Impacts of Nicotinamide Riboside on Functional Capacity and Muscle Physiology in Older Veterans (NR-VET)

Frailty is an age-associated clinical condition of poor physiological reserve that increases risks for falls, hospitalization and mortality. Nicotinamide adenine dinucleotide (NAD) is a critical co-factor needed for many cellular processes. The natural levels of NAD decline aging and this has been linked to physical performance decline in animals. Human trials have demonstrated that nicotinamide riboside (NR), a form of vitamin B3, is safe and effectively increases NAD+ levels. In animal studies, NR improves treadmill performance and muscle quality. Here the investigators propose a double-blind randomized control trial to assess the benefits of NR supplementation on human muscle function and physiology. The investigators anticipate the research findings will support the use of this nutritional supplement to improve the health of Veterans during aging.

Frailty is increasingly seen within the aging population and is driven largely by musculoskeletal declines. Nearly 9 million Veterans are now 65 years of age or older with impairments in functional capacity, reduction in quality of life, and an increase in the use of health care services and associated costs. An estimated 45-50% of those over the age of 85 are frail, which could represent well over 1 million Veterans. Aging, which significantly contributes to frailty, is highly correlated with reduced levels of nicotinamide adenine dinucleotide (NAD+), an essential mediator in mitochondrial function. Restoration of cellular NAD+ levels is gaining support as a therapeutic strategy to maintain and even enhance functional capacity during aging. Nicotinamide riboside (NR) - an NAD+ precursor - enhances physical activity and mitochondrial health in mice. Furthermore, NR was recently shown to be safe in human clinical trials for boosting NAD+, yet the benefits for human physical performance and muscle physiology are unknown. Therefore, the goal of this project is to establish a double-blind randomized control trial to assess the impacts of NR on functional capacity, muscle function and structure, and mRNA signaling in healthy older adults. Towards this goal, this study will investigate healthy older individuals between the ages of 65 and 85 who will receive NR or a placebo for a period of 3 months. Participants will be tested for frailty, gait speed, and muscle strength at each time point. Additionally, muscle biopsies and serum will be collected to assess changes in muscle fiber histology, mitochondrial biomass and activity, and mRNA profiles. This project will provide greater insight into NR supplementation as a therapeutic strategy to stave off frailty and maintain resilience during aging.

muscle, strength, endurance, gait speed, grip strength, frailty, muscle fibers, mitochondria, inflammation, mRNA, aging

The study will be conducted as a double-blind randomized controlled trial. Participants will be randomly assorted to receive either the nicotinamide riboside supplementation or a placebo pill.

The study design participants, care providers, and investigators will be blinded to the group designation of the participants. To accomplish this, the study statistician will coordinate with the VA pharmacy to assign groups to participants and to dispense appropriate treatments to the study coordinator to give to study participants.

Participants in this group will receive NR supplementation at 1000 mg per day (given as 2x250mg capsules morning and 2x250mg at night).

Participants in this group will receive placebo given as 2 pills in the morning and 2 pills at night. Placebo pills contain micro cellulose which is likewise found in NR containing capsules.

Participants are asked to exercise on an upright exercise bike as the resistance increases over time. During the exercise, participants are asked to breath through a mask that is connected to a oxygen and carbon dioxide measuring device. The assessment last for approximately 5-10 minutes and provides data the pertain to an individuals lung capacity, breathing rate, and endurance.

Leg and arm strength will be measured using a small handheld dynamometer where the device is placed on the wrist or ankle as the participant is asked to extend or contract the limb with full force.

Frailty is a syndrome marked by greater susceptibility to adverse outcomes like falls and disability. Frailty diagnosis in this study is conducted as having 3 or more of the following risk factors - unexpected weight loss in a 1 year time frame, weak grip strength measured by a hand dynamometer device, slow gait speed in a 15 foot walk test, low activity levels assessed with a survey question, and poor endurance also assessed by a survey question.

The Short physical performance battery (SPPB) is a battery of test often used in geriatric research to capture functional capacity in older adults. The test includes a balance and coordination assessment via asking participants to hold stances with different foot positions, a gait speed test of approximately 8 feet, and a chair rise timed test where a participant is asked to rise from a chair 5 times.

Quality of life assessment is performed using the Quality of life, enjoyment, and satisfaction questionnaire - short form (Q-LES-Q-SF) survey instrument. The survey instrument scores from 0 to 70 with a greater score representing better quality of life.

Cognitive status will be assessed using the VA - St. Louis University Mental Survey (VA-SLUMS) involving memory tests, shape recognition, and story recall. The survey scores range from 0-30, with a higher score representing greater cognitive capability.

Chronic inflammation may be indicative of distress and lead to chronic diseases. The study will examine changes in inflammatory markers, C-reactive protein, interleukin-6, and interleukin-10.

A muscle biopsy will be performed at baseline and endpoint. From this sample extracts will be created to assess changes in muscle NAD+ content (an expected response from NR supplementation). Additionally, mitochondria will be isolated and assessed for overall content and basal and maximal activity. Finally, the muscle sample will be assessed using histology to observe changes in fiber size and if there is a difference in the number of slow and fast twitch muscle fibers. Finally, changes in message RNA expression will be determined in order to understand how treatment affects cellular function.

Body composition will be measured using bioelectric impedance (BIA) - a technique where participants are asked to stand on the measurement device and hold on to two metal handles. A light - and non-detectable - current is then transmitted allowing for collection of body fat and lean mass in the subject. The assessment takes roughly 2-3 minutes.

Inclusion Criteria: Ages 65-85 Male or female Any race Ability to use an exercise bike Medically cleared for muscle biopsy Exclusion Criteria: Severe Co-morbidity examples include, but not limited to: congestive heart failure class equal to or above III chronic obstructive pulmonary disorder (COPD) gold stage IV chronic kidney disease equal to or above stage A VA-SLUMS cognitive screen score of less than or equal to 20 Body mass index greater than or equal to 40

De-identified individual participant data will be shared in publications and seminars culminating from this study. Additionally, de-identified raw data may be made accessible on a public database for research purposes. Individual participant data will be made available to the participant upon request, with the exception of treatment arm, which can be disclosed at the end of the study to protect blinding of investigators. Individual participant data may also be disclosed to current and future collaborators upon acceptance of a formal request.

individual participant data that is used in publication and/or presentations/seminars may become available during the study or immediately thereafter depending on if the data sufficiently merits dissemination. De-identified raw data associated with a publication, if made accessible, will be made available at the time of publication, otherwise, if not associated with a publication, will be made available at the conclusion of the study (03/30/2025).

De-identified study data that does not containing protected health information (PHI) will be made accessible upon approval of the study team. Written request should be sent to the principal investigator.