Abstract
Sterile inflammation, also known as ‘inflammaging’, is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1’s role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) innate immune response pathway independently of its enzymatic activity. TXNRD1 localizes to cytoplasmic chromatin fragments and interacts with cGAS in a senescence-status-dependent manner, which is necessary for the SASP. TXNRD1 enhances the enzymatic activity of cGAS. TXNRD1 is required for both the tumor-promoting and immune surveillance functions of senescent cells, which are mediated by the SASP in vivo in mouse models. Treatment of aged mice with a TXNRD1 inhibitor that disrupts its interaction with cGAS, but not with an inhibitor of its enzymatic activity alone, downregulated markers of inflammaging in several tissues. In summary, our results show that TXNRD1 promotes the SASP through the innate immune response, with implications for inflammaging. This suggests that the TXNRD1–cGAS interaction is a relevant target for selectively suppressing inflammaging.
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Data availability
RNA-seq datasets of IMR90 cells have been deposited in the Gene Expression Omnibus (GEO) under accession number GSE202664. RNA-seq datasets of mouse tissues have been deposited in the GEO under accession number GSE204841. MS proteomics data have been deposited in the MassIVE (http://massive.ucsd.edu) and ProteomeXchange (http://www.proteomexchange.org) data repositories with accession numbers MSV000089650 and PXD034505, respectively. All other data supporting the findings of this study are available within this article and its supplementary materials. Source data are provided with this paper.
Code availability
The software and algorithms for data analyses used in this study are all well-established from previous work and are referenced throughout the article.
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Acknowledgements
We thank F. Keeney at The Wistar Institute Imaging Facility for qualifying NLRP3 staining in mouse tissues. This work was supported by the US National Institutes of Health (grants R01CA160331 and R01CA276569 to R.Z.; P01AG031862 to P.D.A., S.L.B, R.M., D.S. and R.Z.; R50CA221838 to H.-Y.T.; and R50CA211199 to A.V.K.), US Department of Defense (OC220011 to X.H.) and Cancer Prevention and Research Institute of Texas (CPRIT Scholar in Cancer Research RR230005 to R.Z.). Support of core facilities was provided by the Cancer Center Support Grant (CCSG) CA010815 to The Wistar Institute and P30CA016672 to the University of Texas MD Anderson Cancer Center. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
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X.H., B.Z. and R.Z. designed the experiments. X.H., B.Z., M.T., L.L., E.L.M., X.X., C.F., H.P. and H.-Y.T. performed the experiments and analyzed the data. A.V.K. performed the bioinformatics analysis. A.H., D.S., R.M., K.S.Z. and S.L.B. contributed key experimental materials and participated in the study design. X.H., H.-Y.T., A.V.K. and R.Z. wrote the paper. D.W.S., P.D.A., S.L.B. and R.Z. supervised the study. R.Z. conceived the study.
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Extended data
Extended Data Fig. 1 Purification of CCFs from oncogene-induced senescent cells.
a-c, IMR90 cells were induced into senesce by oncogenic H-RASG12V and were subjected to SA-β-gal staining (a). SA-β-gal positive cells were quantified in the indicated groups (b). Expression of the indicated proteins in the indicated control senescent cells was analyzed by immunoblot (c). Scale bar = 100 μm. d, Schematics of the protocol used for purification of CCFs. e, Intensity heatmap of the thioredoxin-related proteins enriched in CCFs. Sorted by number of the detected peptides with two independent biological repeats. Data represent mean ± s.e.m. n = 3 biologically independent experiments unless otherwise stated. P-values were calculated using a two-tailed t test.
Extended Data Fig. 2 TXNRD1 localizes into CCFs during senescence.
a, Representative images of immunostaining for γH2AX and TXNRD1 in control and oncogenic RAS-induced senescent IMR90 cells. The arrow indicates an example of γH2AX and TXNRD1 positive CCFs in RAS-induced senescent cells. Scale bar = 10 μm. b, Representative images of immunostaining for γH2AX, cGAS and TXNRD1 in young (PD26) and replicative senescent (PD72) IMR90 cells. The arrow indicates an example of γH2AX, cGAS and TXNRD1 positive CCFs in replicative senescent cells. Scale bar = 10 μm. c, Quantification of (a) and (b). d,e, Representative images of immunostaining for γH2AX, cGAS and TXNRD1 in control and oncogenic RAS-induced senescent BJ human fibroblasts. The arrows indicate examples of γH2AX, cGAS and TXNRD1 positive CCFs in RAS-induced senescent cells (d). γH2AX-positive CCFs that are positive for TXNRD1 in senescent BJ cells were quantified (e). Scale bar = 10 μm. Data represent mean ± s.e.m. n = 3 biologically independent experiments.
