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Peer-reviewedCC BYNature Medicine

Biological aging and generational shifts in early-onset cancer risk

  • Ruiyi Tian1,2
  • Xiaoyu Zong2
  • Duo Ren2
  • Stefani Tica3,2
  • Daniel Y. Hong4,2
  • Oluseye K. Oduyale2,5
  • Jason Daniel Buenrostro6,7
  • Ramaswamy Govindan1,8
  • Yin Cao9,10,11,12
12 affiliations
  1. 1Alvin J. Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
  2. 2Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
  3. 3Department of Pediatrics, Division of Gastroenterology, Hepatology & Nutrition, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
  4. 4Department of Radiation Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
  5. 5Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
  6. 6Biology of Adversity Project, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  7. 7Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
  8. 8Department of Medicine, Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA
  9. 9Alvin J. Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. [email protected]
  10. 10Department of Medicine, Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. [email protected]
  11. 11Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. [email protected]
  12. 12Institute for Informatics, Data Science and Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA. [email protected]
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Abstract

Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase for those born 1965–1974 versus 1950–1954, and was associated with early-onset solid cancer risk (hazard ratio (HR) per s.d. 1.08; 95% confidence interval (CI), 1.03–1.13), driven by lung, gastrointestinal and uterine cancers, independent of genetic risks of aging and cancer. Patterns were consistent using alternative systemic aging measures, including the Klemera–Doubal method-defined age gap and metabolomic-based age gap. These findings were validated partially among 10,262 participants in the United States All of Us Research Program. Proteomics-based organ-specific aging analyses linked immune aging with early-onset lung cancer (HR per s.d. 1.89; CI, 1.20–2.97) and adipose tissue aging to early-onset colorectal cancer (HR 1.60; CI, 1.11–2.32). Greater age gap, reflecting more advanced biological aging relative to chronological age, may serve as a driver associated with risk of early-onset solid cancers, highlighting the importance of uncovering underlying mechanisms to guide effective prevention strategies.

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Cite

BibTeXRIS
BibTeX
@article{tian2026biological,
  title = {{Biological aging and generational shifts in early-onset cancer risk}},
  author = {Ruiyi Tian and Xiaoyu Zong and Duo Ren and Stefani Tica and Daniel Y. Hong and Oluseye K. Oduyale and Jason Daniel Buenrostro and Ramaswamy Govindan and Yin Cao},
  journal = {Nature Medicine},
  year = {2026},
  month = jun,
  doi = {10.1038/s41591-026-04448-w},
  url = {https://doi.org/10.1038/s41591-026-04448-w},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Biological aging and generational shifts in early-onset cancer risk
AU  - Ruiyi Tian
AU  - Xiaoyu Zong
AU  - Duo Ren
AU  - Stefani Tica
AU  - Daniel Y. Hong
AU  - Oluseye K. Oduyale
AU  - Jason Daniel Buenrostro
AU  - Ramaswamy Govindan
AU  - Yin Cao
PY  - 2026
DA  - 2026/06/22
JO  - Nature Medicine
DO  - 10.1038/s41591-026-04448-w
UR  - https://doi.org/10.1038/s41591-026-04448-w
AB  - Incidence of early-onset cancer is rising globally in recent generations, which underscores the need to elucidate the influence of emerging generational risk factors. Systemic and organ-specific aging reflects the cumulative impact of exposures and may provide an integrative and complementary approach to understand early-onset cancer risk. Here among 154,169 young adults from the United Kingdom Biobank, systemic aging measured by PhenoAge increased across birth cohorts, with 23% s.d. increase for those born 1965–1974 versus 1950–1954, and was associated with early-onset solid cancer risk (hazard ratio (HR) per s.d. 1.08; 95% confidence interval (CI), 1.03–1.13), driven by lung, gastrointestinal and uterine cancers, independent of genetic risks of aging and cancer. Patterns were consistent using alternative systemic aging measures, including the Klemera–Doubal method-defined age gap and metabolomic-based age gap. These findings were validated partially among 10,262 participants in the United States All of Us Research Program. Proteomics-based organ-specific aging analyses linked immune aging with early-onset lung cancer (HR per s.d. 1.89; CI, 1.20–2.97) and adipose tissue aging to early-onset colorectal cancer (HR 1.60; CI, 1.11–2.32). Greater age gap, reflecting more advanced biological aging relative to chronological age, may serve as a driver associated with risk of early-onset solid cancers, highlighting the importance of uncovering underlying mechanisms to guide effective prevention strategies.
SN  - 1078-8956
SN  - 1546-170X
SN  - 1744-7933
ER  -