Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer

Nature Reviews Cancer volume 25, pages 828–847 (2025)Cite this article

Subjects

Abstract

Somatic mutations in several genes, including key oncogenes and tumour suppressor genes, are present from early life and can accumulate as an individual ages, indicating that the potential for cancer is present and growing throughout life. However, the risk of developing cancer rises sharply after 50–60 years of age, suggesting that the ability of these mutations to undergo clonal expansion and drive cancer development is dependent on the progressive changes in the epigenome and microenvironment that occur during ageing. Epigenetic changes, including DNA methylation and histone modifications, can drive various hallmarks of ageing in precancerous cells, including induction of senescence, the senescence-associated secretory phenotype, genomic instability and reduction of nuclear integrity, metabolic and inflammatory stress responses, stem cell function and differentiation potential, and redox balance. This can also alter the normal immune and stromal cells in the tissue microenvironment, which cumulatively enhances the effects of cancer driver mutations, ultimately promoting cancer development and progression in aged individuals. Unravelling these mechanisms will provide novel preventive and therapeutic strategies to limit the burden and progression of cancer in aged individuals.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Age-associated epigenetic changes are crucial for clonal expansion and tumorigenesis.
Fig. 2: Divergent epigenetic landscapes due to metabolic rewiring in young versus aged stromal and immune cells impacts tumour progression.
Fig. 3: Age-acquired epigenetic alterations in both epithelial and stromal cells converge to promote an inflammatory tissue microenvironment and tumorigenesis.

Similar content being viewed by others

References

  1. de Magalhaes, J. P. How ageing processes influence cancer. Nat. Rev. Cancer 13, 357–365 (2013).

    Article  PubMed  Google Scholar 

  2. Temko, D., Tomlinson, I. P. M., Severini, S., Schuster-Böckler, B. & Graham, T. A. The effects of mutational processes and selection on driver mutations across cancer types. Nat. Commun. 9, 1857 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sinkala, M. Mutational landscape of cancer-driver genes across human cancers. Sci. Rep. 13, 12742 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Iranzo, J., Martincorena, I. & Koonin, E. V. Cancer-mutation network and the number and specificity of driver mutations. Proc. Natl Acad. Sci. USA 115, E6010–E6019 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Martincorena, I. et al. Universal patterns of selection in cancer and somatic tissues. Cell 171, 1029–1041.e21 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tomasetti, C., Marchionni, L., Nowak, M. A., Parmigiani, G. & Vogelstein, B. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc. Natl Acad. Sci. USA 112, 118–123 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Tomasetti, C., Vogelstein, B. & Parmigiani, G. Half or more of the somatic mutations in cancers of self-renewing tissues originate prior to tumor initiation. Proc. Natl Acad. Sci. USA 110, 1999–2004 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Xie, M. et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat. Med. 20, 1472–1478 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Armitage, P. & Doll, R. The age distribution of cancer and a multi-stage theory of carcinogenesis. Br. J. Cancer 8, 1–12 (1954).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Martincorena, I. et al. Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Moore, L. et al. The mutational landscape of human somatic and germline cells. Nature 597, 381–386 (2021).

    Article  CAS  PubMed  Google Scholar 

  13. Li, R. et al. A body map of somatic mutagenesis in morphologically normal human tissues. Nature 597, 398–403 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Lodato, M. A. et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science 359, 555–559 (2018).

    Article  CAS  PubMed  Google Scholar 

  15. Tang, J. et al. The genomic landscapes of individual melanocytes from human skin. Nature 586, 600–605 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brunner, S. F. et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature 574, 538–542 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).

    Article  CAS  PubMed  Google Scholar 

  18. Lee-Six, H. et al. The landscape of somatic mutation in normal colorectal epithelial cells. Nature 574, 532–537 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Yizhak, K. et al. RNA sequence analysis reveals macroscopic somatic clonal expansion across normal tissues. Science 364, eaaw0726 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chatsirisupachai, K. & de Magalhães, J. P. Somatic mutations in human ageing: new insights from DNA sequencing and inherited mutations. Ageing Res. Rev. 96, 102268 (2024).

    Article  PubMed  Google Scholar 

  21. Manders, F., van Boxtel, R. & Middelkamp, S. The dynamics of somatic mutagenesis during life in humans. Front. Aging 2, 802407 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Laconi, E., Marongiu, F. & DeGregori, J. Cancer as a disease of old age: changing mutational and microenvironmental landscapes. Br. J. Cancer 122, 943–952 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sikder, S., Arunkumar, G., Melters, D. P. & Dalal, Y. Breaking the aging epigenetic barrier. Front. Cell Dev. Biol. 10, 943519 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Johnstone, S. E. et al. Large-scale topological changes restrain malignant progression in colorectal cancer. Cell 182, 1474–1489.e23 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhou, W. & Reizel, Y. On correlative and causal links of replicative epimutations. Trends Genet. 41, 60–75 (2024).

    Article  PubMed  Google Scholar 

  26. Bisht, S., Mao, Y. & Easwaran, H. Epigenetic dynamics of aging and cancer development: current concepts from studies mapping aging and cancer epigenomes. Curr. Opin. Oncol. 36, 82–92 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, K. et al. Epigenetic regulation of aging: implications for interventions of aging and diseases. Signal Transduct. Target. Ther. 7, 374 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Jung, M. & Pfeifer, G. P. Aging and DNA methylation. BMC Biol. 13, 7 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Chen, X., Agustinus, A. S., Li, J., DiBona, M. & Bakhoum, S. F. Chromosomal instability as a driver of cancer progression. Nat. Rev. Genet. 26, 31–46 (2025).

    Article  CAS  PubMed  Google Scholar 

  32. Lu, Y. R., Tian, X. & Sinclair, D. A. The information theory of aging. Nat. Aging 3, 1486–1499 (2023).

    Article  PubMed  Google Scholar 

  33. Feser, J. et al. Elevated histone expression promotes life span extension. Mol. Cell 39, 724–735 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Liu, Z. et al. Large-scale chromatin reorganization reactivates placenta-specific genes that drive cellular aging. Dev. Cell 57, 1347–1368.e12 (2022).

