Nicotinamide Adenine Dinucleotide Augmentation in Overweight or Obese Middle-Aged and Older Adults: A Physiologic Study

Abstract

Context: Nicotinamide adenine dinucleotide (NAD) levels decline with aging and age-related decline in NAD has been postulated to contribute to age-related diseases.

Objective: We evaluated the safety and physiologic effects of NAD augmentation by administering its precursor, β-nicotinamide mononucleotide (MIB-626, Metro International Biotech, Worcester, MA), in adults at risk for age-related conditions.

Methods: Thirty overweight or obese adults, ≥ 45 years, were randomized in a 2:1 ratio to 2 MIB-626 tablets each containing 500 mg of microcrystalline β-nicotinamide mononucleotide or placebo twice daily for 28 days. Study outcomes included safety; NAD and its metabolome; body weight; liver, muscle, and intra-abdominal fat; insulin sensitivity; blood pressure; lipids; physical performance, and muscle bioenergetics.

Results: Adverse events were similar between groups. MIB-626 treatment substantially increased circulating concentrations of NAD and its metabolites. Body weight (difference -1.9 [-3.3, -0.5] kg, P = .008); diastolic blood pressure (difference -7.01 [-13.44, -0.59] mmHg, P = .034); total cholesterol (difference -26.89 [-44.34, -9.44] mg/dL, P = .004), low-density lipoprotein (LDL) cholesterol (-18.73 [-31.85, -5.60] mg/dL, P = .007), and nonhigh-density lipoprotein cholesterol decreased significantly more in the MIB-626 group than placebo. Changes in muscle strength, muscle fatigability, aerobic capacity, and stair-climbing power did not differ significantly between groups. Insulin sensitivity and hepatic and intra-abdominal fat did not change in either group.

Conclusions: MIB-626 administration in overweight or obese, middle-aged and older adults safely increased circulating NAD levels, and significantly reduced total LDL and non-HDL cholesterol, body weight, and diastolic blood pressure. These data provide the rationale for larger trials to assess the efficacy of NAD augmentation in improving cardiometabolic outcomes in older adults.

Keywords: blood pressure; geroscience; lipids; metabolic effects; muscle bioenergetics; physical function; β-nicotinamide mononucleotide.

Figure 1.

The flow of study participants in different phases of the trial are shown in the CONSORT diagram.

Figure 2.

Circulating concentrations of NAD, NMN, and NAD metabolites by treatment arms. Mean circulating concentrations of NMN, NAD, and NAD metabolites on days 1, 14, and 28 with the corresponding 95% CI are shown. Point estimates represent the mean and the bars represent 95% CI. NMN, nicotinamide mononucleotide; NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; 1-methyl NAM, 1-methylnicotinamide; 2-PY, N-methyl-2-pyridone-5-carboxamide.

Figure 3.

Changes in body weight, liver fat and intra-abdominal fat. Body weight was recorded in the fasting state in upright position with minimal clothing. Liver fat was measured using the Dixon method and 3 T magnetic resonance imaging. The horizontal line in the box represents the median, the “x” in the box represents the mean, the upper and lower bounds of the box represent quartile range, the upper and lower bars represent the 95% CI, and the dots represent the values outside the 95% CI. Red, placebo arm; blue, treatment arm.

Figure 4.

Changes in total cholesterol, LDL, HDL, and non-HDL cholesterol, and apolipoproteins A1 and B. The change from baseline to days 1 (2 hours after dose) 14 and 28 in total cholesterol, LDL, HDL, and non-HDL cholesterol, and apolipoproteins A1 and B are shown as mean along with the associated 95% CI. P values associated with between group comparisons are also reported. LDL, low-density lipoprotein; HDL, high-density lipoprotein. The horizontal line in the box represents the median, the “x” in the box represents the mean, the upper and lower bounds of the box represent quartile range, the upper and lower bars represent the 95% CI, and the dots represent the values outside the 95% CI. Day 1 TP2, sample collected on day 1, 2 hours after the administration of the first dose. Day 28 TP0, sample collected at time 0 on day 28 approximately 12 hours after the last dose. Day 28 TP2, sample collected on day 28, 2 hours after administration of the dose. Red, placebo arm; blue, treatment arm.

Figure 5.

The change from baseline in systolic and diastolic blood pressure. The horizontal line in the box represents the median, the “x” in the box represents the mean, the upper and lower bounds of the box represent quartile range, the upper and lower bars represent the 95% CI, and the dots represent the values outside the 95% CI. Day 1 TP2, day 1 2 hours after the administration of the first dose; Day 28 TP0, Time 0 on day 28 approximately 12 hours after the last dose; Day 28 TP2, Day 28, 2 hours after administration of the dose at time 0. Red, placebo arm; blue, treatment arm.

Figure 6.

Changes in measures of muscle performance, physical function, and aerobic capacity. Maximal voluntary strength was assessed as 1-repetition maximum (1-RM) in the leg press and chest press exercises. Three measurements were obtained and the highest of the 3 values was used as the criterion measure. Muscle fatigability was assessed as repetition to failure in the leg press and chest press exercises at 80% of previously determined 1-repetition maximum. Aerobic capacity was assessed as VO₂peak during a standardized cardiopulmonary exercise test. The endurance was measured as the time to exhaustion during a constant work rate treadmill exercise. The horizontal line in the box represents the median, the “x” in the box represents the mean, the upper and lower bounds of the box represent quartile range, the upper and lower bars represent the 95% CI, and the dots represent the values outside the 95% CI. Red, placebo arm; blue, treatment arm.

Figure 7.

Changes in intramuscular NAD, PCr recovery, and intramyocellular pH measuring using ultra high field 7 T magnetic resonance imaging. Changes in Intramuscular NAD, βATP, PCr recovery, and intramyocellular pH measured using magnetic resonance spectroscopy. Intramuscular NAD levels were measured using ultra high field 7 T magnetic resonance spectroscopy at rest and during exercise and expressed relative to βATP. The PCr concentrations in the muscle were measured using a 3 T magnetic resonance spectroscopy at rest, during a standardized leg extension exercise to fatigue, and during recovery after cessation of exercise. The rate of PCr recovery is a marker of the rate of ATP synthesis. The lowest intramuscular pH during exercise is also shown. The horizontal line in the box represents the median, the “x” in the box represents the mean, the upper and lower bounds of the box represent quartile range, the upper and lower bars represent the 95% CI, and the dots represent the values outside the 95% CI. NAD, nicotinamide adenine dinucleotide; PCr, phosphocreatine. Red, placebo arm; blue, treatment arm.