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The evolution of cancer and ageing: a history of constraint

Nature Reviews Cancer (2025)Cite this article

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Abstract

Ageing and cancer are ubiquitous in animals. They are fundamental and generally intrinsic to multicellular life. Nonetheless, ageing and cancer rates vary widely across species and understanding their evolution and interaction is of great biological interest. Although cancer arises from uncontrolled cell proliferation, ageing involves cell loss and degeneration, making them seemingly opposite yet interconnected processes. Because cancer can affect young individuals, natural selection will favour the evolution of cancer resistance over processes that maintain health in later life. As such, I propose that species evolve longer lifespans under the constraints imposed by the need to reduce cancer risk. Mechanisms that suppress cancer, such as telomere shortening and cellular senescence, may inadvertently promote ageing by limiting cell proliferation and tissue regeneration. Selection for tumour suppression may also impact stem cell ageing and contribute to the limited ability of adult tissues to regenerate. Overall, although cancer resistance is essential for the evolution of longevity, tumour suppression mechanisms may also contribute to ageing-related tissue degeneration and functional decline. Studying the trade-offs between the evolution of tumour suppression processes and their impact later in life may provide important insights into ageing processes.

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Fig. 1: Antagonistic pleiotropy in tumour suppression and ageing.
Fig. 2: Selection pressure determines trade-offs between cancer and ageing.

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References

  1. Albuquerque, T. A. F., Drummond do Val, L., Doherty, A. & de Magalhães, J. P. From humans to hydra: patterns of cancer across the tree of life. Biol. Rev. Camb. Philos. Soc. 93, 1715–1734 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Vincze, O. et al. Cancer risk across mammals. Nature 601, 263–267 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Compton, Z. T. et al. Cancer prevalence across vertebrates. Cancer Discov. 15, 227–244 (2025).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  5. DeGregori, J. Evolved tumor suppression: why are we so good at not getting cancer? Cancer Res. 71, 3739–3744 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Steliarova-Foucher, E. et al. International incidence of childhood cancer, 2001–10: a population-based registry study. Lancet Oncol. 18, 719–731 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Avraam, D., de Magalhaes, J. P. & Vasiev, B. A mathematical model of mortality dynamics across the lifespan combining heterogeneity and stochastic effects. Exp. Gerontol. 48, 801–811 (2013).

    Article  PubMed  Google Scholar 

  8. Lynch, H. E. et al. Thymic involution and immune reconstitution. Trends Immunol. 30, 366–373 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Yun, M. H. Changes in regenerative capacity through lifespan. Int. J. Mol. Sci. 16, 25392–25432 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Martin, G. M. The genetics and epigenetics of altered proliferative homeostasis in ageing and cancer. Mech. Ageing Dev. 128, 9–12 (2007).

    Article  CAS  PubMed  Google Scholar 

  11. Schmucker, D. L. & Sanchez, H. Liver regeneration and aging: a current perspective. Curr. Gerontol. Geriatr. Res. 2011, 526379 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gerstein, A. D., Phillips, T. J., Rogers, G. S. & Gilchrest, B. A. Wound healing and aging. Dermatol. Clin. 11, 749–757 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Wolf, A. M. The tumor suppression theory of aging. Mech. Ageing Dev. 200, 111583 (2021).

    Article  CAS  PubMed  Google Scholar 

  14. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Ren, P., Zhang, J. & Vijg, J. Somatic mutations in aging and disease. Geroscience 46, 5171–5189 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Finch, C. E. Longevity, Senescence, and the Genome (The Univ. Chicago Press, 1990).

  17. Reinke, B. A. et al. Diverse aging rates in ectothermic tetrapods provide insights for the evolution of aging and longevity. Science 376, 1459–1466 (2022).

    Article  PubMed  Google Scholar 

  18. Voituron, Y., de Fraipont, M., Issartel, J., Guillaume, O. & Clobert, J. Extreme lifespan of the human fish (Proteus anguinus): a challenge for ageing mechanisms. Biol. Lett. 7, 105–107 (2011).

