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Objectives Nicotinamide adenine dinucleotide (NAD+) coenzymes are the central regulators of cellular metabolism. While the NAD + system is dysregulated by metabolic stress and age-related conditions, nicotinamide riboside (NR) augments NAD + levels and may contribute to the reduction of inflammation. As advancing age is often accompanied by chronically elevated inflammation (i.e., ‘inflammaging’), targeting chronic inflammation may be a viable strategy to preserve aspects of health and function. The objective of this study was to investigate the clinical evidence of NR's mitigation of inflammation in humans. Methods We systematically evaluated peer-reviewed, published clinical trials of oral NR supplementation that included analysis of inflammatory markers. There were no restrictions for age, sex, health status, or use of other bioactives. Key study details were assessed to compare experimental designs and results. Results We identified 5 clinical trials of oral NR supplementation that measured inflammation. There was substantial heterogeneity in inflammatory endpoints evaluated. NR dose and treatment duration ranged from 1–2 g/day and 5-d– 6-wks, respectively. Participants varied in age (18–78 years) and health status. In one study, NR was given as part of a nutritional cocktail, while NR was the sole intervention in the remaining studies. Of the 3 studies assessing circulating inflammatory markers, two investigated IL-6 and reported significant reductions in its levels with NR treatment, while effects on MCP-1 and TNF-α were inconsistent. NR significantly lowered gene expression of IL-6 and IL-18, but not NLRP3 or IL-1B in peripheral blood mononuclear cells in one study. Another study documented significant reductions in the gene expression of IFNB and CXCL10, but no change to TNFA expression, in the monocytes of the NR-treated group. Moreover, NR treatment led to lower concentrations of IFNβ, but not TNF-α, in monocytes.\ Conclusions Preliminary evidence suggests that NR may improve some inflammatory measures, with potential for more robust effects among populations with compromised NAD + and higher inflammation status, e.g., elderly or diseased. More work is needed to clarify which inflammatory markers are targeted by NR, and the extent to which they are further modified by dose and participant demographics. Funding Sources N/A.

Objectives Introduction: Demonstrating the benefits of nutritional supplements on healthy aging has been challenging, as research has tended to focus on affecting disease rather than health optimization. We propose that by applying the frameworks of intrinsic capacity and the hallmarks of aging, one can more definitively demonstrate measurable benefits of a nutritional supplement. To test the validity of this approach, research previously and actively being conducted on nicotinamide riboside (NR), a precursor to the essential coenzyme nicotinamide adenine dinucleotide (NAD) was evaluated. NAD levels have been shown to decrease with age, thus NR is widely promoted as a nutritional solution for healthy aging. Objective: The goal of this analysis was to determine if the combined frameworks of intrinsic capacity and the hallmarks of aging can be used to demonstrate the benefits of NR supplementation. Methods For preliminary assessment, a database of current and past NR research was developed. Each study was categorized as applicable to one or more of the proposed framework categories. The data were graphed by category to demonstrate historical growth in the research categories. Results Preliminary results indicated that 30.6% of studies in the database could be categorized as including research on one or more of the hallmarks of aging; the most dominant category was that of mitochondrial dysfunction, encompassing 27 preclinical and 7 clinical studies, followed by genomic instability (17,1), altered intercellular communication (9,2), deregulated nutrient sensing (8,3), stem cell exhaustion (11,0), epigenetic alterations (2,0), and telomere attrition (2,0), respectively. More than half of the studies could also be categorized as relating to one or more domains of intrinsic capacity specifically Vitality (50,2) and Locomotion (19,4), followed by Cognition (5,1), Sensory (4,0), and Psychological (1,0), (preclinical, clinical) respectively. Conclusions NR research can be applied to multiple categories of the hallmarks of aging as well as intrinsic capacity domains, demonstrating the benefits of NR supplementation Positive results from previous and current research will further validate NR as a multidimensional healthy aging supplement. Funding Sources None.

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