Introduction: The escalating global incidence of early-onset gastrointestinal (GI) cancers demands an urgent and thorough exploration of risk factors and biomarkers. Accelerated aging (AA) – a condition where one's biological age significantly exceeds their chronological years – embodies a complex imprint of genomic, epigenomic, environmental, and lifestyle influences. However, two critical questions remained. First, whether biological aging is more prevalent in recent generations. Second, whether AA is associated with risk of early-onset GI cancers.
Methods: To address these critical questions, we conducted a prospective cohort analysis of 148,724 participants from the UK Biobank to characterize the prevalence of AA across generations and examined the associations between AA and the risk of early-onset gastrointestinal cancers. Biological age was assessed using the PhenoAge algorithm, and AA was quantified by standardizing the residuals of biological age after regression against chronological age. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In secondary analyses, we compared the associations with late-onset gastrointestinal cancers (diagnosed after age 55).
Results: Across 1,707,115 person-years, 465 early-onset GI cancer cases occurred. We observed strong evidence of higher prevalence of AA in successive birth cohorts, after controlling for chronological age. For instance, compared to those born in 1950-1954, individuals born in 1965 and after have a 17% (Relative risk=1.17; 95% CI 1.12-1.23) higher risk of AA.
After multivariable adjustment, AA was associated with an increased risk of early-onset GI cancers (HR per SD 1.22, 95% CI 1.11-1.34). Compared with those in the lowest tertile, young adults in the highest tertile of AA had 1.62 times the risk of early-onset GI cancers (HR 1.62, 95% CI 1.27-2.08). Such positive association was driven by stomach cancer (HR per SD 1.67, 95% CI 1.22-2.28) and colorectal cancer (HR per SD 1.16, 95% CI 1.03-1.31). In contrast, the association was weaker for late-onset gastrointestinal cancers (HR per SD 1.16, 95% CI 1.08-1.24).
Conclusion: Accelerated aging is much more prevalent in recent birth cohorts and may emerge as a risk factor as well as a biomarker for early-onset GI cancers. Validation studies in diverse populations as well as mechanistic investigations are needed to further evaluate the impact of the full spectrum of accelerated aging in the etiology of early-onset gastrointestinal cancers and to guide the prevention and early detection.

Daniel Hong

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