Biological aging and generational shifts in early-onset cancer risk.

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.