Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism
| Autor: | Bharath Sunchu, Laura M. Beaver, James Shoaf, Viviana I. Pérez, Emily Ho, Lynda Bradley, Christiane V. Löhr, Ivana Dang, Rong Wang, Stephanie Zhao, Zhen Yu, Kelsey Caples |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Senescence Cyclin-Dependent Kinase Inhibitor p21 Male STAT3 Transcription Factor Aging Cell cycle checkpoint NF-E2-Related Factor 2 Cell Primary Cell Culture Adipose tissue Biology SASP Nrf2 03 medical and health sciences Mice medicine Autophagy Gene silencing Animals Humans STAT3 PI3K/AKT/mTOR pathway Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 β‐gal Cell Proliferation Mice Knockout Sirolimus rapamycin TOR Serine-Threonine Kinases Cell Biology Original Articles Fibroblasts beta-Galactosidase Cell biology 030104 developmental biology medicine.anatomical_structure Phenotype Gene Expression Regulation cell senescence biology.protein Cytokines Female Original Article Signal Transduction |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 |
| Popis: | Summary Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild-type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA-β-galactosidase (β-gal) staining, senescence-associated secretory phenotype (SASP), and p16 and p21 molecular markers. In Nrf2KO fibroblasts, however, rapamycin still decreased β-gal staining and the SASP, but rapamycin did not activate the autophagy pathway or decrease p16 and p21 levels. These observations were further confirmed in vivo using Nrf2KO mice, where rapamycin treatment led to a decrease in β-gal staining and pro-inflammatory cytokines in serum and fat tissue; however, p16 levels were not significantly decreased in fat tissue. Consistent with literature demonstrating that the Stat3 pathway is linked to the production of SASP, we found that rapamycin decreased activation of the Stat3 pathway in cells or tissue samples from both WT and Nrf2KO mice. Our data thus suggest that cell senescence is a complex process that involves at least two arms, and rapamycin uses Nrf2 to regulate cell cycle arrest, but not the production of SASP. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |