Advancements in NMN biotherapy and research updates in the field of digestive system diseases
Journal of Translational Medicine volume 22, Article number: 805 (2024) Cite this article
Abstract
Nicotinamide mononucleotide (NMN), a key intermediate in NAD + synthesis, quickly converts into NAD + in the body. It plays a crucial role in energy metabolism, cellular aging, and circadian rhythm regulation. NMN also influences DNA repair, chromatin remodeling, immunity, and inflammation.
NMN has become a central focus in biomedicine, healthcare, and food science. Recent preclinical studies have shed light on its role in age-related diseases. This review covers the last decade’s research on NMN biotherapy and its applications in digestive system diseases.
Introduction
Nicotinamide mononucleotide (NMN) is vital for NAD + biosynthesis, essential for cellular metabolism and energy. It is rapidly converted into NAD + after ingestion, playing a key role in maintaining cellular functions and redox balance [1].
NAD + is crucial for metabolic pathways like glycolysis and the TCA cycle, vital for energy production. It also acts as a signaling molecule, regulating DNA repair, epigenetic modifications, and immune responses. These functions influence aging and metabolic homeostasis [2].
NAD + levels decrease with age in humans and rodents, leading to age-related pathologies. These include cognitive decline, cancer, and metabolic diseases. Restoring NAD + levels can slow or reverse these conditions. Thus, NAD + metabolism is a key area in aging research and healthspan extension. Researchers are exploring NAD + intermediates to prevent age-related decline.
NMN is an acidic water-soluble compound. It is a bioactive nucleotide formed by the reaction between phosphate groups and nucleosides. These nucleosides are composed of ribose and nicotinamide [4]. The molecular formula of NMN is C11H15N2O8P, and its molecular weight is 334.22 g/mol [5]. Figure 1 shows the molecular structure of NMN. Notably, NMN exists in two forms, i.e., α and β isomers, and β-NMN represents its active form [8]. As a natural intermediate of NAD + , NMN is widely present in foods, such as vegetables, fruits, and meat. Moreover, the NMN content is especially high in plant-based foods such as edamame, avocado, broccoli, cabbage, and cucumber [9, 10]. In terms of subcellular distribution, NMN is mainly present in the cytoplasm, nucleus, and mitochondria in mammalian cells. However, in the human body, NMN has also been detected in tissues and body fluids such as the placenta, blood, and urine [11]. In mammals, NMN is synthesized from nicotinamide (NAM) via the rate-limiting enzyme nicotinamide phosphoribosyl transferase (NAMPT). Moreover, it can also be synthesized from nicotinamide riboside (NR) via NR kinase (NRK)-mediated phosphorylation [8, 9]. As previously mentioned, small amounts of NMN can also be ingested via the consumption of NMN-rich foods. Typically, NMN is converted into NAD + via NMN adenylate transferase (NMNAT), which plays a key role in biological regulation and is an important therapeutic target (Fig. 2) [12].
In recent years, NMN has not only emerged as a key focus of anti-aging research, but has also garnered significant attention due to in vivo studies that have highlighted its wide-ranging pharmacological activities. Thus, NMM has been studied extensively in the field of age-related conditions, such as type 2 diabetes, obesity-related metabolic abnormalities, cardio-cerebral ischemic diseases, and neurodegenerative diseases [1, 8, 10, 11]. Notably, rodent studies have suggested that NMN can effectively enhance NAD + synthesis in peripheral tissues and organs, including the brain [13], blood vessels [14], skeletal muscle [9, 15], adipose tissue [16, 17], pancreas [18], heart [19, 20], liver [9, 21], kidneys [22, 23], and eyes [24, 25], providing several health benefits. In fact, accumulating evidence points to the therapeutic effects of NMN against a variety of key pathophysiological processes in various disease models [1, 12].
This review aimed to comprehensively explore recent advances in NMN biotherapy research, concentrating specifically on its applications in digestive system diseases. By addressing current challenges and emerging trends, novel insights could be provided into NMN’s therapeutic efficacy and potential for future research in this dynamic field.
A comprehensive literature search was conducted using multiple databases, including PubMed, Scopus, and Web of Science. The search terms included “NMN,” “nicotinamide mononucleotide,” “biotherapy,” “preclinical studies,” “animal models,” and various specific health conditions (e.g., diabetes, aging, obesity).
Inclusion and exclusion criteria
Inclusion criteria:
Studies published in peer-reviewed journals.
Research involving preclinical models (e.g., mice, rats) where NMN was administered.
Studies demonstrating clear outcomes related to NMN administration (e.g., biochemical, physiological, and molecular effects).
Research that addressed specific mechanisms of action, such as NAD + restoration, SIRT1 activation, and other pathways.
Exclusion criteria:
Non-peer-reviewed articles, reviews, and meta-analyses.
Studies with insufficient methodological details or those that did not include appropriate controls.
