NAD Supplementation Study

• NAD-precursors (Dietary supplement): Intervention product containing the NAD+-precursors nicotinic acid, nicotinamide, and tryptophan (total of 204 NE per serving) in a whey protein source for 31 days.
• Control (Dietary supplement): Control product containing amino-acid mixture resembling whey-protein not containing the NAD+-precursors nicotinic acid, nicotinamide, and tryptophan. To be taken for 31 days.

Primary outcomes

• Ex vivo mitochondrial respiration [After 4 weeks of supplementation.]: 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.
• Basal metabolic rate [After 4 weeks of supplementation.]: Basal metabolic rate expressed as kcal/kg/min
• In vivo mitochondrial capacity [After 4 weeks of supplementation.]: In vivo mitochondrial capacity measured with 31P-MRS.
• Submaximal exercise energy expenditure [After 4 weeks of supplementation.]: Submaximal exercise energy expenditure expressed as kcal/kg/min

Secondary outcomes

• Glucose tolerance [After 4 weeks of supplementation.]: Glucose tolerance measured by oral glucose tolerance test.
• Ectopic lipid accumulation [After 4 weeks of supplementation.]: Liver and skeletal muscle lipid accumulation measured with H-MRS in vivo.
• Acetylcarnitine levels [After 4 weeks of supplementation.]: Skeletal muscle acetylcarnitine levels measured with H-MRS in vivo, before and after exercise stimulation (cycling).
• Physical function [After 4 weeks of supplementation.]: Measured by Short Physical Performance Battery and Frailty criteria.

Sex: All, ages: 65 Years to 75 Years, accepts healthy volunteers

Inclusion Criteria:

* Males and females
* Age ≥ 65 ≤ 75 years;
* BMI ≥ 20 kg/m2 ≤ 30 kg/m2;
* Normal physical activity levels: maximum of 1 hour per week engagement in a structured exercise session;
* SPPB score 4-9 and (pre-)frail;
* Subject should be in sufficient health to participate in the experiments, to be judged by the responsible physician based on the subject's medical history.

Exclusion Criteria:

* Not meeting all inclusion criteria;
* Smoking;
* Excessive alcohol use and/or drug abuse;
* Subjects with diabetes mellitus type 2;
* Significant food allergies or intolerances concerning the study products;
* Participation in another biomedical study within 1 month before the first study visit, possibly interfering with the study results;
* Medication use known to hamper subject's safety during the study procedures;
* Subjects who use selective serotonin re-uptake inhibitors (SSRI), or selective norepinephrin re-uptake inhibitors (SNRI), or monoamino oxidase inhibitors (MAO-inhibitors), or clomipramine, or St. John's wort (Hypericum perforatum);
* Subjects with contra-indications for MRI;
* Subjects who do not want to be informed about unexpected medical findings;
* Subjects who do not want that their treating physician to be informed;
* Co-morbidities to which the intervention or program the may pose as a complicating factor;
* Inability to participate and/or complete the required measurements.

• Results publication: Connell NJ, Grevendonk L, Fealy CE, Moonen-Kornips E, Bruls YMH, Schrauwen-Hinderling VB, de Vogel J, Hageman R, Geurts J, Zapata-Perez R, Houtkooper RH, Havekes B, Hoeks J, Schrauwen P. NAD+-Precursor Supplementation With L-Tryptophan, Nicotinic Acid, and Nicotinamide Does Not Affect Mitochondrial Function or Skeletal Muscle Function in Physically Compromised Older Adults. J Nutr. 2021 Oct 1;151(10):2917-2931. doi: 10.1093/jn/nxab193. PMID 34191033