MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation

Abstract

The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.

Mitochondria are required for pro‐ageing features of the senescent phenotype

“…The interplay between mitochondria and the mTOR signalling pathway may also be involved in this process, since we have shown that mitochondria clearance reduces mTOR activity and inhibition of mTOR activity inhibits proliferation contributing to quiescence. Recent studies have also shown that the mechanisms by which mTOR impacts on the cell cycle are uncoupled from its effect on the SASP (Herranz et al , 2015; Laberge et al , 2015). While we acknowledge that mitochondrial ablation is a drastic intervention with possible widespread consequences for the cells, our results demonstrate that mitochondria play a central role in many of the transcriptional changes observed during senescence, particularly the SASP, and have, as such, a great therapeutic potential.…”

“…While mTORC1 has previously been implicated in senescence (Pospelova et al , 2012), the mechanisms regulating its activation as well as its links to the pro‐oxidant and pro‐inflammatory features of the phenotype are still unclear. Two recent studies have shown that mTOR inhibition suppressed the senescence‐associated secretion of inflammatory cytokines by suppressing the translation of SASP regulatory proteins IL‐1A and MK2 (Herranz et al , 2015; Laberge et al , 2015). On the other hand, our data show that interventions targeting the mTOR pathway affect the maintenance of a DDR via the generation of ROS, which has been shown to be necessary for the induction of senescence and the SASP (Rodier et al , 2009; Passos et al , 2010).…”

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

“…Inhibition of the SASP probably requires activation of MAPKAPK2, which would explain the decrease in pro‐inflammatory cytokines. In fact, inhibition of MAPKAPK2 by rapamycin has been shown to decrease the levels of pro‐inflammatory cytokines including IL1α, and this effect is highly dependent on mTOR activity (Laberge et al ., 2015; Herranz et al ., 2015). However, we must to understand that the SASP can vary significantly in terms of the quantity and quality of secreted proteins and other factors, depending on the insult used to trigger cell senescence (Maciel‐Baron et al ., 2016; Wiley et al ., 2016); therefore, the composition of the SASP may be vary depending on the tissue and the insult.…”

Anti‐inflammaging effects of human alpha‐1 antitrypsin

“…We irradiated HCA2 cells (human foreskin fibroblasts) to induce cell senescence (Rodier et al ., 2009; Freund et al ., 2011; Kang et al ., 2015; Laberge et al ., 2015). To test the effect of hAAT on senescence formation, HCA2 cells were treated with either hAAT (1 mg mL −1 or 2 mg mL −1 ) or 1× PBS (Fig.…”

“…The chronic inflammation induced by SASP is associated with aging‐related degenerative diseases, fibrotic pulmonary disease, and cancer (Coppe et al ., 2008; Franceschi & Campisi, 2014; Schafer et al ., 2017). DNA damage response and its downstream GATA4, p38MAPK, and mTOR pathways regulate SASP (Rodier et al ., 2009; Freund et al ., 2011; Kang et al ., 2015; Laberge et al ., 2015). All of these pathways converge on NF‐ĸB, the master transcription regulator that controls the expression of immune‐responsive genes (Zhang et al ., 2013; Guo et al ., 2014).…”