Nicotinamide Riboside as an Enhancer of Exercise Therapy in Hypertensive Older Adults (The NEET Trial)
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 1

Summary: 
      More than 80% of older adults have hypertension, with higher prevalence of high systolic
      blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death.
      Novel compound, nicotinamide riboside may enhance the effects of exercise therapy in
      hypertensive older adults.
    

Detailed description: 
      More than 80% of older adults have hypertension, with a higher prevalence of high systolic
      blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death.
      Because drug therapy that lowers SBP is associated with side effects such as hypotension,
      syncope, and kidney dysfunction, there is a great need for effective lifestyle SBP-lowering
      interventions for the older population that can replace drug therapy. While aerobic exercise
      is a recommended lifestyle intervention for controlling SBP and preventing CV disease
      naturally, in older adults it has been shown to be less effective in vascular-tissue
      remodeling because of arterial stiffness, resulting in less efficient SBP control. Reduced
      bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase
      sirtuin1 (SIRT1), may contribute to age-related vascular dysfunction via oxidative stress and
      reduced nitric oxide (NO). Exercise-induced overexpression of NAD+-dependent SIRT1 improves
      the bioavailability of NO. Preclinical evidence suggests that poor vascular function
      improvement in response to exercise in older mice is caused by insufficient NAD+ levels to
      stimulate SIRT1 activity. Importantly, replenishment of NAD+ levels induced vascular
      remodeling, improved vascular function, and reduced SBP in mice. An objective of this study,
      therefore, is to test a combination of aerobic exercise and nicotinamide riboside, a compound
      that replenishes NAD+ levels, to optimize exercise's SBP-lowering effect in hypertensive
      older adults. Initial human clinical trials demonstrated that nicotinamide riboside
      supplementation (1,000 mg/day) was safe and showed a higher potential to reduce SBP and
      arterial stiffness in participants with elevated SBP. As we have preclinical evidence that
      combining NAD+ replenishment with exercise is an ideal strategy for improving vascular
      function, our central hypothesis is that the intervention of aerobic-exercise training
      combined with nicotinamide riboside supplementation will reduce SBP in hypertensive older
      adults more effectively than will exercise alone. We will enroll 54 participants ≥ 55 years
      and older into either: (1) 1,000 mg/day of nicotinamide riboside plus 3 days/week of
      supervised, center-based walking exercise (n=18), or (2) the same exercise program combined
      with placebo (n=18), or (3) 1,000 mg/day of nicotinamide riboside alone (n=18). All
      participants will undergo daytime continuous SBP at baseline, 3 weeks, and 6 weeks, and
      arterial-stiffness measurements by pulse-wave velocity at baseline and at 6 weeks. Elevated
      SBP will be determined as daytime average equal to or above 130 mmHg, measured by the 24-hour
      blood-pressure device. To our knowledge, this study will be the first attempt to enhance
      exercise therapy with nicotinamide riboside in hypertensive older adults. We believe that
      nicotinamide riboside is "the missing piece of the puzzle" in improving vascular remodeling
      and SBP management in older adults. Preliminary evidence from this pilot study may support a
      full-scale Phase III clinical trial in hypertensive older adults. The ultimate goal of this
      line of research is to find adjuvant strategies to improve the exercise's SBP-lowering
      effects in older adults.
    

Intervention name(s): Walking Exercise; Nicotinamide Riboside (NR)
Intervention type(s): Behavioral; Drug
Intervention description(s): Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise.; Participants randomized to this intervention will receive 1,000 mg/day of NR.
Intervention MeSH terms: Niacinamide; Niacin; Nicotinic Acids
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: systolic blood pressure (SBP); cardiovascular (CV) disease