Nicotinamide riboside is so far the only approach to NAD+ upregulation for which there is published human trial data, though other trials for other approaches are underway at the present time. NAD+ declines with age, for reasons that remain comparatively poorly understood, and this has a negative impact on mitochondrial function. Thus there is considerable enthusiasm at the moment for intervening in this known manifestation of aging by tackling the proximate causes, raising NAD+ levels, but without addressing underlying causes.
Researchers here find the potential for adverse effects on glucose metabolism and white adipose tissue function to result from nicotinamide riboside supplementation, but there are a great many details involved: dietary differences and genetic differences in mice appear important as to whether problems arise, and the final sections of the discussion in the paper are worth reading closely. It is hard to say whether or not the discoveries made in mice that are reported in this open access paper will apply to humans, but the specific details suggest that investigation is warranted.
Nicotinamide riboside (NR) is a nicotinamide adenine dinucleotide (NAD+) precursor vitamin. The scarce reports on the adverse effects on metabolic health of supplementation with high-dose NR warrant substantiation. Here, we aimed to examine the physiological responses to high-dose NR supplementation in the context of a mildly obesogenic diet and to substantiate this with molecular data. An 18-week dietary intervention was conducted in male C57BL/6JRccHsd mice, in which a diet with 9000 mg NR per kg diet (high NR) was compared to a diet with NR at the recommended vitamin B3 level (control NR). Both diets were mildly obesogenic (40 en% fat). Metabolic flexibility and glucose tolerance were analyzed and immunoblotting, qRT-PCR, and histology of epididymal white adipose tissue (eWAT) were performed.
Mice fed with high NR showed a reduced metabolic flexibility, a lower glucose clearance rate and aggravated systemic insulin resistance. This was consistent with molecular and morphological changes in eWAT, including sirtuin 1 (SIRT1)-mediated PPARγ (proliferator-activated receptor γ) repression, downregulated AKT/glucose transporter type 4 (GLUT4) signaling, an increased number of crown-like structures and macrophages, and an upregulation of pro-inflammatory gene markers. In conclusion, high-dose NR induces the onset of WAT dysfunction, which may in part explain the deterioration of metabolic health.