The effects of exercise training combined with NR supplementation on metabolic health in older individuals

The number of age-related chronic diseases (like obesity, type 2 diabetes and
cardiovascular diseases) is increasing rapidly worldwide, reaching pandemic
proportions. These age-related chronic diseases are associated with metabolic
disturbances and mitochondrial dysfunction in humans. Nicotinamide adenosine
dinucleotide (NAD) levels play an important role in energy metabolism and
mitochondrial functioning and indeed it has been shown that high concentrations
of NAD+ as well as a high NAD+/NADH ratio are strongly associated with
metabolic and mitochondrial health. In contrast, decreased NAD+ bioavailability
is reported in both ageing and obese humans as well as in diabetic mice. These
findings fuelled the idea of influencing NAD+ bioavailability in order to
improve metabolic disturbances and mitochondrial dysfunction in humans.
Supplementation with nicotinamide riboside (NR), a naturally occurring form of
vitamin B3, may provide a way to boost cellular NAD+ levels. However, in
contrast to animal studies, NR supplementation in humans has so far been
unsuccesful in improving skeletal muscle mitochondrial function, exercise
capacity or insulin sensitivity. Recently, it has been suggested that a
situation where NAD+ levels become limited, is needed for NR supplementation to
exert beneficial health effects. This situation could be achieved by combining
exercise and NR supplementation. However, studies combining NR and exercise are
lacking, which is why we would like to perform such a study here.

The primary objective of this study is to determine whether combined treatment
of exercise and NR imposes greater improvements in skeletal muscle
mitochondrial metabolism in older humans compared to exercise treatment alone.
The secondary objective of this study is to determine whether combined
treatment of exercise and NR imposes greater improvements in sleeping metabolic
rate in older humans compared to exercise treatment alone. As explorative
objectives, we will examine whether combined treatment with exercise and NR
imposes greater improvements in muscle (NAD) metabolites, energy metabolism and
physical performance.

The present study is a randomized, double-blinded, placebo-controlled double
arm longitudinal intervention study in a pre and post design.

Participants will be asked to take two pills of NR (250mg/pill), or placebo,
twice daily (two with breakfast and two with diner, a total of 4 pills/day;
1000mg/day), for 40 days. During days 17-38 of the NR intervention,
participants will perform a 3-weeks supervised exercise training program with
four ~30 min exercise sessions per week (two endurance session on a bike at
70%Wmax and two high intensity interval (HIIT) sessions. Participants will be
randomly assigned to the placebo + exercise or NR + exercise arm. To assess the
outcomes, participants will undergo three test days before the start of the NR
supplementation and repeat these three test days at the end (day 38-40) of NR
supplementation.

Before starting the intervention (exercise training + placebo or exercise
training + NR), participants will visit the University 4 times for the
screening and pre-intervention test days (total time investment 20.5 hours,
divided over 4 days). During the intervention period, subjects will visit the
University 4 times per week for 3 weeks to receive supervised exercise training
(total time investment 6 hours; 2 hours/week). The last exercise session
(training session 12) and post-intervention test day 1 will be combined on day
38. Post-intervention test day 2 will be performed on day 39-40. The time
investment for the post-intervention test days includes 20.5 hours. The main
burden of this study is the large time investment for the exercise training
period (3 weeks, 4 times/week). Moreover, the pre- and post-training test days
comprise several non-invasive and invasive measurements. The used techniques
are safe, but the muscle biopsies can cause some discomfort and may result in a
local bruise or hematoma. Likewise, blood sampling can cause a local hematoma.
The risk of infection and/or prolonged bleeding is very low due to
state-of-the-art techniques and sterility measures. Measurements performed
during the time course of the study can potentially lead to unexpected medical
findings. Subjects will be informed about such a finding and possible advised
to contact a doctor about this. If a subject does not want to be informed about
incidental findings, participation in this study is not possible.