1. Ferlay, J. et al. Estimating the global cancer incidence and mortality in 2018:GLOBOCAN sources and methods. Int. J. Cancer 144, 1941–1953 (2019).
2. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes livercancer through senescence secretome. Nature 499, 97–101 (2013).
3. Schwabe, R. F. & Jobin, C. The microbiome and cancer. Nat. Rev. Cancer 13,800–812 (2013).
4. Schroeder, B. O. & Backhed, F. Signals from the gut microbiota to distantorgans in physiology and disease. Nat. Med. 22, 1079–1089 (2016).
5. Janney, A., Powrie, F. & Mann, E. H. Host-microbiota maladaptation incolorectal cancer. Nature 585, 509–517 (2020).
6. Kostic, A. D. et al. Fusobacterium nucleatum potentiates intestinaltumorigenesis and modulates the tumor-immune microenvironment. CellHost Microbe 14, 207–215 (2013).
7. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis viaactivation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022(2009).
8. Nougayrède, J. P. et al. Escherichia coli induces DNA double-strand breaks ineukaryotic cells. Science 313, 848–851 (2006).
9. Pleguezuelos-Manzano, C. et al. Mutational signature in colorectal cancercaused by genotoxic pks(+) E. coli. Nature 580, 269–273 (2020).
10. Long, X. et al. Peptostreptococcus anaerobius promotes colorectalcarcinogenesis and modulates tumour immunity. Nat. Microbiol. 4,2319–2330 (2019).
11. Fu, T. et al. FXR regulates intestinal cancer stem. Cell Prolif. Cell 176,1098–1112 (2019).
12. Wu, S., Morin, P. J., Maouyo, D. & Sears, C. L. Bacteroides fragilis enterotoxininduces c-Myc expression and cellular proliferation. Gastroenterology 124,392–400 (2003).
13. Sears, C. L. & Garrett, W. S. Microbes, microbiota, and colon cancer. Cell HostMicrobe 15, 317–328 (2014).
14. Wong, S. H. & Yu, J. Gut microbiota in colorectal cancer: mechanisms ofaction and clinical applications. Nat. Rev. Gastroenterol. Hepatol. 16, 690–704(2019).
15. He, Y. et al. Regional variation limits applications of healthy gut microbiomereference ranges and disease models. Nat. Med. 24, 1532–1535 (2018).
16. Voigt, A. Y. et al. Temporal and technical variability of human gutmetagenomes. Genome Biol. 16, 73 (2015).
17. Sinha, R. et al. Assessment of variation in microbial community ampliconsequencing by the Microbiome Quality Control (MBQC) project consortium.Nat. Biotechnol. 35, 1077–1086 (2017).
18. Wirbel, J. et al. Meta-analysis of fecal metagenomes reveals global microbialsignatures that are specific for colorectal cancer. Nat. Med. 25, 679–689(2019).
19. Thomas, A. M. et al. Metagenomic analysis of colorectal cancer datasetsidentifies cross-cohort microbial diagnostic signatures and a link with cholinedegradation. Nat. Med. 25, 667–678 (2019).
20. Zeller, G. et al. Potential of fecal microbiota for early-stage detection ofcolorectal cancer. Mol. Syst. Biol. 10, 766 (2014).
21. Yachida, S. et al. Metagenomic and metabolomic analyses reveal distinct stagespecific phenotypes of the gut microbiota in colorectal cancer. Nat. Med. 25,968–976 (2019).
22. Irrazabal, T., Belcheva, A., Girardin, S. E., Martin, A. & Philpott, D. J. Themultifaceted role of the intestinal microbiota in colon cancer. Mol. Cell 54,309–320 (2014).
23. Collado, M. & Serrano, M. Senescence in tumours: evidence from mice andhumans. Nat. Rev. Cancer 10, 51–57 (2010).
24. He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169,1000–1011 (2017).
25. Lee, S. & Schmitt, C. A. The dynamic nature of senescence in cancer. Nat. CellBiol. 21, 94–101 (2019).
26. Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179,813–827 (2019).
27. Campisi, J. & d’Adda di Fagagna, F. Cellular senescence: when bad thingshappen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007).
28. Kruiswijk, F., Labuschagne, C. F. & Vousden, K. H. p53 in survival, death andmetabolic health: a lifeguard with a licence to kill. Nat. Rev. Mol. Cell Biol. 16,393–405 (2015).
29. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforcessenescence. Cell 133, 1006–1018 (2008).
30. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukindependent inflammatory network. Cell 133, 1019–1031 (2008).
31. Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cellnonautonomous functions of oncogenic RAS and the p53 tumor suppressor.PLoS Biol. 6, 2853–2868 (2008).
32. Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192,547–556 (2011).
33. Chan, A. S. L. & Narita, M. Short-term gain, long-term pain: the senescencelife cycle and cancer. Genes Dev. 33, 127–143 (2019).
34. Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing.Nat. Rev. Drug Discov. 16, 718–735 (2017).
35. Tchkonia, T. & Kirkland, J. L. Aging, cell senescence, and chronic disease:emerging therapeutic strategies. JAMA 320, 1319–1320 (2018).
36. Tanoue, T. et al. A defined commensal consortium elicits CD8 T cells andanti-cancer immunity. Nature 565, 600–605 (2019).
37. Bolyen, E. et al. Reproducible, interactive, scalable and extensible microbiomedata science using QIIME 2. Nat. Biotechnol. 37, 852–857 (2019).