Research where NMN was used in combination with other compounds, making it difficult to isolate the effects of NMN alone.
Quality assessment
Each study was assessed for methodological quality, including the design, sample size, duration of treatment, and statistical analysis. Priority was given to studies with robust experimental designs, such as randomized controlled trials (RCTs) in animal models. Studies with large sample sizes and those including both male and female subjects were also prioritized for their generalizability. Additionally, studies from renowned research teams and institutions were given extra consideration, especially those with a history of impactful publications in aging and metabolic diseases.
Quantitative methodology
Data extraction
Detailed information was extracted from each study, including the dosage of NMN, route of administration, and study duration. The animal models used and the specific health outcomes measured were also documented. Quantitative results related to NAD + levels, gene expression, biochemical markers, and physiological effects were thoroughly recorded.
Comparative analysis
Studies were compared based on the consistency of their findings and the dose–response relationship of NMN. The reproducibility of results across different models and conditions was also evaluated. Meta-analyses of key quantitative outcomes were considered, providing a statistical summary of NMN’s effects on various health parameters.
Representative study selection
From the extensive pool of studies, those with clear, reproducible, and significant outcomes were selected. These studies covered a wide range of conditions affected by NMN, including diabetes, aging, obesity, and more. The selection aimed to showcase NMN’s therapeutic potential across different physiological systems and disease models.
Representative pre-clinical studies on NMN biotherapy
The literature on NMN biotherapy is vast. Due to the impossibility of including all preclinical studies in this review, the focus is on high-quality, representative studies.
Diabetes
Yoshino et al., from Professor Imai S’s team at Washington University School of Medicine, established a diabetes mouse model in 2011. They administered NMN at 500 mg/kg/d and observed improvements in glucose tolerance and insulin sensitivity. They suggested that NAD + synthesis impairment by NAMPT is a key factor in diabetes. NMN was found to enhance insulin sensitivity and restore gene expression involved in oxidative stress and inflammation, possibly through SIRT1 activation [18].
Caton et al. [26] used a fructose-rich diet to create a diabetes model in mice. A single dose of NMN (500 mg/kg i.p.) was administered, showing it could prevent islet dysfunction. In vitro experiments also showed NMN’s ability to counteract TNF-α- and IL-1β-induced islet dysfunction. The study found that NMN reversed the dysregulation of islet marker genes caused by the diet and proinflammatory cytokines, indicating an anti-inflammatory mechanism.
Aging
A 2014 report by the Aging Research team led by Professor Sinclair of Harvard Medical School showed that NMN can extend the lifespan of mice by targeting the SIRT2 pathway through NAD + and enhancing the expression of the checkpoint kinase BubR1, which declines with age [27]. In another study, also by Professor Sinclair’s group, a 1-week (500 mg/kg/d i.p.) intervention with NMN was found to enhance the oxidative metabolic capacity of mitochondria in the skeletal muscles of elderly mice. Further, NMN restored mitochondrial homeostasis and key biochemical markers of muscle health in 22-month-old mice to levels similar to those in 6-month-old mice. This suggests that NMN may be effective in mitigating the body’s aging-related decline [15].
To elucidate the anti-aging potential of NMN, Mills et al. from Washington University School of Medicine provided normally aging C57BL/6 mice with NMN intervention therapy for up to 12 months. The results showed that NMN did not have any obvious toxic effects in the mice. However, NMN effectively alleviated age-related physiological decline, inhibited age-related weight gain, increased energy metabolism, and promoted physical activity. Furthermore, NMN was found to prevent age-related changes in gene expression in important metabolic organs and also improve mitochondrial oxidative metabolism and nuclear protein imbalance in skeletal muscle cells [9].
Obesity
Mills et al. also examined the effect of long-term NMN intervention on age-related weight gain in normally aging mice. Their findings showed that NMN administration can significantly inhibit age-related weight gain in conventionally fed mice in a dose-dependent manner [9]. Further, studies have shown that NMN can reduce fat mass and liver and plasma triglyceride levels in obese mice, and can also attenuate the abnormalities in glucose tolerance caused by maternal obesity or long-term HFD intake, thereby preventing metabolic impairments in male offspring born to obese mothers [28]. Moreover, NMN demonstrated potential in reducing body weight in offspring born to obese dams by improving hepatic fat metabolism [29].
Cardiac health
A 3-day NMN (500 mg/kg/d i.p.) intervention in heart-specific Ndufs4 knockout mice could reduce the acetylation of cardiac mitochondrial proteins and increase the sensitivity of the mitochondrial permeability transition, thus exerting cardioprotective effects [33]. Moreover, studies in Friedreich ataxic cardiomyopathy mice have shown that NMN intervention can restore the cardiac function of mice with cardiomyopathy to near-normal levels in a SIRT3-dependent manner [19]. Meanwhile, Nadtochiy et al. found that the protective effect of NMN against cardiac ischemia–reperfusion injury is partly mediated via glycolytic stimulation, and the downstream protective mechanism involves increased ATP synthesis during ischemia and/or enhanced acidosis during reperfusion [34].