    Article  CAS  PubMed  Google Scholar 

  35. Guo, J. et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Signal Transduct. Target. Ther. 7, 391 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhao, S., Allis, C. D. & Wang, G. G. The language of chromatin modification in human cancers. Nat. Rev. Cancer 21, 413–430 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lee, J.-H., Kim, E. W., Croteau, D. L. & Bohr, V. A. Heterochromatin: an epigenetic point of view in aging. Exp. Mol. Med. 52, 1466–1474 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang, N. et al. A hyper-quiescent chromatin state formed during aging is reversed by regeneration. Mol. Cell 83, 1659–1676.e11 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chen, T. & Dent, S. Y. R. Chromatin modifiers and remodellers: regulators of cellular differentiation. Nat. Rev. Genet. 15, 93–106 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Wang, M., Sunkel, B. D., Ray, W. C. & Stanton, B. Z. Chromatin structure in cancer. BMC Mol. Cell Biol. 23, 35 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Morgan, M. A. & Shilatifard, A. Chromatin signatures of cancer. Genes Dev. 29, 238–249 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pal, S. & Tyler, J. K. Epigenetics and aging. Sci. Adv. 2, e1600584 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Emerson, F. J. & Lee, S. S. Chromatin: the old and young of it. Front. Mol. Biosci. 10, 1270285 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sun, D. et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell 14, 673–688 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shah, P. P. et al. Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev. 27, 1787–1799 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McCauley, B. S. et al. Altered chromatin states drive cryptic transcription in aging mammalian stem cells. Nat. Aging 1, 684–697 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Dalla, E. et al. Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis. Cell 187, 6631–6648.e20 (2024).

    Article  CAS  PubMed  Google Scholar 

  48. Fane, M. E. et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 606, 396–405 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tao, Y. et al. Aging-like spontaneous epigenetic silencing facilitates Wnt activation, stemness, and Braf(V600E)-induced tumorigenesis. Cancer Cell 35, 315–328.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Ren, P., Dong, X. & Vijg, J. Age-related somatic mutation burden in human tissues. Front. Aging 3, 1018119 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Fabre, M. A. et al. The longitudinal dynamics and natural history of clonal haematopoiesis. Nature 606, 335–342 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lee-Six, H. et al. Population dynamics of normal human blood inferred from somatic mutations. Nature 561, 473–478 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yoshida, K. et al. Tobacco smoking and somatic mutations in human bronchial epithelium. Nature 578, 266–272 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Suda, K. et al. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 24, 1777–1789 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Anglesio, M. S. et al. Cancer-associated mutations in endometriosis without cancer. N. Engl. J. Med. 376, 1835–1848 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lawson, A. R. J. et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science 370, 75–82 (2020).

    Article  CAS  PubMed  Google Scholar 

  57. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Milholland, B., Auton, A., Suh, Y. & Vijg, J. Age-related somatic mutations in the cancer genome. Oncotarget 6, 24627–24635 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Abascal, F. et al. Somatic mutation landscapes at single-molecule resolution. Nature 593, 405–410 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Tomasetti, C. & Vogelstein, B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Wang, Y. et al. APOBEC mutagenesis is a common process in normal human small intestine. Nat. Genet. 55, 246–254 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Moody, S. et al. Mutational signatures in esophageal squamous cell carcinoma from eight countries with varying incidence. Nat. Genet. 53, 1553–1563 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer statistics, 2021. CA Cancer J. Clin. 71, 7–33 (2021).

    PubMed  Google Scholar 

  65. Arike, L. et al. Protein turnover in epithelial cells and mucus along the gastrointestinal tract is coordinated by the spatial location and microbiota. Cell Rep. 30, 1077–1087.e3 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Potten, C. S., Gandara, R., Mahida, Y. R., Loeffler, M. & Wright, N. A. The stem cells of small intestinal crypts: where are they? Cell Prolif. 42, 731–750 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Sender, R. & Milo, R. The distribution of cellular turnover in the human body. Nat. Med. 27, 45–48 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Gehart, H. & Clevers, H. Tales from the crypt: new insights into intestinal stem cells. Nat. Rev. Gastroenterol. Hepatol. 16, 19–34 (2019).

    Article  PubMed  Google Scholar 

  69. Schrock, A. B. et al. Genomic profiling of small-bowel adenocarcinoma. JAMA Oncol. 3, 1546–1553 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Aparicio, T. et al. Genomic profiling of small bowel adenocarcinoma: a pooled analysis from 3 databases. Br. J. Cancer 131, 49–62 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pinaev, G. P. Change in the shape and size of actomyosin particles of striated muscles in ontogenesis. Biokhimiia 30, 20–32 (1965).

    CAS  PubMed  Google Scholar 

  72. Hinoi, T. et al. Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation. Cancer Res. 67, 9721–9730 (2007).

    Article  CAS  PubMed  Google Scholar 

  73. Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat. Med. 15, 1016–1022 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Allen, J. et al. Colon tumors in enterotoxigenic Bacteroides fragilis (ETBF)-colonized mice do not display a unique mutational signature but instead possess host-dependent alterations in the APC gene. Microbiol. Spectr. 10, e0105522 (2022).

    Article  PubMed  Google Scholar 

  75. O’Hagan, H. M. et al. Oxidative damage targets complexes containing DNA methyltransferases, SIRT1, and polycomb members to promoter CpG islands. Cancer Cell 20, 606–619 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  76. DeStefano Shields, C. E. et al. Bacterial-driven inflammation and mutant braf expression combine to promote murine colon tumorigenesis that is sensitive to immune checkpoint therapy. Cancer Discov. 11, 1792–1807 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ritchie, K. J., Walsh, S., Sansom, O. J., Henderson, C. J. & Wolf, C. R. Markedly enhanced colon tumorigenesis in Apc(Min) mice lacking glutathione S-transferase Pi. Proc. Natl Acad. Sci. USA 106, 20859–20864 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Evans, E. J. & DeGregori, J. Cells with cancer-associated mutations overtake our tissues as we age. Aging Cancer 2, 82–97 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Jaiswal, S. et al. Age-related clonal hematopoiesis associated with adverse outcomes. N. Engl. J. Med. 371, 2488–2498 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Genovese, G. et al. Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N. Engl. J. Med. 371, 2477–2487 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Steensma, D. P. Clinical consequences of clonal hematopoiesis of indeterminate potential. Hematol. Am. Soc. Hematol. Educ. Program. 2018, 264–269 (2018).

