Inorganic nitrate, nitric oxide and energy metabolism in humans

This research will conducted by a team of scientists with expertise in the conduction of detailed clinical studies and measurement of small molecules in circulating blood or bodily tissues. The overall aim of this programme of research is to understand how nutritional factors and the ageing process influence functions involved in the regulation of body weight and vascular function.
The research will include two independent projects which will have in common the study of a small molecule called Nitric Oxide (NO). This molecule is continuously produced by the body in small amounts and it has several and important effects including regulation of blood pressure, inflammation, exercise performance and memory. Since its official discovery in 1987, research in this area has made important advancements but, for example, we are still far from a full understanding of the nutritional and lifestyle factors that can affect the concentrations of NO in the body.
Our research will try to advance this knowledge by studying how the ageing process and nutritional, dietary and lifestyle factors can influence NO activity. This research will use one of the best methods currently available to measure NO concentrations and some of these methods have been developed by Dr Siervo.
The first project will essentially recruit 72 subjects with an age range between 18 and 75 years and they will be asked to attend the research unit for one visit. During the visit we will perform a series of detailed measurements and collect blood, urine and saliva samples which we will utilise to measure a series of molecules involved in the regulation of blood pressure, blood glucose and inflammation. We will also try to understand how certain genes influence NO concentrations.
The second project will involve the recruitment of 16 healthy older subjects. They will be asked to take a dose every day of a small molecule, called inorganic nitrate, for 14 days. Inorganic nitrate seems to have beneficial effects on the concentrations of NO in the body. Inorganic nitrate is commonly present in difference concentrations in water and food; example of foods with high nitrate content are beetroot, spinach, lettuce. During the study participants will return to the research centre in Newcastle on a few occasions. During these visits we will perform detailed measurements of vascular and metabolic health and we will collect biological (blood, urine, saliva) and tissue samples (muscle, adipose tissue) to understand the precise mechanisms that may explain the effects of inorganic nitrate on bodily functions.
Ultimately, these studies will provide novel and important information on the role of NO in the regulation of vascular and metabolic functions. We will understand better how the ageing process determine changes in physiological function and we will test whether inorganic nitrate could be a potential nutritional intervention that may protect the arteries and increase the efficiency of energy metabolism in older people. This will not only have implications for the research and advance knowledge but it can open potentially a new window for nutritional interventions that may be effective in reducing the risk of metabolic and vascular diseases such as type 2 diabetes, angina or stroke.

The concepts of metabolic and vascular ageing as opposed to chronological ageing form a novel research paradigm useful to ascertain the observed between-subject variability in the association between ageing and cardiovascular and metabolic health outcomes. Older subjects show a greater impairment of endothelial function and control of vascular tone, which are both closely linked to the bio-availability and activity of nitric oxide (NO). The study of genetic, bio-molecular and physiological mechanisms linking ageing and NO metabolism as well as the identification of novel nutritional and lifestyle factors influencing NO synthesis is topical to maintain or restore a healthy ageing phenotype.
The overall aims of the proposed research programme will determine:
a. The association of ageing with NO synthesis and whether it is modified by eNOS polymorphisms
b. The effects of inorganic nitrate supplementation on resting energy expenditure, dietary-induced thermogenesis and absorptive fuel oxidation in the elderly
c. The effects of inorganic nitrate supplementation on mitochondrial respiration in muscular and adipose tissue and changes in core pathways involved in glucose and fat oxidation.

The projects will use advanced, state of the arts methods for the measurement of endothelial and metabolic functions. These include a non invasive measurement of NO production using stable isotopic tracers, and, for the first time, a measurement of the effects of inorganic nitrate on dietary induced thermogenesis and substrate oxidation using indirect calorimetry. These physiological measurements will be coupled to detailed biomolecular investigations of mitochondrial efficiency in muscular and adipose tissue.

This research project has been primarily designed to advance scientific knowledge in order to shed some light on the biological mechanisms that control age-related decline in NO production cardio-metabolic functions and test whether dietary nitrate supplementation could be considered as a potential nutrient with a significant impact on metabolic function and beyond the established effects on vascular health. The observation of beneficial effects of nitrate on energy metabolism could open a new therapeutic area of research for chronic metabolic disorders such as type 2 diabetes and dyslipidaemia. We also believe that the results will have an impact beyond its immediate academic environment (i.e., nutrition and dietetic research), have an influence on metabolic and pharmacology research as well as may influence decision-making of funding and advisory clinical bodies. Its influence, while intended to be significant within academia and clinical practice, may also extend to food industry.
This is an active area of research and research groups in the UK (Exeter, Queen Mary, Southampton, Reading) and internationally (Stockholm, Dussedlorf) are investigating the effects of dietary nitrate on health outcomes. However, our group in Newcastle has developed a unique niche in studying the modulating role of ageing on the effects of nitrate administration; in addition, there is currently a small number of groups with a research interest in the effects of nitrate on energy metabolism in humans (Exeter, Stockholm).
We will make sure that the research will be effectively disseminated through scientific channels and public engagements activities. The details of these activities have already been discussed in our dissemination plans. However, we would like to emphasize that the evidence in this exciting and promising area of research is still limited to support a consensus for nutritional recommendations; therefore, our engagement activities will primarily focused on scientific dissemination, through publications and conferences, and public engagement events within the university and Newcastle local area to promote nutrition research for the promotion of healthy ageing. We also envisage that this three-year research programme will contribute to the nutritional taught programmes at Newcastle University and offer to undergraduate and post-graduate students projects embedded within the various clinical and analytical activities involved in the projects.
Ultimately, the scientists involved in the study will benefit from the multi-disciplinary approach and opportunity to learn and develop new skills in the application of stable isotopic models and bio-molecular analyses.