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

Abstract

SummarySenescent 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.

Oncogenic activation of Nrf2 by specific knockout of Nrf1α that acts as a dominant tumor repressor

“…Our findings demonstrate that the tumor-promoting role of Nrf2 is determined by loss of Nrf1 function, independent of those cytoprotective gene expressions. Even as a braking control of Nrf2 activity, Nrf1 may play a role for 'decision-maker' or 'executor' in the cell senescence and cancer progression, since a secretory phenotype of senescent cells occurs by a Nrf2-independent mechanism (Wang et al, 2017), albeit the relevance to Nrf1 needs to be verified.…”

LncRNA GUARDIN suppresses cellular senescence through a LRP130-PGC1α-FOXO4-p21-dependent signaling axis

“…The senolytic agent rapamycin inhibits senescence through a number of different mechanisms including but not only, inhibition of mTOR (11,12). We investigated whether GUARDIN contributes to or even cooperates with rapamycin to inhibit senescence.…”

“…Inhibition of mTOR signaling by genetic or pharmacological approaches extends lifespan of various model organisms and mice with different genetic backgrounds (7)(8)(9)(10). Indeed, treatment with the mTOR inhibitor rapamycin or its analogs (rapalogs) reduces cellular senescence (11)(12)(13)(14). Nevertheless, the molecular mechanisms involved in rapamycin-mediated inhibition of senescence are not well understood.…”

Aging and senotherapeutics

“…As indicated in Table 1, the mechanisms of the activity of the senomorphic drugs include inhibitors of NFκB and IκB kinase (IKK) 52 , Janus kinase pathway inhibitors (JAK) 52 , inhibitors of PDGF / FGF pathway and TGFBR2 / p21 pathway 42 . It has been shown that rapamycin, a drug currently used to suppress immunity in transplanted organ patients, acts as a SASP suppressant, using a mechanism that includes the inhibition of mTOR kinase, associated with the inclusion of Nrf2-dependent and independent modules 71 . Senomorphic potential is further attributed to some herbal compounds such as quercetin-3-O-beta-D glucuronide, juglanin and quercetagetin 3,4, -dimethyl ether 72,73,74 .…”