    Article  Google Scholar 

  82. Young, A. L., Challen, G. A., Birmann, B. M. & Druley, T. E. Clonal haematopoiesis harbouring AML-associated mutations is ubiquitous in healthy adults. Nat. Commun. 7, 12484 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. van Zeventer, I. A. et al. Prevalence, predictors, and outcomes of clonal hematopoiesis in individuals aged ≥80 years. Blood Adv. 5, 2115–2122 (2021).

    Article  PubMed  Google Scholar 

  84. Reed, S. C., Croessmann, S. & Park, B. H. CHIP happens: clonal hematopoiesis of indeterminate potential and its relationship to solid tumors. Clin. Cancer Res. 29, 1403–1411 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Park, S. J. & Bejar, R. Clonal hematopoiesis in cancer. Exp. Hematol. 83, 105–112 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Patel, S. A. et al. Natural history of clonal haematopoiesis seen in real-world haematology settings. Br. J. Haematol. 204, 1844–1855 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Crane, G. M., Jeffery, E. & Morrison, S. J. Adult haematopoietic stem cell niches. Nat. Rev. Immunol. 17, 573–590 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Moerman, E. J., Teng, K., Lipschitz, D. A. & Lecka-Czernik, B. Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-γ2 transcription factor and TGF-β/BMP signaling pathways. Aging Cell 3, 379–389 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Meunier, P., Aaron, J., Edouard, C. & Vignon, G. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin. Orthop. Relat. Res. 80, 147–154 (1971).

    Article  CAS  PubMed  Google Scholar 

  90. Pangrazzi, L. et al. ‘Inflamm-aging’ influences immune cell survival factors in human bone marrow. Eur. J. Immunol. 47, 481–492 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Caiado, F., Pietras, E. M. & Manz, M. G. Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. J. Exp. Med. 218, e20201541 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Abegunde, S. O., Buckstein, R., Wells, R. A. & Rauh, M. J. An inflammatory environment containing TNFα favors Tet2-mutant clonal hematopoiesis. Exp. Hematol. 59, 60–65 (2018).

    Article  CAS  PubMed  Google Scholar 

  93. SanMiguel, J. M. et al. Distinct tumor necrosis factor alpha receptors dictate stem cell fitness versus lineage output in Dnmt3a-mutant clonal hematopoiesis. Cancer Discov. 12, 2763–2773 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zioni, N. et al. Inflammatory signals from fatty bone marrow support DNMT3A driven clonal hematopoiesis. Nat. Commun. 14, 2070 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Jakobsen, N. A. et al. Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging. Cell Stem Cell 31, 1127–1144.e17 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Liao, M. et al. Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis. Acta Pharm. Sin. B 12, 678–691 (2022).

    Article  CAS  PubMed  Google Scholar 

  97. Caiado, F. et al. Aging drives Tet2+/− clonal hematopoiesis via IL-1 signaling. Blood 141, 886–903 (2023).

    Article  CAS  PubMed  Google Scholar 

  98. Quin, C. et al. Chronic TNF in the aging microenvironment exacerbates Tet2 loss-of-function myeloid expansion. Blood Adv. 8, 4169–4180 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Medyouf, H. et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell 14, 824–837 (2014).

    Article  CAS  PubMed  Google Scholar 

  100. Martincorena, I. Somatic mutation and clonal expansions in human tissues. Genome Med. 11, 35 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Stoler, D. L. et al. The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc. Natl Acad. Sci. USA 96, 15121–15126 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Tsao, J. L. et al. Genetic reconstruction of individual colorectal tumor histories. Proc. Natl Acad. Sci. USA 97, 1236–1241 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Braxton, A. M. et al. 3D genomic mapping reveals multifocality of human pancreatic precancers. Nature 629, 679–687 (2024).

    Article  CAS  PubMed  Google Scholar 

  104. Fischer, C. G. et al. Intraductal papillary mucinous neoplasms arise from multiple independent clones, each with distinct mutations. Gastroenterology 157, 1123–1137.e22 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Cooper, C. S. et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue. Nat. Genet. 47, 367–372 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhou, R. W., Harpaz, N., Itzkowitz, S. H. & Parsons, R. E. Molecular mechanisms in colitis-associated colorectal cancer. Oncogenesis 12, 48 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Takeshima, H. & Ushijima, T. Accumulation of genetic and epigenetic alterations in normal cells and cancer risk. NPJ Precis. Oncol. 3, 7 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Buhigas, C. et al. The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates. Mol. Cancer 21, 183 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yates, J. et al. DNA-methylation variability in normal mucosa: a field cancerization marker in patients with adenomatous polyps. J. Natl Cancer Inst. 116, 974–982 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bediaga, N. G. et al. DNA methylation epigenotypes in breast cancer molecular subtypes. Breast Cancer Res 12, R77 (Sep 29).

