Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

Apr 4, 2017Aging cell

Rapamycin reduces harmful secretions from aging cells through a pathway not involving Nrf2

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Abstract

Rapamycin treatment decreased SA-β-galactosidase staining in both wild-type and Nrf2 knockout mouse fibroblasts.

Nrf2 levels decreased with aging, and silencing the Nrf2 gene led to premature senescence.
In wild-type mouse fibroblasts, rapamycin increased Nrf2 levels, activated autophagy, and reduced cell senescence markers.
In Nrf2 knockout fibroblasts, rapamycin decreased cell senescence indicators but did not activate autophagy or reduce specific cell cycle arrest markers.
In vivo studies with Nrf2 knockout mice showed rapamycin decreased senescence markers and pro-inflammatory cytokines but did not significantly lower p16 levels in fat tissue.
Rapamycin also reduced activation of the Stat3 pathway, which is linked to the production of the senescence-associated secretory phenotype.

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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.

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Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

Abstract

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