Extended Data Fig. 3 Inhibition of TXNRD1 doesn’t affect senescence-associated cell growth arrest.
a, Immunoblot of the indicated proteins in oncogenic RAS-induced senescent IMR90 cells with or without TXNRD1 knockdown. b, γH2AX positive CCFs were quantified in oncogenic RAS-induced senescent IMR90 cells with or without TXNRD1 knockdown. n = 4 biologically independent experiments. c, Immunoblot of the indicated protein in control proliferating and oncogenic RAS-induced senescent IMR90 cells with or without TXNRD1 knockdown or treatment with a pharmacological TXNRD1 inhibitor Tri-1 (5 μM). d, e, Control and oncogenic RAS-induced senescent IMR90 cells with or without TXNRD1 knockdown or treatment with a pharmacological TXNRD1 inhibitor Tri-1 (5 μM) were subjected to SA-β-gal staining or colony formation assays (d). SA-β-gal positive cells were quantified in the indicated groups (e). Scale bar = 100 μm. n = 3 biologically independent experiments. Data represent mean ± s.e.m.
Extended Data Fig. 4 TXNRD1 is required for cGAS-STING activation during therapy-induced senescence.
a, Immunoblot of the indicated proteins in cisplatin-induced senescent PEO1 cells with or without TXNRD1 knockdown. b-d, Representative images of immunostaining for cGAS and γH2AX in cisplatin-induced senescent PEO1 cells with or without TXNRD1 knockdown or treatment with Tri-1 or vehicle control (b). White arrows indicate examples of cGAS and γH2AX positive CCFs in control cells, while the yellow arrows indicate examples of cGAS negative, γH2AX positive CCFs in TXNRD1 knockdown or Tri-1 treated cells. γH2AX-positive CCFs that are positive for cGAS from senescent PEO1 cells with or without TXNRD1 knockdown were quantified (c). γH2AX-positive CCFs that are positive for cGAS from senescent PEO1 cells with or without TXNRD1 inhibitor Tri-1 treatment were quantified (d). Scale bar = 10 μm. e, f, Immunoblot of the indicated protein in control and cisplatin-induced senescent PEO1 cells with or without TXNRD1 knockdown or treatment with a pharmacological TXNRD1 inhibitor Tri-1 (5 μM) (e). In addition, cellular 2’ 3’-cGAMP levels were measured in the indicated cells (f). Data represent mean ± s.e.m. n = 3 biologically independent experiments. P-values were calculated using a two-tailed t test.
Extended Data Fig. 5 TXNRD1 inhibition during senescence induction suppresses the SASP.
a, Schematic of experimental design for determining the effects of TXNRD1 inhibition during induction of senescence in IMR90 cells. b, Heatmap of the SASP genes that were significantly suppressed by both TXNRD1 knockdown and Tri-1 treatment based on RNA-seq analysis. The relative expression levels per replicate and average fold change differences are shown (n = 3 biologically independent experiments). c, d, Expression of the indicated SASP genes in control and oncogenic RAS-induced senescent IMR90 cells with or without TXNRD1 knockdown (c) or Tri-1 treatment (d) was determined by RT-qPCR. n = 4 biologically independent experiments. e, f, Expression of the indicated proteins in oncogenic RAS-induced senescent IMR90 cells with or without TXNRD1 knockout was determined by immunoblot (e), and expression of the indicated SASP genes was determined by RT-qPCR (f). Data represent mean ± s.e.m. n = 3 biologically independent experiments unless otherwise stated. P-values were calculated using a two-tailed t test.
Extended Data Fig. 6 TXN knockdown does not affect cGAS localization or activity.
a–d, Expression of the indicated proteins in IMR90 cells induced to undergo senescence by oncogenic RAS expressing shControl or shTXN (a). The indicated cells were stained for γH2AX and cGAS. DAPI counter staining was used to visualized nuclei. Arrows point to examples of cGAS positive CCFs (b), which was quantified (c). Further, 2’3’-cGAMP levels in the indicated cells were quantified (d). Scale bar = 10 μm. Data represent mean ± s.e.m. n = 3 biologically independent experiments.