  112. Chen, Y., Breeze, C. E., Zhen, S., Beck, S. & Teschendorff, A. E. Tissue-independent and tissue-specific patterns of DNA methylation alteration in cancer. Epigenetics Chromatin 9, 10 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Koka, H. et al. DNA methylation age in paired tumor and adjacent normal breast tissue in Chinese women with breast cancer. Clin. Epigenetics 15, 55 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Luo, J.-H. et al. Genome-wide methylation analysis of prostate tissues reveals global methylation patterns of prostate cancer. Am. J. Pathol. 182, 2028–2036 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Yang, B. et al. Methylation profiling defines an extensive field defect in histologically normal prostate tissues associated with prostate cancer. Neoplasia 15, 399–408 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Chandran, U. R. et al. Differences in gene expression in prostate cancer, normal appearing prostate tissue adjacent to cancer and prostate tissue from cancer free organ donors. BMC Cancer 5, 45 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Yu, Y. P. et al. Gene expression alterations in prostate cancer predicting tumor aggression and preceding development of malignancy. J. Clin. Oncol. 22, 2790–2799 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Kulinczak, M. et al. Endometrial cancer-adjacent tissues express higher levels of cancer-promoting genes than the matched tumors. Genes 13, 1611 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhao, H., Ramos, C. F., Brooks, J. D. & Peehl, D. M. Distinctive gene expression of prostatic stromal cells cultured from diseased versus normal tissues. J. Cell Physiol. 210, 111–121 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Magi-Galluzzi, C. et al. Gene expression in normal-appearing tissue adjacent to prostate cancers are predictive of clinical outcome: evidence for a biologically meaningful field effect. Oncotarget 7, 33855–33865 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Troester, M. A. et al. DNA defects, epigenetics, and gene expression in cancer-adjacent breast: a study from the cancer genome atlas. NPJ Breast Cancer 2, 16007 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Bhandari, Y. R. et al. Transcription factor expression repertoire basis for epigenetic and transcriptional subtypes of colorectal cancers. Proc. Natl Acad. Sci. USA 120, e2301536120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Teschendorff, A. E. et al. Epigenetic variability in cells of normal cytology is associated with the risk of future morphological transformation. Genome Med. 4, 24 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Baba, Y. et al. Epigenetic field cancerization in gastrointestinal cancers. Cancer Lett. 375, 360–366 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Teschendorff, A. E. et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat. Commun. 7, 10478 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Yamashita, S. et al. Genetic and epigenetic alterations in normal tissues have differential impacts on cancer risk among tissues. Proc. Natl Acad. Sci. USA 115, 1328–1333 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Belshaw, N. J. et al. Profiling CpG island field methylation in both morphologically normal and neoplastic human colonic mucosa. Br. J. Cancer 99, 136–142 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Park, S.-K. et al. Field cancerization in sporadic colon cancer. Gut Liver 10, 773–780 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yoshida, S. et al. Epigenetic inactivation of FAT4 contributes to gastric field cancerization. Gastric Cancer 20, 136–145 (2017).

    Article  CAS  PubMed  Google Scholar 

  130. Zhang, B. et al. Helicobacter pylori CagA induces tumor suppressor gene hypermethylation by upregulating DNMT1 via AKT-NFκB pathway in gastric cancer development. Oncotarget 7, 9788–9800 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Spitzwieser, M. et al. Hypermethylation of CDKN2A exon 2 in tumor, tumor-adjacent and tumor-distant tissues from breast cancer patients. BMC Cancer 17, 260 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Majewski, T. et al. Whole-organ genomic characterization of mucosal field effects initiating bladder carcinogenesis. Cell Rep. 26, 2241–2256.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Vermeulen, L. et al. Defining stem cell dynamics in models of intestinal tumor initiation. Science 342, 995–998 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Galandiuk, S. et al. Field cancerization in the intestinal epithelium of patients with Crohn’s ileocolitis. Gastroenterology 142, 855–864.e8 (2012).

    Article  PubMed  Google Scholar 

  135. Hill, W. et al. Lung adenocarcinoma promotion by air pollutants. Nature 616, 159–167 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Alonso-Curbelo, D. et al. A gene-environment-induced epigenetic program initiates tumorigenesis. Nature 590, 642–648 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Braakhuis, B. J., Tabor, M. P., Kummer, J. A., Leemans, C. R. & Brakenhoff, R. H. A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res. 63, 1727–1730 (2003).

    CAS  PubMed  Google Scholar 

  138. Ciwinska, M. et al. Mechanisms that clear mutations drive field cancerization in mammary tissue. Nature 633, 198–206 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. van Neerven, S. M. et al. Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature 594, 436–441 (2021).

    Article  PubMed  Google Scholar 

  140. Flanagan, D. J. et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature 594, 430–435 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Colom, B. et al. Mutant clones in normal epithelium outcompete and eliminate emerging tumours. Nature 598, 510–514 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Abby, E. et al. Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth. Nat. Genet. 55, 232–245 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Marongiu, F. & DeGregori, J. The sculpting of somatic mutational landscapes by evolutionary forces and their impacts on aging-related disease. Mol. Oncol. 16, 3238–3258 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Schneider, G., Schmidt-Supprian, M., Rad, R. & Saur, D. Tissue-specific tumorigenesis: context matters. Nat. Rev. Cancer 17, 239–253 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Haigis, K. M., Cichowski, K. & Elledge, S. J. Tissue-specificity in cancer: the rule, not the exception. Science 363, 1150–1151 (2019).

    Article  CAS  PubMed  Google Scholar 

  146. Shi, Q. et al. Notch signaling pathway in cancer: from mechanistic insights to targeted therapies. Signal Transduct. Target. Ther. 9, 128 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Teschendorff, A. E. et al. Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer. Genome Res. 20, 440–446 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Maegawa, S. et al. Widespread and tissue specific age-related DNA methylation changes in mice. Genome Res. 20, 332–340 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Zhu, T., Zheng, S. C., Paul, D. S., Horvath, S. & Teschendorff, A. E. Cell and tissue type independent age-associated DNA methylation changes are not rare but common. Aging 10, 3541–3557 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Yang, L. et al. Functional characterization of age-dependent p16 epimutation reveals biological drivers and therapeutic targets for colorectal cancer. J. Exp. Clin. Cancer Res. 42, 113 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Fennell, L. et al. Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium. Gut 71, 1127–1140 (2022).

    Article  CAS  PubMed  Google Scholar 

  152. Pentinmikko, N. et al. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature 571, 398–402 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tian, Y. et al. APC and P53 mutations synergise to create a therapeutic vulnerability to NOTUM inhibition in advanced colorectal cancer. Gut 72, 2294–2306 (2023).

    Article  CAS  PubMed  Google Scholar 

  154. Turrell, F. K. et al. Age-associated microenvironmental changes highlight the role of PDGF-C in ER+ breast cancer metastatic relapse. Nat. Cancer 4, 468–484 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Hayward, N. K. et al. Whole-genome landscapes of major melanoma subtypes. Nature 545, 175–180 (2017).

