Lausanne, Switzerland – October 11th, 2016. Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells which exists in two forms: oxidised (NAD+) and reduced (NADH).
NAD+ plays a vital role in processes linked to fuel utilisation and energy metabolism. It is a crucial metabolite for cellular energy production and most metabolic routes defining carbohydrate, lipid and amino acid utilisation. Decreases in intracellular NAD+ levels are a hallmark of metabolic and age-related diseases. As such, diverse strategies aimed to increase cellular NAD+ levels by supplementation with NAD+ precursors, such as nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR), have proven to be therapeutically helpful in preclinical studies. In particular in the prevention of metabolic and age-related diseases, including type 2 diabetes.
Researchers at the Nestlé Institute of Health Sciences (NIHS) recently led a successful global multi-centre study to better understand the effectiveness and mode of action of different NAD+ precursors by focusing on the activity of the nicotinamide riboside kinase 1 (NRK1) enzyme. The results of the research were published today in Nature Communications.
Little is currently known about the physiological role of NRK1. By exploring how NRK1 levels affect the ability of NR and NMN to improve NAD+ synthesis in a range of tissues, the researchers were able to empirically demonstrate that NRK1 is the essential and rate-limiting activity for the utilisation of NR and NMN as NAD+ precursors. Conversely, the research showed that NR and NMN actions on NAD+ synthesis are blunted by NRK1 deficiency. This is important, as there are several tissues and situations in which cells respond poorly to NR. Enhancing NRK1 activity through natural compounds could therefore be of great interest to improve NR responsiveness.
“This study represents a significant step forward in our understanding of Vitamin B3 metabolism”, explains Carles Canto from NIHS, who led the research. “It is the first time that the role of an enzyme working on NR has been clarified through in-depth mechanistic studies, opening up new opportunities to modulate the benefits of NR as a relatively new form of Vitamin B3 supplementation.”
Joanna Ratajczak, PhD student at NIHS affiliated to the EPFL, École polytechnique fédérale de Lausanne, and first author of the paper, explains: “Through our research, we have for the first time identified NRK1 as the central rate-limiting enzyme for the metabolism of both NR and NMN and, consequently, for their metabolic benefits. Our findings also provide compelling evidence for the extracellular conversion of NMN to NR for subsequent conversion to NAD+ through the NRK pathway.”
NIHS Head Ed Baetge adds: “There is often ambiguous information in the public domain about food supplements and their health benefits that has no scientific base. We do things differently. We generate scientific knowledge that will provide clarity in the field. This latest research is an important step forward that exemplifies our commitment to science-based nutrition.”
What is NR?
Nicotinamide riboside (NR) is a newly discovered form of Vitamin B3, and a natural precursor to NAD+ found in milk and, potentially, other natural sources.
Vitamin B3 supplementation, in the form of niacin, was used in the past as an effective lipid lowering agent. However, side effects compromised its protracted medical use. NR, however, would overcome this potential issue. Indeed, recent work suggests NR might have multiple health benefits, albeit the concentrations used in these studies form larger quantities than those naturally occurring in foods.
NR has demonstrated insulin-sensitising and neuroprotective properties, together and a remarkable ability to protect against the negative effects of high-caloric diets. These benefits, however, still need to be confirmed in humans.
NIHS is a biomedical research institute, part of Nestlé’s global R&D network, dedicated to fundamental research aimed at understanding health and disease and developing science-based, targeted nutritional solutions for the maintenance of health. To achieve its aim, NIHS employs state-of-the-art technologies and biological models to characterise health and disease with a holistic and integrated approach. The ultimate goal of the Institute is to develop knowledge that can empower people to better maintain their health through nutritional approaches, especially in relation to their molecular profile and lifestyle status.
Ratajczak, J, Joffraud, M, Trammell, SAJ, Ras, R, Canela, N, Boutant, M, Kulkarni, SS, Rodrigues, M, Redpath, P, Migaud, M, Auwerx, J, Yanes, O, Brenner, C and Canto, C (2016). NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells. Nature Communications, 2016; Oct 11; 7: 13103.
Cantó C, Houtkooper RH, Pirinen E, Youn DY, Oosterveer MH, Cen Y, Fernandez-Marcos PJ, Yamamoto H, Andreux PA, Cettour-Rose P, Gademann K, Rinsch C, Schoonjans K, Sauve AA, Auwerx J. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metabolism, 2012; Jun 6;15(6):838-47.
Gomes AP, Price NL, Ling AJ, Moslehi JJ, Montgomery MK, Rajman L, White JP, Teodoro JS, Wrann CD, Hubbard BP, Mercken EM, Palmeira CM, de Cabo R, Rolo AP, Turner N, Bell EL, Sinclair DA. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell, 2013; Dec 19;155(7):1624-38.
Gong B, Pan Y, Vempati P, Zhao W, Knable L, Ho L, Wang J, Sastre M, Ono K, Sauve AA, Pasinetti GM. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models. Neurobiol Aging, 2013; Jun;34(6):1581-8.
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Laura Camurri, Communications, NIHS