Nicotinamide mononucleotide (NNM) is an orally bioavailable NAD+ precursor that has demonstrated beneficial effects against aging and aging-associated diseases in animal models. NMN is ultimately converted to NAD+, a redox cofactor that mediates many metabolic enzymes. NAD+ also serves as the substrate for poly(ADP-ribose) polymerase (PARP) and sirtuins, and regulates various biological processes, such as metabolism, DNA repair, gene expression, and stress responses. Previous mouse models showed that NMN administration can increase NAD+ in various organs and ameliorate aging-related diseases, such as obesity, diabetes, heart failure, stroke, kidney failure, and Alzheimer’s disease through NAD+-mediated pathways. However, evidence of its effect on humans is still scarce. In this study, we conducted a placebo-controlled, randomized, double blind, parallel-group trial to investigate the safety of orally administered NMN and its efficacy to increase NAD+ levels in thirty healthy subjects. Healthy volunteers received 250 mg/day of NMN (n = 15) or placebo (n = 15) for 12 weeks, and physiological and laboratory tests were performed during this period. In addition, NAD+ and its related metabolites in whole blood were examined. Oral supplementation of NMN for 12 weeks caused no abnormalities in physiological and laboratory tests, and no obvious adverse effects were observed. NAD+ levels in whole blood were significantly increased after NMN administration. We also observed the significant rise in nicotinic acid mononucleotide (NAMN) levels, but not in NMN. We also found that the increased amount of NAD+ was strongly correlated with pulse rate before the administration of NMN. These results suggest that oral administration of NMN is a safe and practical strategy to boost NAD+ levels in humans.Clinical Trial Registration: JRCT [https://jrct.niph.go.jp/], identifier: [jRCTs041200034].

A decrease in the intracellular level of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme for metabolic activity, causes various age-related diseases and metabolic abnormalities. Both in-vivo and in-vitro studies have shown that increasing certain NAD+ levels in cell or tissue by supplementing nicotinamide mononucleotide (NMN), a precursor of NAD+, alleviates age-related diseases and metabolic disorders. In recent years, several clinical trials have been performed to elucidate NMN efficacy in humans. However, previous clinical studies with NMN have not reported on the safety of repeated daily oral administration of ≥ 1000 mg/shot in healthy adult men and women, and human clinical trials on NMN safety are limited. Therefore, we conducted a randomized, double-blind, placebo-controlled, parallel-group study to evaluate the safety of 1250 mg of β-NMN administered orally once daily for up to 4 weeks in 31 healthy adult men and women aged 20–65 years. Oral administration of β-NMN did not result in changes exceeding physiological variations in multiple clinical trials, including anthropometry, hematological, biochemical, urine, and body composition analyses. Moreover, no severe adverse events were observed during the study period. Our results indicate that β-NMN is safe and well-tolerated in healthy adult men and women an oral dose of 1250 mg once daily for up to 4 weeks.Trial registration Clinicaltrials.gov Identifier: UMIN000043084. Registered 21/01/2021. https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000049188.

Glutathione (GSH) is present in almost all human cells and has a beneficial effect on human skin brightness. Cysteinylglycine (Cys-Gly) and γ-glutamylcysteine (γ-Glu-Cys) are GSH synthesis components. In this study, we defined glutathione (GSH), cysteinylglycine (Cys-Gly), and γ-glutamylcysteine (γ-Glu-Cys) as cysteine peptide and performed a randomized, double-blind, placebo-controlled study to investigate the effects of orally administered cysteine peptide on human skin brightness using a CM-26d portable spectrophotometer in healthy males and females aged between 20 and 65 years old. Eligible participants were randomly allocated into three groups (cysteine peptide 45 mg: n = 16, 90 mg: n = 15, and placebo: n = 16). Each subject ingested six tablets every day for 12 weeks, and skin brightness was measured at 0, 4, 8, and 12 weeks. As a result, the 45 mg group exhibited arm brightening in a time-dependent manner, and a significant difference was observed compared to the placebo at week 12 (p = 0.028). Moreover, no serious adverse events and changes related to 270 mg study food were observed in the safety trial. Here, we suggest that cysteine peptide is a promising and safe compound for human skin brightness.