    Article  CAS  PubMed  Google Scholar 

  156. Cancer Genome Atlas Network Genomic classification of cutaneous melanoma. Cell 161, 1681–1696 (2015).

    Article  Google Scholar 

  157. Shain, A. H. & Bastian, B. C. From melanocytes to melanomas. Nat. Rev. Cancer 16, 345–358 (2016).

    Article  CAS  PubMed  Google Scholar 

  158. Stransky, N. et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Meucci, S., Keilholz, U., Tinhofer, I. & Ebner, O. A. Mutational load and mutational patterns in relation to age in head and neck cancer. Oncotarget 7, 69188–69199 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  160. Liu, Y. & Yang, Q. The roles of EZH2 in cancer and its inhibitors. Med. Oncol. 40, 167 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Chhabra, Y. et al. Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy. Cell 187, 6016–6034.e25 (2024).

    Article  CAS  PubMed  Google Scholar 

  162. Harman, D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol. 11, 298–300 (1956).

    Article  CAS  PubMed  Google Scholar 

  163. Harman, D. The biologic clock: the mitochondria? J. Am. Geriatr. Soc. 20, 145–147 (1972).

    Article  CAS  PubMed  Google Scholar 

  164. Bokov, A., Chaudhuri, A. & Richardson, A. The role of oxidative damage and stress in aging. Mech. Ageing Dev. 125, 811–826 (2004).

    Article  CAS  PubMed  Google Scholar 

  165. Mockett, R. J., Sohal, B. H. & Sohal, R. S. Expression of multiple copies of mitochondrially targeted catalase or genomic Mn superoxide dismutase transgenes does not extend the life span of Drosophila melanogaster. Free Radic. Biol. Med. 49, 2028–2031 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Cabreiro, F. et al. Increased life span from overexpression of superoxide dismutase in Caenorhabditis elegans is not caused by decreased oxidative damage. Free Radic. Biol. Med. 51, 1575–1582 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Varadaraj, K., Gao, J., Mathias, R. T. & Kumari, S. S. GPX1 knockout, not catalase knockout, causes accelerated abnormal optical aberrations and cataract in the aging lens. Mol. Vis. 28, 11–20 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Pollock, N. et al. Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and neuromuscular junctions in mice. eNeuro 10, ENEURO.0086-22.2023 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  169. Srinivas, U. S., Tan, B. W. Q., Vellayappan, B. A. & Jeyasekharan, A. D. ROS and the DNA damage response in cancer. Redox Biol. 25, 101084 (2019).

    Article  CAS  PubMed  Google Scholar 

  170. Li, T.-S. & Marbán, E. Physiological levels of reactive oxygen species are required to maintain genomic stability in stem cells. Stem Cell 28, 1178–1185 (2010).

    Article  CAS  Google Scholar 

  171. van Soest, D. M. K. et al. Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA. Nat. Commun. 15, 2725 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Tubbs, A. & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Cell 168, 644–656 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Schulz, T. J. et al. Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab. 6, 280–293 (2007).

    Article  CAS  PubMed  Google Scholar 

  174. Ristow, M. & Zarse, K. How increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis). Exp. Gerontol. 45, 410–418 (2010).

    Article  CAS  PubMed  Google Scholar 

  175. Lapointe, J. & Hekimi, S. When a theory of aging ages badly. Cell Mol. Life Sci. 67, 1–8 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Fisher, G. J. et al. Skin aging from the perspective of dermal fibroblasts: the interplay between the adaptation to the extracellular matrix microenvironment and cell autonomous processes. J. Cell Commun. Signal. 17, 523–529 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Kaur, A. et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532, 250–254 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Martinez-Outschoorn, U., Sotgia, F. & Lisanti, M. P. Tumor microenvironment and metabolic synergy in breast cancers: critical importance of mitochondrial fuels and function. Semin. Oncol. 41, 195–216 (2014).

    Article  CAS  PubMed  Google Scholar 

  179. Lisanti, M. P. et al. Hydrogen peroxide fuels aging, inflammation, cancer metabolism and metastasis: the seed and soil also needs ‘fertilizer’. Cell Cycle 10, 2440–2449 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Martinez-Outschoorn, U. E. et al. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: a new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle 9, 3256–3276 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Wiley, C. D. & Campisi, J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat. Metab. 3, 1290–1301 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Gomes, A. P. et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 155, 1624–1638 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Bai, P. & Cantó, C. The role of PARP-1 and PARP-2 enzymes in metabolic regulation and disease. Cell Metab. 16, 290–295 (2012).

    Article  CAS  PubMed  Google Scholar 

  185. Imai, S. & Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol. 24, 464–471 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Camacho-Pereira, J. et al. CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell Metab. 23, 1127–1139 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Chini, C. C. S., Tarragó, M. G. & Chini, E. N. NAD and the aging process: role in life, death and everything in between. Mol. Cell Endocrinol. 455, 62–74 (2017).

    Article  CAS  PubMed  Google Scholar 

  188. Chini, C. et al. The NADase CD38 is induced by factors secreted from senescent cells providing a potential link between senescence and age-related cellular NAD+ decline. Biochem. Biophys. Res. Commun. 513, 486–493 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Bernasocchi, T. & Mostoslavsky, R. Subcellular one carbon metabolism in cancer, aging and epigenetics. Front. Epigenet. Epigenom. 2, 1451971 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  190. Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27–42 (2017).

    Article  CAS  PubMed  Google Scholar 

  191. Reid, M. A., Dai, Z. & Locasale, J. W. The impact of cellular metabolism on chromatin dynamics and epigenetics. Nat. Cell Biol. 19, 1298–1306 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Etchegaray, J.-P. & Mostoslavsky, R. Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol. Cell 62, 695–711 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Etoh, K. et al. Citrate metabolism controls the senescent microenvironment via the remodeling of pro-inflammatory enhancers. Cell Rep. 43, 114496 (2024).

    Article  CAS  PubMed  Google Scholar 

  194. Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16, 582–598 (2016).

    Article  CAS  PubMed  Google Scholar 

  195. Ahmadzadeh, H. et al. Modeling the two-way feedback between contractility and matrix realignment reveals a nonlinear mode of cancer cell invasion. Proc. Natl Acad. Sci. USA 114, E1617–E1626 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Wisdom, K. M. et al. Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nat. Commun. 9, 4144 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Kaur, A. et al. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov. 9, 64–81 (2019).

