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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NF-κB, p38, mTOR and C/EBPβ signalling pathways are major components of the SASP.
“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]
The Results sections on rapamycin and NF-κB activity support roles for mTOR and NF-κB in regulating the SASP. The cited passages do not establish p38 or C/EBPβ as major SASP pathways, so this paper supports only part of the four-pathway statement. No page numbers are available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRapamycin lowers the senescence-associated secretory phenotype and preserves cell-cycle arrest but does not kill senescent cells.
“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]
Rapamycin and its analogue RAD001 reduced the protumorigenic SASP, prevented senescence, impaired SASP-mediated immune recognition of oncogene-expressing cells, and improved liver dysfunction in naturally aged mice.
“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 nutrient sensing pathways mTOR and NAD are involved in SASP regulation.
“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 mTOR inhibitor rapamycin has the context-dependent potential to induce senescence, diminish NF-κB activity, suppress the pro-inflammatory SASP at the translational level, and limit the growth-promoting effect of senescent bystander fibroblasts on prostate tumours.
“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]
The serine/threonine kinase MK2 indirectly stabilizes many transcripts that encode cytokines.
“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]
The Results sections on IL1A translation and NF-κB activity discuss changes in cytokine transcript abundance and translation, but do not address MK2 or stabilization of cytokine-encoding transcripts. Searches for MK2 and its full kinase name found no passage supporting the attributed mechanism. (LLM, conf=0.72)
Experimental — accuracy not yet measuredmTOR differentially regulates translation of IL-1A and MAPKAP2 through 4EBP1.
“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
Inhibition of mTOR by rapamycin suppresses secretion of inflammatory cytokines by senescent cells.
“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
IL-1α is the key driver of the SASP, with upstream expression controlled in part by ATM/ATR-mediated liberation of GATA4 from p62-directed autophagy and/or an mTORC1-dependent pathway.
“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]
Reducing the SASP through senostatic or senomorphic approaches may be less toxic and has been effective in animal models.
“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
Hypoxia impairs mTOR activity, leading to reduced IL-1α translation to support NF-κB activity and SASP induction.
“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]
An increase in mTORC1 activity is essential for implementing the SASP by modulating translation of IL-1α and MAPKAPK2.
“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]
The secretome of senescent tumor cells can drive tumor progression by promoting inflammation and potentially stimulating growth and invasiveness of nearby tumor cells.
“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]
SASP inhibition by mTOR inhibitor rapamycin can suppress capacity of senescent fibroblasts to stimulate prostate tumor growth in mice.
“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]
Inhibition of mTOR by rapamycin selectively inhibits SASP and SA β-gal staining of senescent cells without affecting cell cycle arrest.
“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
Rapamycin treatment suppressed SA-βgal activity (~50%) in irradiated cells.
“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]
The mTOR pathway is a negative regulator of autophagy and is implicated in cellular senescence, notably through SA-βgal activity and expression of p16 and p21 markers.
“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]
These factors are commonly described as the mediator of the pro-disease functions of senescent cells in vivo.
“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]
Co-injection of senescent fibroblasts increases tumourigenicity in xenograft models, including primary breast cancer tissues.
“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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“Thus, these results indicate that BRD4 inactivation uncouples the SASP from the cell-cycle arrest during senescence, and imply that BET inhibitors may be valuable at modulating SASP activity in vivo, such as has been recently reported for the mTOR inhibitor rapamycin (28, 29).”
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“Rapamycin, an immunosuppressant, decreases the SASP and maintains cell cycle arrest but does not kill Sncs (24).”
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BackgroundMethodSkin Aging, Cellular Senescence and Natural Polyphenols
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Cellular senescence and SASP in tumor progression and therapeutic opportunities
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- 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
- Health Sciences › Medicine › Physiology › 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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