ABSTRACT
The tissue decline due to aging is associated with the deterioration of adult stem cell function. Here we show the number and proliferative activity of intestinal stem cells (ISCs) but not Paneth cells decline during aging, as does ISC function assessed ex vivo. Levels of SIRT1 and activity of mTORC1 also decline with aging. The treatment with the NAD(+) precursor nicotinamide riboside (NR) rejuvenates ISCs from aged mice and reverses an impaired ability to repair gut damage. The effect of NR is blocked by the mTORC1 inhibitor rapamycin or the SIRT1 inhibitor EX527. These findings demonstrate that small molecules affecting the NAD/SIRT1/mTORC1 axis may guide a translational path for maintenance of the intestine during aging.
Subject(s)
Adult Stem Cells/cytology , Adult Stem Cells/drug effects , Aging/drug effects , Intestinal Mucosa/cytology , NAD/metabolism , Niacinamide/analogs & derivatives , Rejuvenation , Aging/metabolism , Animals , Carbazoles/pharmacology , Cell Proliferation/drug effects , Cells, Cultured , Dextran Sulfate/administration & dosage , Dextran Sulfate/pharmacology , Intestinal Mucosa/drug effects , Male , Mice , Mice, Inbred C57BL , Niacinamide/administration & dosage , Niacinamide/antagonists & inhibitors , Niacinamide/metabolism , Niacinamide/pharmacology , Pyridinium Compounds , Sirolimus/pharmacologyABSTRACT
Nicotinamide riboside (NR) is in wide use as an NAD+ precursor vitamin. Here we determine the time and dose-dependent effects of NR on blood NAD+ metabolism in humans. We report that human blood NAD+ can rise as much as 2.7-fold with a single oral dose of NR in a pilot study of one individual, and that oral NR elevates mouse hepatic NAD+ with distinct and superior pharmacokinetics to those of nicotinic acid and nicotinamide. We further show that single doses of 100, 300 and 1,000 mg of NR produce dose-dependent increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans. We also report that nicotinic acid adenine dinucleotide (NAAD), which was not thought to be en route for the conversion of NR to NAD+, is formed from NR and discover that the rise in NAAD is a highly sensitive biomarker of effective NAD+ repletion.
Subject(s)
Niacinamide/analogs & derivatives , Administration, Oral , Animals , Biological Availability , Biomarkers/metabolism , Humans , Leukocytes, Mononuclear/metabolism , Liver/metabolism , Male , Metabolome , Mice, Inbred C57BL , Middle Aged , NAD/analogs & derivatives , NAD/blood , NAD/urine , Niacinamide/administration & dosage , Niacinamide/chemistry , Niacinamide/metabolism , Pyridinium Compounds , Vitamins/metabolismABSTRACT
Two new diterpene glycosides in addition to five known glycosides have been isolated from a commercial extract of the leaves of Stevia rebaudiana. Compound 1 (rebaudioside KA) was shown to be 13-[(O-ß-d-glucopyranosyl)oxy]ent-kaur-16-en-19-oic acid 2-O-ß-d-glucopyranosyl-ß-d-glucopyranosyl ester and compound 2, 12-α-[(2-O-ß-d-glucopyranosyl-ß-d-glucopyranosyl)oxy]ent-kaur-16-en-19-oic acid ß-d-glucopyranosyl ester. Five additional known compounds were identified, rebaudioside E, rebaudioside M, rebaudioside N, rebaudioside O, and stevioside, respectively. Enzymatic hydrolysis of stevioside afforded the known ent-kaurane aglycone 13-hydroxy-ent-kaur-16-en-19-oic acid (steviol) (3). The isolated metabolite 1 possesses the ent-kaurane aglycone steviol (3), while compound 2 represents the first example of the isomeric diterpene 12-α-hydroxy-ent-kaur-16-en-19-oic acid existing as a glycoside in S. rebaudiana. The structures of the isolated metabolites 1 and 2 were determined based on comprehensive 1D- and 2D-NMR (COSY, HSQC, and HMBC) studies. A high-quality crystal of compound 3 has formed, which allowed the acquisition of X-ray diffraction data that confirmed its structure. The structural similarities between the new metabolites and the commercially available stevioside sweeteners suggest the newly isolated metabolites should be examined for their organoleptic properties. Accordingly rebaudiosides E, M, N, O, and KA have been isolated in greater than gram quantities.
