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MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation
Open accessAbstract
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.
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In the citing paper
“The NF- κB, p38, mTOR and C/EBPβ signalling pathways are major components of the SASP 63-67 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [66]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Rapamycin, an immunosuppressant, decreases the SASP and maintains cell cycle arrest but does not kill Sncs (24).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [24]
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In the citing paper
“Treatment with rapamycin (and its analogue RAD001)232 attenuated the protumorigenic SASP230, prevented senescence233, impaired SASP-mediated immune recognition of oncogene-expressing cells and ameliorated liver dysfunction in naturally aged mice231.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [231]
The cited source says what the claim attributes to it.
In the citing paper
“In addition, the nutrient sensing pathways, mTOR and NAD, are involved in SASP regulation.56, 57, 58”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [56]
The cited source says what the claim attributes to it.
In the citing paper
“In various preclinical studies, the mTOR inhibitor rapamycin might have the context-dependent potential to induce senescence 45 , diminish NF-κB activity 65,66 , suppress the pro-inflammatory SASP at the translational level, and limit the growth-promoting effect of senescent bystander fibroblasts on prostate tumours 66 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [66]
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In the citing paper
“and the serine/threonine kinase MK2, which indirectly stabilizes many cytokine-encoding transcripts231.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [231]
Experimental — accuracy not yet measuredIn the citing paper
“It also differentially regulates translation of IL-1A, the master regulator of SASP that subsequently engages IL-6/IL-8 (Orjalo et al., 2009; Laberge et al., 2015) and MAP kinase-activated protein kinase 2 (MAPKAP2) through 4EBP1, a translation repressor protein (Herranz et al., 2015).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Laberge et al., 2015
In the citing paper
“Inhibition of mTOR by rapamycin suppresses the secretion of inflammatory cytokines by senescent cells (Herranz et al., 2015; Laberge et al., 2015).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Laberge et al., 2015
In the citing paper
“IL-1α is the key driver of the SASP 79,80 , with upstream expression controlled in part by ATM/ATRmediated liberation of GATA4 from p62-directed autophagy 81 and/or an mTORC1-dependent pathway 82 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [82]
In the citing paper
“As an alternative approach, reduction of the SASP through “senostatic” or “senomorphic” approaches may be less toxic and has been shown to be effective in animal models (Birch and Passos, 2017; Georgilis et al., 2018; Laberge et al., 2015; Laberge et al., 2012; Niedernhofer and Robbins, 2018; Xu et al., 2015; Yoshimoto et al., 2013).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Laberge et al., 2015
In the citing paper
“Hypoxia impairs mammalian target of rapamycin (mTOR) activity, leading to reduced IL-1α translation to support NF-κB activity and SASP induction [162,163].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [163]
In the citing paper
“The increase in mTORC1 activity is essential for implementing the SASP by modulating the translation of IL-1α and MAP kinase-activated protein kinase 2 (MAPKAPK2) [162,163].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [163]
In the citing paper
“the secretome of senescent tumor cells can also drive tumor progression by promoting inflammation and potentially stimulating the growth and invasiveness of nearby tumor cells [148,154,163].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [163]
In the citing paper
“SASP inhibition by the mTOR inhibitor rapamycin can suppress the capacity of senescent fibroblasts to stimulate prostate tumor growth in mice [163].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [163]
In the citing paper
“inhibition of mTOR by rapamycin selectively inhibits the SASP and SA β‐gal staining of senescent cells without affecting their cell cycle arrest”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Laberge et al., 2015
In the citing paper
“Rapamycin treatment suppressed SA-βgal activity (~ 50%) in irradiated cells (Fig. 5H), as expected [68]”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [68]
In the citing paper
“The mTOR pathway is a negative regulator of autophagy and is implicated in cellular senescence [67], most notably through SA-βgal activity and the expression of p16 and p21 markers [67], [68].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [68]
In the citing paper
“These factors are commonly described as the mediator of the pro-disease functions of senescent cells in vivo59.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [59]
In the citing paper
“These in vitro observations have been further substantiated in vivo, where co-injection of senescent fibroblasts has been shown to increase tumourigenicity in xenograft models, including primary breast cancer tissues.26,45–47”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [46]
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Metadata
- Authors
- Laberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., Limbad, C., Demaria, M., Li, P., Hubbard, G. B., Ikeno, Y., Javors, M., Desprez, P.-Y., Benz, C. C., Kapahi, P., Nelson, P. S., & Campisi, J.
- Affiliations
- Chinese Academy of Sciences (CN)
- Buck Institute for Research on Aging (US)
- The University of Texas at San Antonio Health Science Center (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Campisi, Judith
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2015-07-06
- Volume
- 17
- Issue
- 8
- Pages
- 1049-1061
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC4691706
- OpenAlex
- W1033197108
- Cited by
- 1,160
- References
- 72
- Citations by year
- 2026: 119 · 2025: 114 · 2024: 109 · 2023: 99 · 2022: 137 · 2021: 122 · 2020: 112 · 2019: 87 · 2018: 89 · 2017: 78 · 2016: 72 · 2015: 22
- FWCI
- 64.11
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-04-06)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (AG041122, R56AG009909, AG017242, AG-09909, RL1AG032113, AG045288, P01AG025901, R01AG045835, R37AG009909, P01AG041122, K99AG045288, AG032113, P01AG017242, AG000266-16, AG025901, P30AG013319, P30AG044271, T32AG000266)
- National Cancer Institute (CA097186, CA155679, R21CA155679, U24CA143858, CA165573, R01CA165573, CA071468, CA164188, R01CA071468, CA143858, U01CA164188, P50CA097186)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- mTOR, TORC1, rapamycin, senescence-associated secretory phenotype, cellular senescence, interleukin-6, NF-κB, senescence-associated inflammation, age-related cancer, longevity, translational regulation
- MeSH terms
- Animals, Anti-Inflammatory Agents, Antineoplastic Agents, Dose-Response Relationship, Drug, Fibroblasts, Humans, Male, Mitoxantrone, Phenotype, Prostatic Neoplasms, RNA, Messenger, Time Factors, Transcription, Genetic, Transfection, Interleukin-6, Up-Regulation, Gene Expression Regulation, Neoplastic, NF-kappa B, Mice, SCID, Cellular Senescence, Inflammation Mediators, Sirolimus, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Interleukin-1alpha, TOR Serine-Threonine Kinases
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