    Article  CAS  PubMed  Google Scholar 

  198. Ecker, B. L. et al. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov. 9, 82–95 (2019).

    Article  CAS  PubMed  Google Scholar 

  199. Francescone, R. et al. Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast-driven nutritional support and immunosuppression. Cancer Discov. 11, 446–479 (2021).

    Article  CAS  PubMed  Google Scholar 

  200. Dai, Q. et al. Aging aggravates liver fibrosis through downregulated hepatocyte SIRT1-induced liver sinusoidal endothelial cell dysfunction. Hepatol. Commun. 8, e0350 (2024).

    Article  PubMed  Google Scholar 

  201. Huang, K. et al. Variation in senescent-dependent lung changes in inbred mouse strains. J. Appl. Physiol. 102, 1632–1639 (2007).

    Article  PubMed  Google Scholar 

  202. Northcott, J. M., Dean, I. S., Mouw, J. K. & Weaver, V. M. Feeling stress: the mechanics of cancer progression and aggression. Front. Cell Dev. Biol. 6, 17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Pickup, M. W., Mouw, J. K. & Weaver, V. M. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 15, 1243–1253 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Lu, P., Weaver, V. M. & Werb, Z. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196, 395–406 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Marino-Bravante, G. E. et al. Age-dependent loss of HAPLN1 erodes vascular integrity via indirect upregulation of endothelial ICAM1 in melanoma. Nat. Aging 4, 350–363 (2024).

    Article  CAS  PubMed  Google Scholar 

  207. Li, X. et al. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct. Target. Ther. 8, 239 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Chaudhary, J. K., Danga, A. K., Kumari, A., Bhardwaj, A. & Rath, P. C. Role of chemokines in aging and age-related diseases. Mech. Ageing Dev. 223, 112009 (2024).

    Article  PubMed  Google Scholar 

  209. Oishi, Y. & Manabe, I. Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech. Dis. 2, 16018 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Trastus, L. A. & d’Adda di Fagagna, F. The complex interplay between aging and cancer. Nat. Aging 5, 350–365 (2025).

    Article  PubMed  Google Scholar 

  211. Quail, D. F. & Dannenberg, A. J. The obese adipose tissue microenvironment in cancer development and progression. Nat. Rev. Endocrinol. 15, 139–154 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Reuter, S., Gupta, S. C., Chaturvedi, M. M. & Aggarwal, B. B. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic. Biol. Med. 49, 1603–1616 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Lucafò, M., Curci, D., Franzin, M., Decorti, G. & Stocco, G. Inflammatory bowel disease and risk of colorectal cancer: an overview from pathophysiology to pharmacological prevention. Front. Pharmacol. 12, 772101 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Zhao, H. et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct. Target. Ther. 6, 263 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).

    Article  PubMed  Google Scholar 

  217. Taniguchi, K. & Karin, M. NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18, 309–324 (2018).

    Article  CAS  PubMed  Google Scholar 

  218. Karin, M. & Greten, F. R. NF-κB: linking inflammation and immunity to cancer development and progression. Nat. Rev. Immunol. 5, 749–759 (2005).

    Article  CAS  PubMed  Google Scholar 

  219. Karin, M. & Clevers, H. Reparative inflammation takes charge of tissue regeneration. Nature 529, 307–315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    Article  CAS  PubMed  Google Scholar 

  221. De Simone, V. et al. Th17-type cytokines, IL-6 and TNF-α synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene 34, 3493–3503 (2015).

    Article  PubMed  Google Scholar 

  222. Kaler, P., Godasi, B. N., Augenlicht, L. & Klampfer, L. The NF-κB/AKT-dependent Induction of Wnt signaling in colon cancer cells by macrophages and IL-1β. Cancer Microenviron. 2, 69–80 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Lee, G. et al. Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis. Gastroenterology 139, 869–881 (2010).

    Article  CAS  PubMed  Google Scholar 

  224. Schwitalla, S. et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013).

    Article  CAS  PubMed  Google Scholar 

  225. Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).

    Article  CAS  PubMed  Google Scholar 

  226. Zabransky, D. J. et al. Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer Res. 84, 1221–1236 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Parikh, N., Shuck, R. L., Gagea, M., Shen, L. & Donehower, L. A. Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene-induced lung tumors in aged mice. Aging Cell 17, e12691 (2018).

    Article  PubMed  Google Scholar 

  228. Olafsson, S. et al. Somatic evolution in non-neoplastic IBD-affected colon. Cell 182, 672–684.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Kakiuchi, N. et al. Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis. Nature 577, 260–265 (2020).

    Article  CAS  PubMed  Google Scholar 

  230. Nanki, K. et al. Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature 577, 254–259 (2020).

    Article  CAS  PubMed  Google Scholar 

  231. Jain, N. et al. DNA methylation correlates of chronological age in diverse human tissue types. Epigenetics Chromatin 17, 25 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Tarkhov, A. E. et al. Nature of epigenetic aging from a single-cell perspective. Nat. Aging 4, 854–870 (2024).

    Article  PubMed  Google Scholar 

  233. Slieker, R. C., Relton, C. L., Gaunt, T. R., Slagboom, P. E. & Heijmans, B. T. Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception. Epigenetics Chromatin 11, 25 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Hannum, G. et al. Genome-wide methylation profiles reveal quantitative views of human aging rates. Mol. Cell 49, 359–367 (2013).

