| First Author | Nacarelli T | Year | 2019 |
| Journal | Nat Cell Biol | Volume | 21 |
| Issue | 3 | Pages | 397-407 |
| PubMed ID | 30778219 | Mgi Jnum | J:282984 |
| Mgi Id | MGI:6384077 | Doi | 10.1038/s41556-019-0287-4 |
| Citation | Nacarelli T, et al. (2019) NAD(+) metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol 21(3):397-407 |
| abstractText | 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-kappaB 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. |
