BIOLOGICAL aging may help explain why early-onset cancer risk is rising across more recent generations globally.
Biological Aging and Generational Cancer Risk
Accelerated biological aging may be associated with a higher risk of early-onset solid cancers, according to an integrated cohort analysis of young adults from the UK Biobank and the U.S. All of Us Research Program. The findings suggest that age gap, defined as biological profiles appearing older than expected for chronological age, could help capture cumulative exposure patterns linked to cancer development before age 55.
Among 154,169 UK Biobank participants, systemic aging measured by PhenoAge increased across birth cohorts. Compared with participants born in 1950–1954, those born in 1965–1974 had a 23% higher standardized PhenoAge-defined age gap. In the All of Us cohort, which included 10,262 participants, PhenoAge-defined age gap also increased across generations, with participants born in 1990–1999 showing a 92% higher standardized age gap compared with those born in 1965–1969.
Early-Onset Cancer Risk Rises With Age Gap
Over 953,582 person-years of follow-up in the UK Biobank, each standard deviation increase in PhenoAge-defined age gap was associated with an 8% higher risk of early-onset solid cancers. The association was driven mainly by lung cancer, gastrointestinal cancers, including colorectal cancer, and uterine cancer.
The relationship remained consistent after excluding participants with less than 2 years of follow-up and after adjustment for leukocyte telomere length and genetic predisposition to aging or cancer. Alternative measures of systemic aging, including the Klemera–Doubal method and metabolomic-based age gap, showed directionally similar patterns, although the strength of association varied by cancer site.
In the All of Us validation cohort, 104 early-onset solid cancer cases were identified over 14,791 person-years. Each standard deviation increase in PhenoAge-defined age gap was associated with a 22% higher risk of early-onset solid cancers.
Organ-Specific Aging May Clarify Cancer Pathways
Proteomics-based organ-specific aging analyses offered further biological insight. Immune tissue aging was associated with early-onset lung cancer, while adipose tissue aging was associated with early-onset colorectal cancer. These associations persisted after adjustment for systemic aging, suggesting that organ-specific aging may contribute independently to cancer susceptibility.
The results support biological aging as a potential integrative marker of physiological dysregulation, rather than a replacement for established risk factors. As an observational study, residual confounding cannot be excluded, and site-specific findings require larger, longitudinal validation. Still, the data point to accelerated systemic and organ-specific aging as possible clues to why early-onset cancer is increasing in newer generations.
Reference
Tian R et al. Biological aging and generational shifts in early-onset cancer risk. Nat Med. 2026;doi:10.1038/s41591-026-04448-w.
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