In line with these findings, research from the Cleveland Clinic has also demonstrated that NMN can maintain cardiac mitochondrial homeostasis, protecting heart-specific KLF4-deficient mice from heart failure due to stress overload [20]. Similarly, Wu et al. revealed that NMN can alleviate isoproterenol-induced cardiac fibrosis by regulating oxidative stress and Smad3 acetylation [35].
Brain health
According to a study by Stein et al., continuous supplementation with NMN during aging can maintain the proliferation and self-renewal of neural stem and progenitor cells (NSPCs) in mice [13]. Moreover, another study from the group led by Imai S showed that NMN can partially attenuate physical activity deficits in adipocyte-specific Nampt knockout mice [36].
In one study focused on preventing ischemic brain injury, mice received NMN at the start of reperfusion or 30 minutes after ischemic injury. The results showed NMN protects hippocampal CA1 neurons from death and preserves function after global cerebral ischemia [37]. Wei et al. found NMN may treat brain injury from intracranial hemorrhage by reducing neuroinflammation and oxidative stress [38]. The Nrf2/HO-1 signaling pathway activation also plays a role in NMN’s neuroprotective effects after intracranial hemorrhage [38].
In a mouse model of global cerebral ischemia, a single dose of 62.5 mg/kg NMN normalized mitochondrial NAD + levels and protein acetylation. It also reduced reactive oxygen species (ROS) levels in the hippocampus and inhibited mitochondrial fragmentation. These effects were dependent on SIRT3, suggesting NMN protects against ischemic brain injury through SIRT3 [39].
In a mouse model of Alzheimer’s disease, NMN reduced amyloid precursor protein (APP) levels and reversed oxygen consumption deficits in brain mitochondria. It also reduced mitochondrial fragmentation in neurons, improving mitochondrial function [40]. These findings highlight NMN’s neuroprotective role. Additionally, NMN supplementation in aged mice enhanced Cask expression in the hippocampus, improving cognitive function [41].
Kidney function
NMN supplementation restored renal SIRT1 activity and NAD + pool in 20-month-old mice. This effect was more pronounced in 3-month-old mice. NMN significantly protected young and old mice from cisplatin-induced acute kidney injury. However, SIRT1 gene inhibition weakened NMN’s renoprotective effects [23].
Yasuda et al. demonstrated NMN’s renoprotective role in early diabetic nephropathy by upregulating Sirt1 and activating the NAD + rescue pathway [22]. NMN also ameliorated adriamycin-induced renal injury through Twist2-mediated epigenetic inhibition of NMN/NAD consumption [44].
Sepsis
Sepsis is a major cause of death in intensive care units, leading to multiple organ failure. Cao et al.’s studies showed NMN prevents mitochondrial dysfunction and inhibits bacterial transmission in septic mice. It controls inflammation via SIRT3 signaling, reducing organ damage and improving survival [45]. In sepsis-associated encephalopathy, NMN activates NAD + /SIRT1 signaling, reducing hippocampal inflammation and oxidative stress. It improves memory and reduces neuronal damage [46].
Other conditions
NMN promotes mesenchymal stromal cells (MSCs) expansion in vitro and in vivo. It stimulates osteogenic transformation of endogenous MSCs and protects mouse bones from aging and radiation damage. NMN upregulates SIRT1 expression, regulating MSCs in aging bone marrow. This promotes bone formation and reduces adipogenesis [49].
In a rat model of hemorrhagic shock, rats treated with NMN showed significant reductions in lactic acidosis and serum IL-6 levels. These are strong predictors of patient mortality. NMN, whether used as a pretreatment or an adjunct during resuscitation, extended the time rats could endure severe shock by nearly 25%. It also significantly improved survival after resuscitation [50].
NMN restores the NAD + /SIRT1 axis function, effectively alleviating HIF-1α-induced adipose fibrosis and inflammation. This highlights NMN’s role in regulating HIF-1α and the adipose tissue fibrosis caused by hypoxia [51].
HIV-1 infection leads to abnormal immune activation and CD4 + T cell depletion. This causes various clinical manifestations associated with acquired immune deficiency syndrome. Mo et al. found that NMN, combined with cART treatment, significantly increased CD4 + T cells in HIV-infected huPBL mice. Their research suggests NMN treatment can enhance cART’s effect in restoring CD4 + T cell populations in mice [52].
Following the second wave of NAD + research in the early twenty-first century [53], numerous studies on NMN have been conducted. Two large research teams, led by Professor Sinclair at Harvard Medical School and Professor Imai at the University of Washington School of Medicine, have made significant contributions. Their work has shown NMN’s multiple health benefits in treating age-related diseases.
Reference :
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05614-9