Extended Data Fig. 7 TXNRD1 is required for SASP function in vivo.
a, TOV21G ovarian cancer cell growth in conditioned medium collected from control and senescent IMR90 cells with or without TXNRD1 knockdown or Tri-1 treatment. After 7 days of incubation, the cell numbers were determined and normalized to the numbers of the cells cultured in conditioned media collected from control proliferating IMR90 cells. Data represent mean ± s.e.m. n = 3 biologically independent experiments unless otherwise stated. P-values were calculated using a two-tailed t test. b, c, TOV21G and oncogene-induced senescent IMR90 cells with or without TXNRD1 inhibition were subcutaneously co-injected into the right dorsal flank of 6–8-week-old NSG female mice (n = 5 biologically independent mice per group). Shown are images of tumors dissected in the indicated groups at the end of experiments (b). Tumor growth in the indicated treatment groups was measured at the indicated time points (c). Data represent mean ± s.e.m. d, Validation of Txnrd1 knockdown by immunostaining in mouse NIH 3T3 cells. Arrows point to dsRed-expressing shRen control, shTxnrd1 #1 and shTxnrd1 #2. Scale bars = 10 μm. The experiment was repeated twice with similar results.
Extended Data Fig. 8 Tri-1 suppresses NLRP3 positivity in replicative senescent cells.
a, b, Knockdown of Caspase 1 (a) and GSDMD (b) in senescent IMR90 cells was validated by RT-qPCR. n = 4 biologically independent experiments. c, Expression of IL1β in ER-RAS induced (by 4-OHT) senescent IMR90 cells with or without the knockdown of GSDMD or Caspase 1 was determined by RT-qPCR analysis. n = 3 biologically independent experiments. d, e, Representative images of immunostaining for NLRP3 in ER-RAS induced (by 4-OHT) senescent IMR90 cells with or without the indicated treatments (d). NLRP3 positive cells were quantified (e). n = 3 biologically independent experiments. Scale bars = 10 μm. f, g, Representative images of immunostaining for ASC to visualize inflammasome formation in the indicated control and ER-RAS induced (by 4-OHT) senescent IMR90 cells (f). ASC speck positive cells were quantified (g). n = 3 biologically independent experiments. Nigericin, a known inducer of inflammasome formation, was used as a positive control (10 μM for 4 hours). Scale bars = 10 μm. h, Expression of Txnrd1 in young (4 months) and aged mice (22 months) with or without Tri-1 treatment was determined by RT-qPCR analysis. n = 4 biologically independent mice per group. i, j, Immunoblot of the indicated proteins in the ovary tissues harvested from young (4 months) and aged mice (22 months) (i). The intensity of the indicated proteins was quantified by NIH ImageJ software and normalized against a loading control β-actin expression (j). n = 5 biologically independent mice per group. Data represent mean ± s.e.m. P-values were calculated using a two-tailed t test.
Extended Data Fig. 9 Tri-1 and auranofin do not affect p16 and p53 signatures in aged mouse ovaries.
a, Heatmap of the SASP genes that were significantly upregulated in ovaries from aged mice (22 months) compared with young mice (4 months) (n = 10 biologically independent mice in young group, n = 9 biologically independent mice in aged group). b, Heatmap of the SASP genes that were significantly suppressed by Tri-1 treatment in aged mouse ovaries (n = 4 biologically independent mice per group). c-e, Ingenuity Pathway Analysis of the 1920 genes that were significantly different in aged vs young mice ovaries. Common gene expression changes induced by Tri-1 and auranofin treatments showed expected common inhibition of GSR and TXNRD1 regulators (c). Transcription factors with altered activity were listed with p53 and p16 among them (d). P values were calculated by a Fisher Exact Test estimated by Ingenuity Pathway Analysis Software. Both these two age-associated signatures were not affected with either Tri-1 or auranofin treatment in the aged mice (e). P values were calculated by hypergeometrical test.
Extended Data Fig. 10 Suppression of SASP by Tri-1 treatment in aged mouse ovary.
a, Expression of the indicated SASP genes in ovaries from young (4 months) or aged (22 months) mice treated with Tri-1 or vehicle control was determined by RT-qPCR. n = 4 biologically independent mice per group. b,c, Immunoblot of the indicated proteins in the ovary tissues harvested from aged mice (22 months) with or without Tri-1 or auranofin treatments (b). The intensity of the indicated proteins was quantified by NIH ImageJ software and normalized against a loading control β-actin expression (c). n = 5 biologically independent mice per group. d, Expression of p16 in ovaries from young (4 months) or aged (22 months) mice treated with Tri-1 or vehicle control was determined by RT-qPCR. n = 4 biologically independent mice per group. Data represent mean ± s.e.m. P-values were calculated using a two-tailed t test.
Supplementary information
Supplementary Information
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Supplementary Tables 1 and 2
Supplementary Table 1: List of proteins identified with at least five peptides and at least fivefold higher intensity in purified CCFs than in the control condition. Supplementary Table 2: List of primers used in this study.
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Hao, X., Zhao, B., Towers, M. et al. TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation. Nat Aging 4, 185–197 (2024). https://doi.org/10.1038/s43587-023-00564-1
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DOI: https://doi.org/10.1038/s43587-023-00564-1
