NR Supplementation and Exercise
Condition: Overweight and Obesity; Aging; Type 2 Diabetes
MeSH terms: Overweight
Study type: Interventional

Summary: 
      The number of age-related chronic diseases (like obesity, type 2 diabetes and cardiovascular
      diseases) is increasing rapidly worldwide, reaching pandemic proportions. These age-related
      chronic diseases are associated with metabolic disturbances and mitochondrial dysfunction in
      humans. Nicotinamide adenosine dinucleotide (NAD) levels play an important role in energy
      metabolism and mitochondrial functioning and indeed it has been shown that high
      concentrations of NAD+ as well as a high NAD+/NADH ratio are strongly associated with
      metabolic and mitochondrial health. In contrast, decreased NAD+ bioavailability is reported
      in both ageing and obese humans as well as in diabetic mice. These findings fueled the idea
      of influencing NAD+ bioavailability in order to improve metabolic disturbances and
      mitochondrial dysfunction in humans. Supplementation with nicotinamide riboside (NR), a
      naturally occurring form of vitamin B3, may provide a way to boost cellular NAD+ levels.
      However, in contrast to animal studies, NR supplementation in humans has so far been
      unsuccessful in improving skeletal muscle mitochondrial function, exercise capacity or
      insulin sensitivity. Recently, it has been suggested that a situation where NAD+ levels
      become limited, is needed for NR supplementation to exert beneficial health effects. This
      situation could be achieved by combining exercise and NR supplementation. However, studies
      combining NR and exercise are lacking, which is why we would like to perform such a study
      here.
    

Detailed description: 
      Rationale: The number of age-related chronic diseases (like obesity, type 2 diabetes and
      cardiovascular diseases) is increasing rapidly worldwide, reaching pandemic proportions.
      These age-related chronic diseases are associated with metabolic disturbances and
      mitochondrial dysfunction in humans. Nicotinamide adenosine dinucleotide (NAD) levels play an
      important role in energy metabolism and mitochondrial functioning and indeed it has been
      shown that high concentrations of NAD+ as well as a high NAD+/NADH ratio are strongly
      associated with metabolic and mitochondrial health. In contrast, decreased NAD+
      bioavailability is reported in both ageing and obese humans as well as in diabetic mice.
      These findings fueled the idea of influencing NAD+ bioavailability in order to improve
      metabolic disturbances and mitochondrial dysfunction in humans. Supplementation with
      nicotinamide riboside (NR), a naturally occurring form of vitamin B3, may provide a way to
      boost cellular NAD+ levels. However, in contrast to animal studies, NR supplementation in
      humans has so far been unsuccessful in improving skeletal muscle mitochondrial function,
      exercise capacity or insulin sensitivity. Recently, it has been suggested that a situation
      where NAD+ levels become limited, is needed for NR supplementation to exert beneficial health
      effects. This situation could be achieved by combining exercise and NR supplementation.
      However, studies combining NR and exercise are lacking, which is why we would like to perform
      such a study here.

      Objective: The primary objective of this study is to determine whether combined treatment of
      exercise and NR imposes greater improvements in skeletal muscle mitochondrial metabolism in
      older humans compared to exercise treatment alone. The secondary objective is to determine
      whether combined treatment of exercise and NR supplementation imposes greater improvements in
      sleeping metabolic rate (SMR). As explorative objectives, we will examine whether combined
      treatment with exercise and NR imposes greater improvements in muscle (NAD) metabolites,
      energy metabolism and physical performance.

      Study design: The present study is a randomized, double-blinded, placebo-controlled double
      arm longitudinal intervention study in a pre and post design.

      Study population: 30 older male and (postmenopausal) female participants, aged 65 - 80 years
      with a BMI between 25-35 kg/m2 will perform this study (15 participants in the
      exercise+placebo group, 15 participants in the exercise+NR group). From experience with
      similar studies, we estimate a drop-out rate of 20% and a screening failure of 50% (due to
      the strict inclusion criteria), resulting in maximally 36 subjects that have to be included
      and 72 subjects that have to be screened (maximally).

      Intervention (if applicable): Participants will be asked to take two pills of NR
      (250mg/pill), or placebo, twice daily (two with breakfast and two with diner, a total of 4
      pills/day; 1000mg/day), for 40 days. During days 17-38 of the NR intervention, participants
      will perform a 3-weeks supervised exercise training program with four ~30 min exercise
      sessions per week (two endurance session on a bike at 70%Wmax and two high intensity interval
      (HIIT) sessions. Participants will be randomly assigned to the placebo + exercise or NR +
      exercise arm. To assess the outcomes, participants will undergo three test days before the
      start of the NR supplementation and repeat these three test days at the end (day 38-40) of NR
      supplementation.

      Main study parameters/endpoints: The primary study endpoints is ex vivo skeletal muscle
      mitochondrial function measured via high-resolution respirometry. Explorative objectives are
      muscle (NAD) metabolites, energy metabolism and physical performance.
    

Intervention name(s): Niagen; Exercise
Intervention type(s): Dietary Supplement; Other
Intervention description(s): Participants in the NR supplementation + exercise group will undergo oral NR supplementation for 40 days. NiagenTM is the name for the dietary supplement containing NR (ChromaDex, Inc. Irvine, USA). The total dosage of NR per day will be 1000mg. This supplementation time of 40 days 1000mg/day; During days 17-38 of the NR/placebo intake, participants will perform a 3-weeks supervised exercise training program with four ~30 min exercise sessions per week (two endurance session on a bike at 70%Wmax and two high intensity interval (HIIT) sessions.
Other intervention name(s): Nicotinamide Riboside (NR)
Intervention MeSH terms: Niacinamide
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: The present study is a randomized, double-blinded, placebo-controlled double arm longitudinal intervention study in a pre and post design.
Masking: Double (Participant, Investigator)
Primary purpose: Prevention
Keywords: exercise; NR supplementation; NAD metabolism