Effects of Nicotinamide Riboside on the Airway Inflammation of Older Adults With COPD: A Randomized, Double-blind, Placebo-controlled Clinical Trial (NR-COPD)

Chronic obstructive pulmonary disease (COPD) is a major problem that affect more and more people worldwide with over three million deaths reported every year. COPD has been described as a disease of accelerated lung aging and is associated with oxidative stress and an increased inflammatory response to for instance viral infections. Therefore, in the current pandemic COPD patients are considered at high risk of COVID-19-related death and interventions in this group are crucial.

A major event in aging is the loss of nicotinamide adenine dinucleotide (NAD+)-a loss which may be important in promoting the pro-inflammatory environment that occur with aging and therefore possibly COPD. Indeed, NAD+ is emerging as a central metabolic molecule involved in multiple age-related pathways including inflammation and metabolic control. Recently, it was shown that age-associated NAD+ loss is due to macrophage M1-polarization, suggesting that NAD+ is required for macrophage activation, an event that is involved in the pulmonary inflammatory response. In humans, the therapeutic potential of boosting NAD+ levels through supplementation with one of its more bioavailable precursors has therefore gained attention.

Nicotinamide riboside (NR) is a NAD+ precursor and recent work suggests that aging can be ameliorated by even short-term treatment with NR. This vitamin B3-analog is naturally occurring, is readily taken up through oral administration and has been tested in human trials with few side effects. Notably, NR treatment in humans decreases circulating markers of inflammation. In addition, NAD+ replenishment may facilitate overall greater resilience of older patients considering the anti-aging effects of NR allowing these patients to better cope with infections. Interestingly, NR has been shown to return aging tissues to a younger state, possibly through augmentation of the sirtuin enzyme family-known to play an important role in almost all cellular functions. COPD patients have reduced sirtuin levels in the airways likely due to oxidative stress. Because sirtuins are NAD+-dependent, supplementation with NR could serve as a treatment option for patients with COPD through activation of sirtuins. In addition, NAD+ replenishment may facilitate overall greater resilience of older patients considering the anti-aging effects of nicotinamide riboside allowing these patients to better cope with infections.

The chosen dosage is 2 g per day given orally. This dose has been shown to be safe and tolerated. The dose will be split in two with ingestion of 1 g in the morning and 1 g in the evening. NR is a naturally occurring vitamin B3 analog produced by yeast and found in multiple food products at low concentration. Many organisms including humans cannot produce NR but have instead evolved methods to convert this into the central redox modulator NAD+.

The efficacy and safety of NR supplementation has been tested in a number of studies in both healthy middle-aged and older adults and in patients suffering from metabolic disease. Since this is a natural compound widely found in nature no subjects have yet developed allergic responses to the molecule, and repeated doses of up to 2 g orally per day have demonstrated an acceptable safety profile. No treatment-emergent adverse events have so far been reported for NR.