    Article  CAS  PubMed  Google Scholar 

  236. Bell, C. G. et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 20, 249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Lu, A. T. et al. Universal DNA methylation age across mammalian tissues. Nat. Aging 3, 1144–1166 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Wilkinson, G. S. et al. DNA methylation predicts age and provides insight into exceptional longevity of bats. Nat. Commun. 12, 1615 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Chen, B. H. et al. DNA methylation-based measures of biological age: meta-analysis predicting time to death. Aging 8, 1844–1865 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Marioni, R. E. et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16, 25 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Lu, A. T. et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging 11, 303–327 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Yang, J.-H. et al. Loss of epigenetic information as a cause of mammalian aging. Cell 186, 305–326.e27 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Xie, W. et al. DNA methylation patterns separate senescence from transformation potential and indicate cancer risk. Cancer Cell 33, 309–321.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Zhou, W. et al. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat. Genet. 50, 591–602 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Cruickshanks, H. A. et al. Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495–1506 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  246. Hong, T. et al. TET2 modulates spatial relocalization of heterochromatin in aged hematopoietic stem and progenitor cells. Nat. Aging 3, 1387–1400 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Zhu, X. et al. Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention. Signal Transduct. Target. Ther. 6, 245 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  248. Criscione, S. W. et al. Reorganization of chromosome architecture in replicative cellular senescence. Sci. Adv. 2, e1500882 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  249. Sati, S. et al. 4D genome rewiring during oncogene-induced and replicative senescence. Mol. Cell 78, 522–538 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Zhang, X. et al. The loss of heterochromatin is associated with multiscale three-dimensional genome reorganization and aberrant transcription during cellular senescence. Genome Res. 31, 1121–1135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Wang, B., Han, J., Elisseeff, J. H. & Demaria, M. The senescence-associated secretory phenotype and its physiological and pathological implications. Nat. Rev. Mol. Cell Biol. 25, 958–978 (2024).

    Article  CAS  PubMed  Google Scholar 

  252. Schwartz, R. E. et al. Insights into epithelial cell senescence from transcriptome and secretome analysis of human oral keratinocytes. Aging 13, 4747–4777 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Abbadie, C., Pluquet, O. & Pourtier, A. Epithelial cell senescence: an adaptive response to pre-carcinogenic stresses? Cell Mol. Life Sci. 74, 4471–4509 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Wilkinson, H. N. & Hardman, M. J. Senescence in wound repair: emerging strategies to target chronic healing wounds. Front. Cell Dev. Biol. 8, 773 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  256. Ruhland, M. K. et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat. Commun. 7, 11762 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013).

    Article  CAS  PubMed  Google Scholar 

  258. Ruhland, M. K. & Alspach, E. Senescence and immunoregulation in the tumor microenvironment. Front. Cell Dev. Biol. 9, 754069 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Schellenberg, A. et al. Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks. Aging 3, 873–888 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  261. Gorbunova, V. et al. The role of retrotransposable elements in ageing and age-associated diseases. Nature 596, 43–53 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Liu, X. et al. Resurrection of endogenous retroviruses during aging reinforces senescence. Cell 186, 287–304.e26 (2023).

    Article  CAS  PubMed  Google Scholar 

  263. Wu, Z., Qu, J. & Liu, G.-H. Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases. Nat. Rev. Mol. Cell Biol. 25, 979–1000 (2024).

    Article  CAS  PubMed  Google Scholar 

  264. Pang, W. W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Sudo, K., Ema, H., Morita, Y. & Nakauchi, H. Age-associated characteristics of murine hematopoietic stem cells. J. Exp. Med. 192, 1273–1280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Beerman, I. et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell 12, 413–425 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Kuribayashi, W. et al. Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche. J. Exp. Med. 218, e20192283 (2021).

    Article  CAS  PubMed  Google Scholar 

  268. Adelman, E. R. et al. Aging human hematopoietic stem cells manifest profound epigenetic reprogramming of enhancers that may predispose to leukemia. Cancer Discov. 9, 1080–1101 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  269. Djeghloul, D. et al. Age-associated decrease of the histone methyltransferase SUV39H1 in HSC perturbs heterochromatin and B lymphoid differentiation. Stem Cell Rep. 6, 970–984 (2016).

    Article  CAS  Google Scholar 

  270. Keenan, C. R. et al. Extreme disruption of heterochromatin is required for accelerated hematopoietic aging. Blood 135, 2049–2058 (2020).

    Article  PubMed  Google Scholar 

  271. Park, M. D. et al. Hematopoietic aging promotes cancer by fueling IL-1α-driven emergency myelopoiesis. Science 386, eadn0327 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Itokawa, N. et al. Epigenetic traits inscribed in chromatin accessibility in aged hematopoietic stem cells. Nat. Commun. 13, 2691 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Wertheimer, A. M. et al. Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192, 2143–2155 (2014).

    Article  CAS  PubMed  Google Scholar 

  274. Zhang, H., Weyand, C. M. & Goronzy, J. J. Hallmarks of the aging T-cell system. FEBS J. 288, 7123–7142 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Kityo, C. et al. Lymphoid tissue fibrosis is associated with impaired vaccine responses. J. Clin. Invest. 128, 2763–2773 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  276. Moskowitz, D. M. et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2, eaag0192 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  277. Cao, W. et al. TRIB2 safeguards naive T cell homeostasis during aging. Cell Rep. 42, 112195 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Zhang, H. et al. Aging-associated HELIOS deficiency in naive CD4+ T cells alters chromatin remodeling and promotes effector cell responses. Nat. Immunol. 24, 96–109 (2023).

    Article  CAS  PubMed  Google Scholar 

  279. Mogilenko, D. A. et al. Comprehensive profiling of an aging immune system reveals clonal GZMK+ CD8+ T cells as conserved hallmark of inflammaging. Immunity 54, 99–115.e12 (2021).

    Article  CAS  PubMed  Google Scholar 

  280. Elinav, E. et al. Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759–771 (2013).

    Article  CAS  PubMed  Google Scholar 

  281. Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Chiba, T., Marusawa, H. & Ushijima, T. Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology 143, 550–563 (2012).

    Article  CAS  PubMed  Google Scholar 

  283. Jang, J.-H., Kim, D.-H. & Surh, Y.-J. Dynamic roles of inflammasomes in inflammatory tumor microenvironment. NPJ Precis. Oncol. 5, 18 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  284. Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).