    Article  PubMed  Google Scholar 

  19. Cayuela, H. et al. Slow life-history strategies are associated with negligible actuarial senescence in western Palaearctic salamanders. Proc. Biol. Sci. 286, 20191498 (2019).

    PubMed  PubMed Central  Google Scholar 

  20. Harper, J. M., Leathers, C. W. & Austad, S. N. Does caloric restriction extend life in wild mice? Aging Cell 5, 441–449 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Gorbunova, V., Seluanov, A., Zhang, Z., Gladyshev, V. N. & Vijg, J. Comparative genetics of longevity and cancer: insights from long-lived rodents. Nat. Rev. Genet. 15, 531–540 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Oka, K., Yamakawa, M., Kawamura, Y., Kutsukake, N. & Miura, K. The naked mole-rat as a model for healthy aging. Annu. Rev. Anim. Biosci. 11, 207–226 (2023).

    Article  PubMed  Google Scholar 

  23. Butler, G., Baker, J., Amend, S. R., Pienta, K. J. & Venditti, C. No evidence for Peto’s paradox in terrestrial vertebrates. Proc. Natl Acad. Sci. USA 122, e2422861122 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Seluanov, A., Gladyshev, V. N., Vijg, J. & Gorbunova, V. Mechanisms of cancer resistance in long-lived mammals. Nat. Rev. Cancer 18, 433–441 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Leroi, A. M., Koufopanou, V. & Burt, A. Cancer selection. Nat. Rev. Cancer 3, 226–231 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Cagan, A. et al. Somatic mutation rates scale with lifespan across mammals. Nature 604, 517–524 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Vogelstein, B. & Kinzler, K. W. The multistep nature of cancer. Trends Genet. 9, 138–141 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. 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 

  29. Robinson, P. S. et al. Increased somatic mutation burdens in normal human cells due to defective DNA polymerases. Nat. Genet. 53, 1434–1442 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Robinson, P. S. et al. Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells. Nat. Commun. 13, 3949 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Guevara-Aguirre, J. et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci. Transl. Med. 3, 70ra13 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    Article  CAS  PubMed  Google Scholar 

  33. Jassim, A., Rahrmann, E. P., Simons, B. D. & Gilbertson, R. J. Cancers make their own luck: theories of cancer origins. Nat. Rev. Cancer 23, 710–724 (2023).

    Article  CAS  PubMed  Google Scholar 

  34. Sell, S. On the stem cell origin of cancer. Am. J. Pathol. 176, 2584–2494 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Tomasetti, C., Li, L. & Vogelstein, B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355, 1330–1334 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhuang, X. et al. Ageing limits stemness and tumorigenesis by reprogramming iron homeostasis. Nature 637, 184–194 (2025).

    Article  CAS  PubMed  Google Scholar 

  37. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).

    Article  CAS  PubMed  Google Scholar 

  38. Brunet, A., Goodell, M. A. & Rando, T. A. Ageing and rejuvenation of tissue stem cells and their niches. Nat. Rev. Mol. Cell Biol. 24, 45–62 (2023).

    Article  CAS  PubMed  Google Scholar 

  39. Oh, J., Lee, Y. D. & Wagers, A. J. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat. Med. 20, 870–880 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Dos Santos, G. A., Magdaleno, G. D. V. & de Magalhães, J. P. Evidence of a pan-tissue decline in stemness during human aging. Aging 16, 5796–5810 (2024).

    PubMed  PubMed Central  Google Scholar 

  41. de Magalhães, J. P. Distinguishing between driver and passenger mechanisms of aging. Nat. Genet. 56, 204–211 (2024).

    Article  PubMed  Google Scholar 

  42. Rose, M. R. Evolutionary Biology of Aging (Oxford Univ. Press, 1991).

  43. Medawar, P. B. An Unsolved Problem of Biology (H. K. Lewis, 1952).

  44. Williams, G. C. Pleiotropy, natural selection, and the evolution of senescence. Evolution 11, 398–411 (1957).

    Article  Google Scholar 

  45. Austad, S. N. & Hoffman, J. M. Is antagonistic pleiotropy ubiquitous in aging biology? Evol. Med. Public Health 2018, 287–294 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Carter, A. J. & Nguyen, A. Q. Antagonistic pleiotropy as a widespread mechanism for the maintenance of polymorphic disease alleles. BMC Med. Genet. 12, 160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shokeir, M. H. Investigation on Huntington’s disease in the Canadian prairies. II. Fecundity and fitness. Clin. Genet. 7, 349–353 (1975).

