A Nampt inhibitor FK866 mimics vitamin B3 deficiency by causing senescence of human fibroblastic Hs68 cells via attenuation of NAD(+)-SIRT1 signaling.
Vitamin B3 (niacin) deficiency can cause pellagra with symptoms of dermatitis, diarrhea and dementia. However, it is unclear whether the vitamin B3 deficiency causes human aging. FK866 (a Nampt inhibitor) can reduce intracellular NAD(+) level and induce senescence of human Hs68 cells. However, the mechanisms underlying FK866-induced senescence of Hs68 cells are unclear. In this study, we used FK866 to mimic the effects of vitamin B3 deficiency to reduce the NAD(+) level and investigated the mechanisms of FK866-induced senescence of Hs68 cells. We hypothesized that FK866 induced the senescence of Hs68 cells via an attenuation of NAD(+)-silent information regulator T1 (SIRT1) signaling. We found that FK866 induced cell senescence and diminished cellular NAD(+) levels and SIRT1 activity (detected by acetylation of p53), and these effects were dramatically antagonized by co-treatment with nicotinic acid, nicotinamide, or NAD(+). In contrast, the protein expression of SIRT1, AMP-activated protein kinase, mammalian target of rapamycin, and nicotinamide phosphoribosyltransferase (Nampt) was not affected by FK866. In addition, the role of GSH in the FK866-induced cells senescence may be limited, as N-acetylcysteine did not antagonize FK866-induced cell senescence. These results suggest that FK866 induces cell senescence via attenuation of NAD(+)-SIRT1 signaling. The effects of vitamin B3 deficiency on human aging warrant further investigation.
Department of BioIndustry Technology, Dayeh University, Changhua, Taiwan.
Tuzz-Ying
TY
Song
School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.|Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan.
Shu-Lan
SL
Yeh
Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan.
Miao-Lin
ML
Hu
School of Nutrition, Chung Shan Medical University, Taichung, Taiwan.
Mei-Yau
MY
Chen
School of Nutrition, Chung Shan Medical University, Taichung, Taiwan. naeman@csmu.edu.tw.|Department of Nutrition, Chung Shan Medical University Hospital, Taichung, Taiwan. naeman@csmu.edu.tw.
Nae-Cherng
NC
Yang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000178:Acrylamides / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D009243:NAD / Q000378:metabolism* / Q000494:pharmacology; D009249:NADP / Q000378:metabolism; D009525:Niacin / Q000494:pharmacology; D009536:Niacinamide / Q000172:deficiency* / Q000494:pharmacology; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000178:Acrylamides; D016207:Cytokines; D004791:Enzyme Inhibitors; C480543:N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide; D010880:Piperidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D009243:NAD; D009536:Niacinamide; D009525:Niacin; D009249:NADP; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005978:Glutathione
Aging; FK866; Hs68 cells; NAD+; Niacin; SIRT1; Vitamin B3 deficiency