38. Segata, N. et al. Metagenomic biomarker discovery and explanation. GenomeBiol. 12, R60 (2011).
39. Flemer, B. et al. The oral microbiota in colorectal cancer is distinctive andpredictive. Gut 67, 1454–1463 (2018).
40. Brennan, C. A. & Garrett, W. S. Fusobacterium nucleatum—symbiont,opportunist and oncobacterium. Nat. Rev. Microbiol. 17, 156–166 (2019).
41. Rubinstein, M. R. et al. Fusobacterium nucleatum promotes colorectalcarcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadAadhesin. Cell Host Microbe 14, 195–206 (2013).
42. Bullman, S. et al. Analysis of Fusobacterium persistence and antibioticresponse in colorectal cancer. Science 358, 1443–1448 (2017).
43. Takahashi, A. et al. DNA damage signaling triggers degradation of histonemethyltransferases through APC/CCdh1 in senescent cells. Mol. Cell 45,123–131 (2012).
44. Takahashi, Y. et al. A refined culture system for human induced pluripotentstem cell-derived intestinal epithelial organoids. Stem Cell Rep. 10, 314–328(2018).
45. Aquino-Martinez, R. et al. LPS-induced premature osteocyte senescence:implications in inflammatory alveolar bone loss and periodontal diseasepathogenesis. Bone 132, 115220 (2020).
46. Kagan, J. C. et al. TRAM couples endocytosis of Toll-like receptor 4 to theinduction of interferon-beta. Nat. Immunol. 9, 361–368 (2008).
47. Ridlon, J. M., Kang, D. J. & Hylemon, P. B. Bile salt biotransformations byhuman intestinal bacteria. J. Lipid Res. 47, 241–259 (2006).
48. Hsu, R. Y. et al. LPS-induced TLR4 signaling in human colorectal cancer cellsincreases beta1 integrin-mediated cell adhesion and liver metastasis. CancerRes. 71, 1989–1998 (2011).
49. Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolitesand colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).
50. Takeuchi, S. et al. Intrinsic cooperation between p16INK4a and p21Waf1/Cip1 inthe onset of cellular senescence and tumor suppression in vivo. Cancer Res. 70,9381–9390 (2010).
51. Munro, J., Barr, N. I., Ireland, H., Morrison, V. & Parkinson, E. K. Histonedeacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Exp. Cell Res.295, 525–538 (2004).
52. Pazolli, E. et al. Chromatin remodeling underlies the senescence-associatedsecretory phenotype of tumor stromal fibroblasts that supports cancerprogression. Cancer Res. 72, 2251–2261 (2012).
53. Sato, M. et al. Three CoA transferases involved in the production of shortchain fatty acids in Porphyromonas gingivalis. Front. Microbiol. 7, 1146 (2016).
54. Cummings, J. H., Pomare, E. W., Branch, W. J., Naylor, C. P. & Macfarlane, G.T. Short chain fatty acids in human large intestine, portal, hepatic and venousblood. Gut 28, 1221–1227 (1987).
55. Colnot, S. et al. Colorectal cancers in a new mouse model of familialadenomatous polyposis: influence of genetic and environmental modifiers.Lab. Invest. 84, 1619–1630 (2004).
56. Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates agedhematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016).
57. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesisbarrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
58. Dimri, G. P. et al. A biomarker that identifies senescent human cells in cultureand in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).
59. Cristofalo, V. J. SA beta Gal staining: biomarker or delusion. Exp. Gerontol.40, 836–838 (2005).
60. Imai, Y. et al. Crosstalk between the Rb pathway and AKT signaling forms aquiescence-senescence switch. Cell Rep. 7, 194–207 (2014).
61. Lee, B. Y. et al. Senescence-associated beta-galactosidase is lysosomal betagalactosidase. Aging Cell 5, 187–195 (2006).
62. Bultman, S. J. & Jobin, C. Microbial-derived butyrate: an oncometabolite ortumor-suppressive metabolite? Cell Host Microbe 16, 143–145 (2014).
63. Belcheva, A. et al. Gut microbial metabolism drives transformation of MSH2-deficient colon epithelial cells. Cell 158, 288–299 (2014).
64. Singh, V. et al. Dysregulated microbial fermentation of soluble fiber inducescholestatic liver cancer. Cell 175, 679–694 (2018).
65. Momen-Heravi, F. et al. Periodontal disease, tooth loss and colorectal cancerrisk: results from the Nurses’ Health Study. Int. J. Cancer 140, 646–652 (2017).
66. Kale, A., Sharma, A., Stolzing, A., Desprez, P. Y. & Campisi, J. Role of immunecells in the removal of deleterious senescent cells. Immun. Ageing 17, 16(2020).
67. Krouwer, V. J., Hekking, L. H., Langelaar-Makkinje, M., Regan-Klapisz, E. &Post, J. A. Endothelial cell senescence is associated with disrupted cell-celljunctions and increased monolayer permeability. Vasc. Cell 4, 12 (2012).
68. Takayama, N. et al. Transient activation of c-MYC expression is critical forefficient platelet generation from human induced pluripotent stem cells. J.Exp. Med. 207, 2817–2830 (2010).
69. Tsukahara, T. et al. High-sensitivity detection of short-chain fatty acids inporcine ileal, cecal, portal and abdominal blood by gas chromatography-massspectrometry. Anim. Sci. J. 85, 494–498 (2014).
70. Sugiura, Y. et al. Visualization of in vivo metabolic flows reveals acceleratedutilization of glucose and lactate in penumbra of ischemic heart. Sci. Rep. 6,32361 (2016)