Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice
Long-Term administration of Nicotinamide mononucleotide mitigates age-associated physiological decline in mice was an animal study conducted in C57 laboratory mice divided into three groups: controls, 100 mg/kg per day of NMN, and 300 mg/kg per day of NMN. The NMN was administered orally and the mice were followed longitudinally over 12 months. Initial experiments established that oral administration of NMN resulted in significant increases in plasma NMN and liver NAD+ in minutes. Additionally, using isotopic NMN, the authors further demonstrated that the administered NMN was quickly absorbed into the bloodstream, transported to the liver where it was converted to NAD+ and rapidly transported to peripheral muscle tissue within 30 minutes. The longitudinal follow-up of the mice showed that NMN was associated with a dose-dependent reduction in age-associated weight gain, an average of 4% for the 100 mg/kg and 9% for 300mg/kg, respectively (p < 0.001). Other long-term results highlighted that NMN supplementation appeared to improve insulin sensitivity and lowered triglycerides, fatty acids, and cholesterol. Genetic analysis of the treated animals demonstrated that NMN supplementation was associated with a reduction in the transcriptional changes that are associated with aging and that these effects appeared to be most prominent in the mitochondria of skeletal muscle.[1]
Contents
Article Abstract
NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12-month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.
Implications
There are several significant points highlighted by this manuscript. First, this research establishes that oral administration is a viable route of administration for NMN and underscores that oral NMN supplementation, at least in animals, results in significant plasma increases of NMN and hepatic increases of NAD+. Additionally, this manuscript highlights that long-term NMN administration appears safe and leads to improvements in insulin sensitivity as well as several age-associated conditions such as weight gain and age-associated changes in gene expression. In total, the manuscript highlights that oral administration of NMN is feasible for the purposes of raising plasma levels and affecting several of the previously described in vitro effects of NMN.
Additional research
This study presented convincing evidence that orally administered NMN reliably is imported to the bloodstream where it is transported to the liver and eventual target end-organs. Further research is recommended by the authors to better characterize which end-organs are most impacted by NMN administration, with special attention to potential central nervous system targets. Additionally, further studies evaluating the optimal dose of NMN to better understand the potential range of doses which should be considered for human administration.
Institution
Dr. Shin-ichiro Imai, the principal investigator for this study, has been an active researcher in the area of NMN. His lab at Washington University in St. Louis has produced several other manuscripts investigating the role of sirtuins in longevity and insulin sensitivity as well as the metabolism of NAD+.[2][3][4]
Funding
This study was funded under a sponsored research collaboration between Washington University in St. Louis and Oriental Yeast Company, a manufacturer of NMN.
Authors/Researchers
- Kathryn F. Mills – Department of Developmental Biology, Washington University
- Shoehi Yoshida – Oriental Yeast Company
- Liana R. Stein - Department of Developmental Biology, Washington University
- Alessia Grozio - Department of Developmental Biology, Washington University
- Shunsuke Kubota – Department of Ophthalmology, Washington University
- Yo Sasaki – Department of Genetics, Washington University
- Philip Redpath – School of Pharmacy, Queen’s University of Belfast
- Marie E. Migaud - School of Pharmacy, Queen’s University of Belfast
- Rajendra S. Apte - Department of Developmental Biology, Washington University
- Koji Uchida - Oriental Yeast Company
- Jun Yoshino – Division of Geriatrics and Nutritional Science, Washington University
- Shin-ichiro Imai - Department of Developmental Biology, Washington University
References
- ↑ Mills KF, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016;24(6):795-806.
- ↑ Moynihan KA, Grimm AA, Plueger MM, et al. Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2005;2(2):105-117.
- ↑ Luo J, Nikolaev AY, Imai S ichiro, et al. Negative control of p53 by Sir2α promotes cell survival under stress. Cell. 2001;107(2):137-148.
- ↑ Revollo JR, Grimm AA, Imai SI. The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. J Biol Chem. 2004;279(49):50754-50763.