    Article  CAS  PubMed  Google Scholar 

  48. Sørensen, S. A., Fenger, K. & Olsen, J. H. Significantly lower incidence of cancer among patients with Huntington disease: an apoptotic effect of an expanded polyglutamine tract? Cancer 86, 1342–1346 (1999).

    Article  PubMed  Google Scholar 

  49. Bae, B. I. et al. p53 mediates cellular dysfunction and behavioral abnormalities in Huntington’s disease. Neuron 47, 29–41 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Denoth Lippuner, A., Julou, T. & Barral, Y. Budding yeast as a model organism to study the effects of age. FEMS Microbiol. Rev. 38, 300–325 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Schaible, R. et al. Constant mortality and fertility over age in Hydra. Proc. Natl Acad. Sci. USA 112, 15701–15706 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Domazet-Lošo, T. et al. Naturally occurring tumours in the basal metazoan Hydra. Nat. Commun. 5, 4222 (2014).

    Article  PubMed  Google Scholar 

  53. Ou, L. et al. Animal models of cardiac disease and stem cell therapy. Open Cardiovasc. Med. J. 4, 231–239 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Chen, Z. Y. & Zhang, Y. Animal models of Alzheimer’s disease: applications, evaluation, and perspectives. Zool. Res. 43, 1026–1040 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. West, M. D. et al. Toward a unified theory of aging and regeneration. Regen. Med. 14, 867–886 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L. & Kroemer, G. Meta-hallmarks of aging and cancer. Cell Metab. 35, 12–35 (2023).

    Article  PubMed  Google Scholar 

  57. Montégut, L., López-Otín, C. & Kroemer, G. Aging and cancer. Mol. Cancer 23, 106 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Aunan, J. R., Cho, W. C. & Søreide, K. The biology of aging and cancer: a brief overview of shared and divergent molecular hallmarks. Aging Dis. 8, 628–642 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Henry, C. J. & DeGregori, J. Modelling the ageing dependence of cancer evolutionary trajectories. Nat. Rev. Cancer https://doi.org/10.1038/s41568-025-00838-3 (2025).

    Article  PubMed  Google Scholar 

  60. Chatsirisupachai, K., Palmer, D., Ferreira, S. & de Magalhães, J. P. A human tissue-specific transcriptomic analysis reveals a complex relationship between aging, cancer, and cellular senescence. Aging Cell 18, e13041 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Aramillo Irizar, P. et al. Transcriptomic alterations during ageing reflect the shift from cancer to degenerative diseases in the elderly. Nat. Commun. 9, 327 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Gomes, N. M. et al. Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination. Aging Cell 10, 761–768 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Seluanov, A. et al. Distinct tumor suppressor mechanisms evolve in rodent species that differ in size and lifespan. Aging Cell 7, 813–823 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Tian, X. et al. Evolution of telomere maintenance and tumour suppressor mechanisms across mammals. Philos. Trans. R. Soc. Lond. B Biol. Sci. 373, 20160443 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Rangarajan, A., Hong, S. J., Gifford, A. & Weinberg, R. A. Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6, 171–183 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. de Magalhaes, J. P., Costa, J. & Church, G. M. An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts. J. Gerontol. A Biol. Sci. Med. Sci. 62, 149–160 (2007).

