Nicotinamide Adenine Dinucleotide and Skeletal Muscle Metabolic Phenotype

Study Overview
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Brief Summary
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This study is designed to assess the physiological consequences of elevating Nicotinamide Adenine Dinucleotide (NAD+) availability using Nicotinamide Riboside (NR) supplementation in skeletal muscle tissue, and examine its effect upon muscle metabolic phenotype.

Detailed Description
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-NAD+ sensitive metabolic decline in ageing, including sarcopenia, leads to a reduction in energy metabolism, contribute to chronic inflammation, disposing individuals to metabolic disease and overall decreased later-life health. Prominent metabolic changes include a decline in NAD+ content and deterioration in muscle NAD+ mediated signalling and mitochondrial function, ultimately compromising skeletal muscle and whole body energy homeostasis. The most efficient means to boost NAD+ in muscle appears to be oral delivery of NR, and participants will be supplemented with 1000mg NR (2x x250mg tablets twice daily) for 3 weeks. Hypothesis: elevating skeletal muscle NAD+ bioavailability using NR supplementation will increase markers of mitochondrial function and that will manifest as a more favourable metabolic profile. Study Setting: the study will be carried out at the NIHR/Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital Birmingham.

Official Title
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Nicotinamide Adenine Dinucleotide and Skeletal Muscle Metabolic Phenotype (NADMet)

Conditions
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Aging

Intervention / Treatment
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* Dietary Supplement: Nicotinamide Riboside
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male sex Age 70-80 years BMI 20-30kg/m2 Participants who are able to discontinue aspirin for 3 days prior to the muscle biopsy Participants who are able to discontinue statins and vitamin D supplements for a week before the second visit and for the duration of the study Exclusion Criteria: Serious active medical conditions including inflammatory diseases or malignancies Significant past medical history including diabetes mellitus, ischaemic heart disease, cerebrovascular disease, significant respiratory disease requiring medication, epilepsy High blood pressure (BP>160/100mmHg) Oral Anticoagulants (like Warfarin, Dabigatran, Rivaroxaban) or Clopidogrel therapy which will increase the risk of bruising following a muscle biopsy

Ages Eligible for Study
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Minimum Age: 70 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotinamide Riboside<br>1000mg (2x250mg tablets twice daily) | Dietary Supplement: Nicotinamide Riboside<br> <br> |
| Placebo Comparator: Placebo<br>Two tablets twice daily | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitochondrial function assessment in skeletal muscle using high resolution respirometry | Mitochondrial function assessment on muscle biopsies using high resolution respirometry | Following 3 weeks of NR supplementation | 
| Skeletal muscle NAD+ levels in vastus lateralis biopsy using targeted metabolomics |  | Following 3 weeks of NR supplementation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement in response to oral glucose tolerance test/HOMA-IR |  | Following 3 weeks of NR supplementation | 
| Improvement in lipid profile |  | Following 3 weeks of NR supplementation | 
| Muscle Arterio-Venous Difference - Tissue-specific metabolite trafficking, oxygen consumption and CO2 production |  | Following 3 weeks of NR supplementation | 
| Muscle biopsy: adaptive expression profile (genomic) |  | Following 3 weeks of NR supplementation | 
| Changes in resting metabolic rate using indirect calorimetry |  | Following 3 weeks of NR supplementation | 
| 24 hour urine collection - NAD+ metabolomics and changes in steroid ratios using Gas chromatography/ mass spectrometry |  | Following 3 weeks of NR supplementation | 
| Muscle strength - grip testing |  | Following 3 weeks of NR supplementation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nicotinamide Riboside, Nicotinamide Adenine Dinucleotide, Skeletal muscle, Metabolism