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NAD.sup.+ metabolism governs the proinflammatory senescence-associated secretome
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NAD.sup.+ metabolism governs the proinflammatory senescence-associated secretome
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Journal Article
NAD.sup.+ metabolism governs the proinflammatory senescence-associated secretome
2019
Overview
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.sup.+ metabolism influences both tissue ageing and cancer. However, the role of NAD.sup.+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD.sup.+ 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.sup.+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD.sup.+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-[kappa]B activity. We conclude that NAD.sup.+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD.sup.+ augmentation should be administered with precision.
Publisher
Nature Publishing Group