    Article  PubMed  Google Scholar 

  67. Kuo, C. L., Pilling, L. C., Kuchel, G. A., Ferrucci, L. & Melzer, D. Telomere length and aging-related outcomes in humans: a Mendelian randomization study in 261,000 older participants. Aging Cell 18, e13017 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gurinovich, A. et al. SNP rs6543176 is associated with extreme human longevity but increased risk for cancer. Geroscience 47, 3163–3168 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Narita, M. Cellular senescence and chromatin organisation. Br. J. Cancer 96, 686–691 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sharpless, N. E. & DePinho, R. A. Telomeres, stem cells, senescence, and cancer. J. Clin. Invest. 113, 160–168 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pelicci, P. G. Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence? J. Clin. Invest. 113, 4–7 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Pardal, R., Molofsky, A. V., He, S. & Morrison, S. J. Stem cell self-renewal and cancer cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors. Cold Spring Harb. Symp. Quant. Biol. 70, 177–185 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, Z. et al. Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature 621, 196–205 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wright, W. E., Piatyszek, M. A., Rainey, W. E., Byrd, W. & Shay, J. W. Telomerase activity in human germline and embryonic tissues and cells. Dev. Genet. 18, 173–179 (1996).

    Article  CAS  PubMed  Google Scholar 

  75. Bedelbaeva, K. et al. Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proc. Natl Acad. Sci. USA 107, 5845–5850 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rodier, F., Campisi, J. & Bhaumik, D. Two faces of p53: aging and tumor suppression. Nucleic Acids Res. 35, 7475–7484 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hesse, R. G., Kouklis, G. K., Ahituv, N. & Pomerantz, J. H. The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration. eLife 4, e07702 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Wang, H. et al. Premature aging and reduced cancer incidence associated with near-complete body-wide Myc inactivation. Cell Rep. 42, 112830 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Cai, Y. et al. Decoding aging-dependent regenerative decline across tissues at single-cell resolution. Cell Stem Cell 30, 1674–1691.e8 (2023).

    Article  CAS  PubMed  Google Scholar 

  80. Glaberman, S. et al. Do turtles get cancer? BioScience https://doi.org/10.1093/biosci/biaf100 (2025).

    Article  Google Scholar 

  81. Joven, A., Elewa, A. & Simon, A. Model systems for regeneration: salamanders. Development 146, dev167700 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yun, M. H. Salamander insights into ageing and rejuvenation. Front. Cell Dev. Biol. 9, 689062 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  83. de Magalhães, J. P. The longevity bottleneck hypothesis: could dinosaurs have shaped ageing in present-day mammals? Bioessays 46, e2300098 (2024).

    Article  PubMed  Google Scholar 

  84. Chu, X. L. et al. Temperature responses of mutation rate and mutational spectrum in an Escherichia coli strain and the correlation with metabolic rate. BMC Evol. Biol. 18, 126 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Lindahl, T. & Nyberg, B. Rate of depurination of native deoxyribonucleic acid. Biochemistry 11, 3610–3618 (1972).

    Article  CAS  PubMed  Google Scholar 

  86. Lindgren, D. The temperature influence on the spontaneous mutation rate. I. Literature review. Hereditas 70, 165–178 (1972).

    Article  CAS  PubMed  Google Scholar 

  87. Hirose, K. et al. Evidence for hormonal control of heart regenerative capacity during endothermy acquisition. Science 364, 184–188 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Hayek, S. et al. Prevalence and predictors of frailty in childhood cancer survivors and siblings: a report from the childhood cancer survivor study. J. Clin. Oncol. 38, 232–247 (2020).

    Article  PubMed  Google Scholar 

  89. Strongman, H. et al. Medium and long-term risks of specific cardiovascular diseases in survivors of 20 adult cancers: a population-based cohort study using multiple linked UK electronic health records databases. Lancet 394, 1041–1054 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Wang, S., Prizment, A., Thyagarajan, B. & Blaes, A. Cancer treatment-induced accelerated aging in cancer survivors: biology and assessment. Cancers 13, 427 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gems, D. & Kern, C. C. Biological constraint, evolutionary spandrels and antagonistic pleiotropy. Ageing Res. Rev. 101, 102527 (2024).

