NAD+ metabolism governs the proinflammatory senescence-associated secretome.
Nat Cell Biol
; 21(3): 397-407, 2019 03.
Article
em En
| MEDLINE
| ID: mdl-30778219
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Citocinas
/
Senescência Celular
/
Mediadores da Inflamação
/
NAD
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article