NAD+ metabolism governs the proinflammatory senescence-associated secretome

Autor: Shuai Wu, Katherine M. Aird, Joseph A. Zundell, David W. Speicher, Takeshi Fukumoto, David C. Schultz, Ken-ichi Noma, Zachary T. Schug, Osamu Iwasaki, Lena Lau, Rugang Zhang, Timothy Nacarelli, Nail Fatkhutdinov, Hsin Yao Tang, Joseph A. Baur, Andrew V. Kossenkov, Gregory David
Rok vydání: 2019
Předmět:
Zdroj: Nature Cell Biology. 21:397-407
ISSN: 1476-4679
1465-7392
Popis: Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.
Databáze: OpenAIRE
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