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NR Supplementation and Exercise

Primary Purpose

Overweight and Obesity, Aging, Type 2 Diabetes

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Niagen
Exercise
Sponsored by
Maastricht University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Overweight and Obesity focused on measuring exercise, NR supplementation, NAD metabolism

Eligibility Criteria

65 Years - 80 Years (Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Participants are able to provide signed and dated written informed consent prior to any study specific procedures
  • Aged ≥ 65 and ≤ 80 years
  • Body mass index (BMI) 25 - 35 kg/m2
  • Stable dietary habits (no weight loss or gain > 5 kg in the past 3 months)
  • No signs of active cardiovascular disease, liver or kidney malfunction

Exclusion Criteria:

  • Type 2 diabetes
  • Patients with congestive heart failure and and/or severe renal and or liver insufficiency
  • Uncontrolled hypertension
  • Any contra-indication for MRI scanning
  • Alcohol consumption of >3 servings per day for man and >2 servings per day for woman
  • Smoking
  • Unstable body weight (weight gain or loss > 5kg in the last 3 months)
  • Engagement in structured exercise activities > 2 hours a week
  • Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the Investigator which would possibly hamper our study results
  • Medication use known to hamper subject's safety during the study procedures
  • Subjects who do not want to be informed about unexpected medical findings
  • Use of food supplements containing NR or Resveratrol (similar working mechanisms)

Sites / Locations

  • Maastricht University

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Exercise + NR

Exercise + Placebo

Arm Description

Participants will be asked to take two pills of NR (250mg/pill) twice daily (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. 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.

Participants will be asked to take two pills of placebo, twice daily (a total of 4 pills/day), for 40 days. During days 17-38 of the 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. 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 the placebo supplementation.

Outcomes

Primary Outcome Measures

Ex vivo muscle mitochondrial function
Ex vivo mitochondrial function in skeletal muscle measured by oxygen consumption in muscle fibres (muscle biopsy vastus lateralis) on lipid-derived and carbohydrate-derived substrates.

Secondary Outcome Measures

Maximal aerobic capacity
Maximal aerobic capacity measured during a VO2max cycling test in ml/kg/min
Physical performance
Physical performance is measured during a 6-minute walk test (6MWT) expressed as the distance covered during 6 minutes walking as well as the time necessary to stand up from a chair (TCST).
Skeletal muscle NAD concentrations (ex-vivo)
Skeletal muscle NAD metabolites are measured in muscle biopsies using metabolomics
Skeletal muscle NAD concentration (in-vivo)
Skeletal muscle NAD metabolites are measured in vivo using phosphorus magnetic resonance spectroscopy in the m. vastus lateralis.
Intrahepatic lipid content
Intrahepatic lipid content is measured using proton magnetic resonance spectroscopy
Upper leg muscle mass
Upper leg muscle mass is measured with magnetic resonance imaging
Body composition
Body composition is measured using the BodPod technique and fat mass (kg and %) and fat-free mass (kg) will be determined.
Quality of life
Quality of life will be assessed by a questionnaire (in arbitrary units measured via the 32-item survey)
Blood metabolites
Metabolites in the blood (i.e. glucose, free fatty acids, triglycerides, cholesterol, insulin in mmol/L taken via a venepuncture)
Submaximal exercise energy expenditure
Submaximal exercise energy expenditure will be measured via indirect calorimetry during a 60-minute submaximal cycling exercise at 50% Wmax
Sleeping metabolic rate
Sleeping metabolic rate will be measured during a 11 hour stay in a respiration chamber via indirect calorimetry
Exercise efficiency
Exercise efficiency will be measured during a 60-minute submaximal cycling test via indirect calorimetry in kJ/min

Full Information

First Posted
May 25, 2021
Last Updated
February 9, 2023
Sponsor
Maastricht University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT04907110
Brief Title
NR Supplementation and Exercise
Official Title
The Effects of Exercise Training Combined With NR Supplementation on Metabolic Health in Older Individuals
Study Type
Interventional

2. Study Status

Record Verification Date
February 2023
Overall Recruitment Status
Completed
Study Start Date
August 10, 2021 (Actual)
Primary Completion Date
December 2, 2022 (Actual)
Study Completion Date
December 7, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University Medical Center

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Overweight and Obesity, Aging, Type 2 Diabetes
Keywords
exercise, NR supplementation, NAD metabolism

