SIRT1 Controls Enteroendocrine Progenitor Cell Proliferation in High-Fat Diet-Fed Mice.

BACKGROUND & AIMS: We aimed to investigate how sirtuin 1 (SIRT1), a conserved mammalian Nicotinamide adenine dinucleotide+-dependent protein deacetylase, regulates the number of enteroendocrine cells (EECs). EECs benefit metabolism, and their increase potentially could treat type 2 diabetes and obesity. METHODS: We used mice with specific Sirt1 disruption in the intestinal epithelium (VilKO, villin-Cre+, and Sirt1flox/flox mice) or enteroendocrine progenitor cells (EEPCs) (NgnKO, neurogenin 3-Cre+, Sirt1flox/flox mice) and mice with increased SIRT1 activity owing to overexpression (Sir2d mice) or 24-hour fasting. Mice were fed a high-fat diet (HFD), and blood glucagon-like peptide 1 (GLP-1) and glucose levels were measured. Intestinal tissues, EECs, and formed organoids were analyzed using quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS: In HFD-fed VilKO and NgnKO mice, an increase in EECs (42.3% and 37.2%), GLP-1- or GLP-2-producing L cells (93.0% and 61.4%), and GLP-1 (85.7% and 109.6%) was observed after glucose loading, explaining the improved metabolic phenotype of HFD-VilKO mice. These increases were associated with up-regulated expression of neurogenin 3 (EEPC marker) in crypts of HFD-VilKO and HFD-NgnKO mice, respectively. Conversely, Sir2d or 24-hour fasted mice showed a decrease in EECs (21.6%), L cells (41.6%), and proliferative progenitor cells. SIRT1 overexpression- or knockdown-mediated change in the progenitor cell proliferation was associated with Wnt/ß-catenin activity changes. Notably, Wnt/ß-catenin inhibitor completely suppressed EEC and L-cell increases in HFD-VilKO mice or organoids from HFD-VilKO and HFD-NgnKO mice. CONCLUSIONS: Intestinal SIRT1 in EECs modulates the EEPC cycle by regulating ß-catenin activity and can control the number of EECs in HFD-fed mice, which is a previously unknown role.

Blood levels of nicotinic acid negatively correlate with hearing ability in healthy older men.

BACKGROUND: Age-related hearing loss (ARHL) is a common phenomenon observed during aging. On the other hand, the decrease in Nicotinamide adenine dinucleotide (NAD +) levels is reported to be closely related to the age-related declines in physiological functions such as ARHL in animal studies. Moreover, preclinical studies confirmed NAD + replenishment effectively prevents the onset of age-related diseases. However, there is a paucity of studies on the relationship between NAD+ metabolism and ARHL in humans. METHODS: This study was analyzed the baseline results of our previous clinical trial, in which nicotinamide mononucleotide or placebo was administered to 42 older men (Igarashi et al., NPJ Aging 8:5, 2022). The correlations between blood levels of NAD+-related metabolites at baseline and pure-tone hearing thresholds at different frequencies (125, 250, 500, 1000, 2000, 4000, and 8000 Hz) in 42 healthy Japanese men aged > 65 years were analyzed using Spearman's rank correlation. Multiple linear regression analysis was performed with hearing thresholds as the dependent variable and age and NAD+-related metabolite levels as independent variables. RESULTS: Positive associations were observed between levels of nicotinic acid (NA, a NAD+ precursor in the Preiss-Handler pathway) and right- or left-ear hearing thresholds at frequencies of 1000 Hz (right: r = 0.480, p = 0.001; left: r = 0.422, p = 0.003), 2000 Hz (right: r = 0.507, p < 0.001, left: r = 0.629, p < 0.001), and 4000 Hz (left: r = 0.366, p = 0.029). Age-adjusted multiple linear regression analysis revealed that NA was an independent predictor of elevated hearing thresholds (1000 Hz (right): p = 0.050, regression coefficient (ß) = 1610; 1000 Hz (left): p = 0.026, ß = 2179; 2000 Hz (right): p = 0.022, ß = 2317; 2000 Hz (left): p = 0.002, ß = 3257). Weak associations of nicotinic acid riboside (NAR) and nicotinamide (NAM) with hearing ability were observed. CONCLUSIONS: We identified negative correlations between blood concentrations of NA and hearing ability at 1000 and 2000 Hz. NAD+ metabolic pathway might be associated with ARHL onset or progression. Further studies are warranted. TRIAL REGISTRATION: The study was registered at UMIN-CTR (UMIN000036321) on 1st June 2019.

Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men.

Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD + ) upon the administration of nicotinamide mononucleotide (NMN), an NAD + precursor, can mitigate aging-related disorders; however, human data on this are limited. We investigated whether the chronic oral supplementation of NMN can elevate blood NAD + levels and alter physiological dysfunctions in healthy older participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test, which should be validated in larger studies; however, NMN exerted no significant effect on body composition. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.