al., 2023, Journal of Medicinal Chemistry), and exploring strategies for channeling NAMPT to address life and death (Velma Ganga Reddy et al., 2024, Journal of Medicinal Chemistry). Alessio Nencioni and colleagues at the University of Genoa reviewed advances in NAD-lowering agents for cancer treatment (Moustafa Ghanem et al., 2021, Nutrients). Valentina Audrito's group at the University of Torino discussed NAMPT as a critical driver and therapeutic target for cancer (Massimiliano Gasparrini et al., 2022, The International Journal of Biochemistry & Cell Biology). Sheng Jiang and collaborators at Nanjing Medical University reviewed recent advances in targeting NAMPT for cancer drug discovery (He Tang et al., 2023, European Journal of Medicinal Chemistry). Xiaoming Zha's team at Shandong University summarized the updated progress and perspectives of drug discovery targeting NAMPT (Fei Wen et al., 2024, Bioorganic & Medicinal Chemistry).

Takashi Nakagawa's group at Keio University identified BST1 as a regulator of NR metabolism (Keisuke Yaku et al., 2021, Nature Communications). Eduardo N. Chini's team at the Mayo Clinic demonstrated that CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels (Claudia C.S. Chini et al., 2020, Nature Metabolism). Anthony J. Covarrubias and Eric Verdin's group at the Buck Institute for Research on Aging showed that senescent cells promote tissue NAD+ decline during aging via the activation of CD38+ macrophages (Anthony J. Covarrubias et al., 2020, Nature Metabolism).

Metabolic Engineering for NMN Production

Another significant area of advancement is the metabolic engineering of microorganisms for efficient NMN production. Han Li's group at Tianjin University optimized Escherichia coli for NMN biosynthesis (W. B. Black et al., 2020, Microbial Cell Factories). Bo Yu's team at Jiangnan University engineered Escherichia coli for NMN biosynthesis from nicotinamide (Yang Liu et al., 2021, Microbial Biotechnology). Jingwen Zhou's group at Tsinghua University systematically engineered Escherichia coli for efficient NMN production from nicotinamide (Zhongshi Huang et al., 2021, ACS Synthetic Biology, Zhongshi Huang et al., 2022, ACS Synthetic Biology). Beom Soo Kim's team at the Korea Advanced Institute of Science and Technology (KAIST) enhanced NMN production by high cell density culture of engineered Escherichia coli (Anoth Maharjan et al., 2023, Process Biochemistry). Yu‐Guo Zheng's group at East China University of Science and Technology improved an enzymatic cascade synthesis of NMN via protein engineering and reaction-process reinforcement (Feng Peng et al., 2024, Biotechnology Journal). Shinichiro Shoji and colleagues at the University of Tsukuba explored metabolic design for selective NMN production from glucose and nicotinamide (Shinichiro Shoji et al., 2020, Metabolic Engineering).

Conclusion

The past five years have witnessed significant advancements in the field of NAD+ metabolism. Research has focused on the therapeutic potential of NAD+ precursors like NMN and NR in various age-related diseases and physiological conditions. Furthermore, efforts to modulate NAD+ metabolism through enzymatic targeting and metabolic engineering have shown promise. While the field is rapidly evolving, further research is needed to fully elucidate the long-term effects and optimal strategies for NAD+ augmentation in humans.

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