7. Study Design

Primary Purpose
Prevention
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
The present study is a randomized, double-blinded, placebo-controlled double arm longitudinal intervention study in a pre and post design.
Masking
ParticipantInvestigator
Masking Description
Participants and Investigator will be blinded for the study material (i.e. NR or placebo).
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Exercise + NR
Arm Type
Experimental
Arm Description
Participants will be asked to take two pills of NR (250mg/pill) twice daily (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. 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.
Arm Title
Exercise + Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will be asked to take two pills of placebo, twice daily (a total of 4 pills/day), for 40 days. During days 17-38 of the 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. 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 the placebo supplementation.
Intervention Type
Dietary Supplement
Intervention Name(s)
Niagen
Other Intervention Name(s)
Nicotinamide Riboside (NR)
Intervention Description
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
Intervention Type
Other
Intervention Name(s)
Exercise
Intervention Description
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.
Primary Outcome Measure Information:
Title
Ex vivo muscle mitochondrial function
Description
Ex vivo mitochondrial function in skeletal muscle measured by oxygen consumption in muscle fibres (muscle biopsy vastus lateralis) on lipid-derived and carbohydrate-derived substrates.
Time Frame
Pre-intervention test day 3 + day 40 of the intervention NR/Placebo + exercise
Secondary Outcome Measure Information:
Title
Maximal aerobic capacity
Description
Maximal aerobic capacity measured during a VO2max cycling test in ml/kg/min
Time Frame
Pre-intervention test day 1 + Day 38
Title
Physical performance
Description
Physical performance is measured during a 6-minute walk test (6MWT) expressed as the distance covered during 6 minutes walking as well as the time necessary to stand up from a chair (TCST).
Time Frame
Pre-intervention test day 1 + Day 38
Title
Skeletal muscle NAD concentrations (ex-vivo)
Description
Skeletal muscle NAD metabolites are measured in muscle biopsies using metabolomics
Time Frame
Pre-intervention test day 3 + Day 40
Title
Skeletal muscle NAD concentration (in-vivo)
Description
Skeletal muscle NAD metabolites are measured in vivo using phosphorus magnetic resonance spectroscopy in the m. vastus lateralis.
Time Frame
Pre-intervention test day 3 + Day 40
Title
Intrahepatic lipid content
Description
Intrahepatic lipid content is measured using proton magnetic resonance spectroscopy
Time Frame
Pre-intervention test day 1 + Day 38
Title
Upper leg muscle mass
Description
Upper leg muscle mass is measured with magnetic resonance imaging
Time Frame
Pre-intervention test day 1 + Day 38
Title
Body composition
Description
Body composition is measured using the BodPod technique and fat mass (kg and %) and fat-free mass (kg) will be determined.
Time Frame
Pre-intervention test day 1 + Day 38
Title
Quality of life
Description
Quality of life will be assessed by a questionnaire (in arbitrary units measured via the 32-item survey)
Time Frame
Pre-intervention test day 1 + Day 38
Title
Blood metabolites
Description
Metabolites in the blood (i.e. glucose, free fatty acids, triglycerides, cholesterol, insulin in mmol/L taken via a venepuncture)
Time Frame
Pre-intervention test day 3 + Day 40
Title
Submaximal exercise energy expenditure
Description
Submaximal exercise energy expenditure will be measured via indirect calorimetry during a 60-minute submaximal cycling exercise at 50% Wmax
Time Frame
Pre-intervention test day 3 + Day 40
Title
Sleeping metabolic rate
Description
Sleeping metabolic rate will be measured during a 11 hour stay in a respiration chamber via indirect calorimetry
Time Frame
Pre-intervention test day 2 + Day 39
Title
Exercise efficiency
Description
Exercise efficiency will be measured during a 60-minute submaximal cycling test via indirect calorimetry in kJ/min
Time Frame
Pre-intervention test day 3 + Day 40

10. Eligibility

Sex
All
Minimum Age & Unit of Time
65 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Participants are able to provide signed and dated written informed consent prior to any study specific procedures Aged ≥ 65 and ≤ 80 years Body mass index (BMI) 25 - 35 kg/m2 Stable dietary habits (no weight loss or gain > 5 kg in the past 3 months) No signs of active cardiovascular disease, liver or kidney malfunction Exclusion Criteria: Type 2 diabetes Patients with congestive heart failure and and/or severe renal and or liver insufficiency Uncontrolled hypertension Any contra-indication for MRI scanning Alcohol consumption of >3 servings per day for man and >2 servings per day for woman Smoking Unstable body weight (weight gain or loss > 5kg in the last 3 months) Engagement in structured exercise activities > 2 hours a week Previous enrolment in a clinical study with an investigational product during the last 3 months or as judged by the Investigator which would possibly hamper our study results Medication use known to hamper subject's safety during the study procedures Subjects who do not want to be informed about unexpected medical findings Use of food supplements containing NR or Resveratrol (similar working mechanisms)
Facility Information:
Facility Name
Maastricht University
City
Maastricht
ZIP/Postal Code
6229 ER
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Data can be obtained with the principal investigator if desired.

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NR Supplementation and Exercise

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