    Article  CAS  PubMed  Google Scholar 

  285. Carrière, C., Young, A. L., Gunn, J. R., Longnecker, D. S. & Korc, M. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem. Biophys. Res. Commun. 382, 561–565 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  286. Burdziak, C. et al. Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis. Science 380, eadd5327 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Gidekel Friedlander, S. Y. et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16, 379–389 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  288. Gopalan, V. et al. A transcriptionally distinct subpopulation of healthy acinar cells exhibit features of pancreatic progenitors and pancreatic ductal adenocarcinoma. Cancer Res. 81, 3958–3970 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Zhu, L. et al. Multi-organ mapping of cancer risk. Cell 166, 1132–1146.e7 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Tao, Y. et al. Cell-free multi-omics analysis reveals potential biomarkers in gastrointestinal cancer patients’ blood. Cell Rep. Med. 4, 101281 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Fox-Fisher, I. et al. Remote immune processes revealed by immune-derived circulating cell-free DNA. eLife 10, e70520 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Pouli, D. et al. Imaging mitochondrial dynamics in human skin reveals depth-dependent hypoxia and malignant potential for diagnosis. Sci. Transl. Med. 8, 367ra169 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  293. Pouli, D. et al. Label-free, high-resolution optical metabolic imaging of human cervical precancers reveals potential for intraepithelial neoplasia diagnosis. Cell Rep. Med. 1, 100017 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Teo, Y. V. et al. Cell-free DNA as a biomarker of aging. Aging Cell 18, e12890 (2019).

    Article  PubMed  Google Scholar 

  295. Joo, J. E. et al. DNA methylation signatures and the contribution of age-associated methylomic drift to carcinogenesis in early-onset colorectal cancer. Cancers 13, 2589 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Roehrig, A. et al. Single-cell multiomics reveals the interplay of clonal evolution and cellular plasticity in hepatoblastoma. Nat. Commun. 15, 3031 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Chen, A. C. Y. et al. The aged tumor microenvironment limits T cell control of cancer. Nat. Immunol. 25, 1033–1045 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254 (2000).

    Article  CAS  PubMed  Google Scholar 

  299. Fane, M. & Weeraratna, A. T. How the ageing microenvironment influences tumour progression. Nat. Rev. Cancer 20, 89–106 (2020).

    Article  CAS  PubMed  Google Scholar 

  300. Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018).

    Article  CAS  PubMed  Google Scholar 

  301. Cassetta, L. & Pollard, J. W. A timeline of tumour-associated macrophage biology. Nat. Rev. Cancer 23, 238–257 (2023).

    Article  CAS  PubMed  Google Scholar 

  302. Soto-Heredero, G., Gómez de Las Heras, M. M., Escrig-Larena, J. I. & Mittelbrunn, M. Extremely differentiated T cell subsets contribute to tissue deterioration during aging. Annu. Rev. Immunol. 41, 181–205 (2023).

    Article  CAS  PubMed  Google Scholar 

  303. Britanova, O. V. et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J. Immunol. 192, 2689–2698 (2014).

    Article  CAS  PubMed  Google Scholar 

  304. Solana, R. & Mariani, E. NK and NK/T cells in human senescence. Vaccine 18, 1613–1620 (2000).

    Article  CAS  PubMed  Google Scholar 

  305. Hibino, S. et al. Inflammation-induced tumorigenesis and metastasis. Int. J. Mol. Sci. 22, 5421 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Wang, J., Li, D., Cang, H. & Guo, B. Crosstalk between cancer and immune cells: role of tumor-associated macrophages in the tumor microenvironment. Cancer Med. 8, 4709–4721 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  307. Zhao, B. et al. Aging microenvironment and antitumor immunity for geriatric oncology: the landscape and future implications. J. Hematol. Oncol. 16, 28 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  308. Fane, M. E. et al. sFRP2 supersedes VEGF as an age-related driver of angiogenesis in melanoma, affecting response to anti-VEGF therapy in older patients. Clin. Cancer Res. 26, 5709–5719 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Hariharan Easwaran

  2. Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Ashani T. Weeraratna

Authors
  1. Hariharan Easwaran
    View author publications

    Search author on:PubMed Google Scholar

  2. Ashani T. Weeraratna
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Hariharan Easwaran or Ashani T. Weeraratna.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Cancer thanks Andrew Teschendorff and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Age-associated mutation signatures

Distinct patterns of somatic mutations, often identified as single-base substitution (SBS) signatures, accumulate with age and reflect a lifetime of DNA damage from both internal processes and environmental exposures.

Clonal haematopoiesis of indeterminate potential

(CHIP). The presence of somatic mutations associated with haematological malignancies in blood or bone marrow cells of individuals without detectable cancer.

Clonal takeovers

The process by which a single clone of cells becomes dominant within a tissue, driven either by acquisition of advantageous mutations that enhance its fitness or simply by random chance through the stochastic drift of neutral mutations.

CpG-island promoter regions

Genomic sequences, typically 200 bp long, that are rich in guanine and cytosine nucleotides (GC content >50%) and an observed to expected CpG ratio of >0.6, which enable specific epigenetic regulatory processes and transcription factor access.

Intestinal crypts

Structures located between the villi in the epithelial lining of the small and large intestines that have a crucial role in producing new intestinal cells and secreting digestive enzymes and mucus.

NAD+–sirtuin pathway

A biological pathway involving NAD+ and sirtuin enzymes, which is crucial in regulating cellular metabolism and ageing processes.

Negative selection

Refers to the process by which deleterious mutations are removed from a population, which in tumour evolution is almost entirely absent, permitting cancer genomes to accumulate a massive burden of potentially deleterious passenger mutations.

One-carbon cycle

The central biochemical network that transfers single carbon units — such as methyl (-CH3), methylene (-CH2-) or formyl (-CHO) groups — for crucial cellular processes such as DNA synthesis, amino acid metabolism, epigenetic regulation (methylation of DNA and proteins) and redox balance.

Pancreatic intraepithelial neoplasias

(PanINs). Microscopic lesions found in the pancreatic ducts that exhibit abnormal cellular changes and can progress to pancreatic cancer.

Positive selection

In the context of cancers, refers to the evolutionary force that favours the proliferation of cells with advantageous driver mutations, which actively contribute to tumour development and progression.

Tricarboxylic acid (TCA) cycle

The oxidation of acetyl-CoA derived from carbohydrates, fats and proteins to generate electron carriers that feed into the electron transport chain to produce ATP through oxidative phosphorylation in the mitochondrial matrix.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Easwaran, H., Weeraratna, A.T. Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer. Nat Rev Cancer 25, 828–847 (2025). https://doi.org/10.1038/s41568-025-00868-x

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41568-025-00868-x

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer