RESUMO
Cellular immortalization is a complex process that requires multiple genetic alterations to overcome restricting barriers, including senescence. Not surprisingly, many of these alterations are associated with cancer; two tumor suppressor pathways, the cellular tumor antigen p53 and p16-Retinoblastoma (RB) pathways, are the best-characterized examples, but their mutations alone are known to be insufficient to drive full immortalization. En et al. identified a role for the lamin B receptor (LBR) in promoting cellular proliferation and immortalization in p53- and RB-deficient cells by maintaining their genome integrity and suppressing senescence. Thus, modulation of LBR could be exploited to treat cancer and potentially also to promote cell rejuvenation.
Assuntos
Senescência Celular , Instabilidade Genômica , Receptor de Lamina B , Proteína Supressora de Tumor p53 , Senescência Celular/genética , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Animais , Proteína do Retinoblastoma/genética , Proteína do Retinoblastoma/metabolismo , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologiaRESUMO
Whereas cholesterol is vital for cell growth, proliferation, and remodeling, dysregulation of cholesterol metabolism is associated with multiple age-related pathologies. Here we show that senescent cells accumulate cholesterol in lysosomes to maintain the senescence-associated secretory phenotype (SASP). We find that induction of cellular senescence by diverse triggers enhances cellular cholesterol metabolism. Senescence is associated with the upregulation of the cholesterol exporter ABCA1, which is rerouted to the lysosome, where it moonlights as a cholesterol importer. Lysosomal cholesterol accumulation results in the formation of cholesterol-rich microdomains on the lysosomal limiting membrane enriched with the mammalian target of rapamycin complex 1 (mTORC1) scaffolding complex, thereby sustaining mTORC1 activity to support the SASP. We further show that pharmacological modulation of lysosomal cholesterol partitioning alters senescence-associated inflammation and in vivo senescence during osteoarthritis progression in male mice. Our study reveals a potential unifying theme for the role of cholesterol in the aging process through the regulation of senescence-associated inflammation.
Assuntos
Inflamação , Lisossomos , Masculino , Animais , Camundongos , Inflamação/metabolismo , Regulação para Cima , Lisossomos/metabolismo , Senescência Celular/fisiologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Mamíferos/metabolismoRESUMO
Natural products and their derivatives historically represent alternatives to conventional synthetic molecules for pharmacotherapy, ranging from cancer chemotherapeutics to cosmetic ingredients that exert anti-aging activities. Cellular senescence is considered a main driver of skin aging, yet natural products that target skin senescence in a specific manner are not thoroughly explored. Here, we performed a focused compound screen to identify natural products that exert anti-senescence effects. We found that Isatis tinctoria, woad extracts, displayed a senolytic effect on senescent human skin fibroblasts. Furthermore, treatment with woad extracts attenuated the expression of pro-inflammatory senescence-associated secretory phenotype (SASP), showing a senostatic activity. Intriguingly, woad extracts displayed only a marginal cytotoxic effect toward senescent human lung fibroblasts. Thus, our results reveal the potential activities of woad extracts for targeting skin senescence and suggest that woad extracts could be an attractive ingredient for cosmetics to prevent skin aging.