    Article  PubMed  Google Scholar 

  92. Gould, S. J. The evolutionary biology of constraint. Daedalus 109, 39–52 (1980).

    Google Scholar 

  93. Wilkinson, J. E. et al. Rapamycin slows aging in mice. Aging Cell 11, 675–682 (2012).

    Article  CAS  PubMed  Google Scholar 

  94. Longo, V. D. & Fontana, L. Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol. Sci. 31, 89–98 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. de Magalhaes, J. P. Ageing as a software design flaw. Genome Biol. 24, 51 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Jing, J. et al. Hedgehog signaling in tissue homeostasis, cancers, and targeted therapies. Signal Transduct. Target. Ther. 8, 315 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Shin, K. et al. Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder. Nature 472, 110–114 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cho, A. et al. An endogenous anti-aging factor, sonic hedgehog, suppresses endometrial stem cell aging through SERPINB2. Mol. Ther. 27, 1286–1298 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Maeso-Díaz, R. et al. Aging reduces liver resiliency by dysregulating Hedgehog signaling. Aging Cell 21, e13530 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Rallis, A. et al. Hedgehog signaling modulates glial proteostasis and lifespan. Cell Rep. 30, 2627–2643.e5 (2020).

    Article  CAS  PubMed  Google Scholar 

  101. Liao, X. et al. Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis 30, 131–140 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Ok, C. Y., Singh, R. R. & Vega, F. Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms. Am. J. Pathol. 180, 2–11 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Watkins, D. N. et al. Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Karhadkar, S. S. et al. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

    Article  CAS  PubMed  Google Scholar 

  105. Power, J. D. & Schlaggar, B. L. Neural plasticity across the lifespan. Wiley Interdiscip. Rev. Dev. Biol. https://doi.org/10.1002/wdev.216 (2017).

  106. 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 

  107. Johnstone, S. E., Gladyshev, V. N., Aryee, M. J. & Bernstein, B. E. Epigenetic clocks, aging, and cancer. Science 378, 1276–1277 (2022).

    Article  CAS  PubMed  Google Scholar 

  108. Abad, M. et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 502, 340–345 (2013).

    Article  CAS  PubMed  Google Scholar 

  109. Ohnishi, K. et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 156, 663–677 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Taguchi, J. et al. DMRT1-mediated reprogramming drives development of cancer resembling human germ cell tumors with features of totipotency. Nat. Commun. 12, 5041 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Huyghe, A., Trajkova, A. & Lavial, F. Cellular plasticity in reprogramming, rejuvenation and tumorigenesis: a pioneer TF perspective. Trends Cell Biol. 34, 255–267 (2024).

    Article  CAS  PubMed  Google Scholar 

  112. Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, 1719–1733.e12 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Chen, Y. et al. Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice. Science 373, 1537–1540 (2021).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The author is grateful to current and past members of the Genomics of Ageing and Rejuvenation Lab for valuable discussions and, in particular, to I. Viegas for comments on previous drafts. Work in our laboratory is supported by grants from LongeCity, Longevity Impetus Grants/Hevolution Foundation and the Biotechnology and Biological Sciences Research Council.

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  1. Genomics of Ageing and Rejuvenation Lab, Department of Inflammation and Ageing, College of Medicine and Health, University of Birmingham, Birmingham, UK

    João Pedro de Magalhães

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Correspondence to João Pedro de Magalhães.

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J.P.d.M. is CSO of YouthBio Therapeutics, an adviser/consultant for the BOLD Longevity Growth Fund and NOVOS and the founder of Magellan Science Ltd, a company providing consulting services in longevity science.

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Glossary

Antagonistic pleiotropy

A theory by George Williams that advocates the existence of genetic variants beneficial early in life but harmful later in life.

Cellular senescence

The cessation of cell division of normally proliferating cells.

Cerebral cavernous malformations

A type of brain venous malformation leading to a slowing of blood flow.

Endothermy

The ability of an organism to maintain a relatively constant body temperature.

Fixation

The process by which a single genetic variant becomes the only variant of a given gene in a population.

Hydra

A genus of small freshwater jellyfish-like animals with regenerative abilities.

Hyperplasia

The enlargement of an organ or tissue caused by cell proliferation.

Negligible senescence

When organisms do not exhibit evidence of biological ageing process.

Sarcopenia

A type of muscle loss that occurs with ageing.

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de Magalhães, J.P. The evolution of cancer and ageing: a history of constraint. Nat Rev Cancer (2025). https://doi.org/10.1038/s41568-025-00861-4

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