Accelerated biological aging could be associated with an increased risk of several early-onset cancers and may be more common among more recent birth cohorts.
Investigators analyzed the data from 154,169 patients younger than 55 years in the UK Biobank and 10,262 patients in the All of Us Research Program to examine whether biological aging differed across generations and whether those differences were associated with a heightened early-onset cancer risk. Biological aging was assessed using several blood-based measures, including PhenoAge, the Klemera-Doubal method (KDM), and metabolomic aging scores. The primary outcome was incident solid cancer diagnosed prior to 55 years.
In the UK Biobank cohort, patients born between 1965 and 1974 had a 23% higher PhenoAge-defined age gap comapred with those born between 1950 and 1954, indicating greater biological aging relative to chronological age. The investigators also reported that each 1–standard deviation increase in PhenoAge-defined age gap was associated with an 8% higher likelihood of early-onset solid cancer. Patients in the highest tertile of age gap had a 15% higher risk of early-onset solid cancer compared with those in the lowest tertile.
The investigators reported the strongest site-specific associations for lung, gastrointestinal, and endometrial cancers. Each 1–standard deviation increase in biological age gap was associated with a 57% higher likelihood of early-onset lung cancer, a 17% higher likelihood of gastrointestinal cancer, and a 31% higher likelihood of endometrial cancer. The associations were weaker for cancers diagnosed after 55 years.
Analyses using alternative aging measures produced broadly similar findings. KDM-defined age gap was associated with an increased risk of early-onset lung and gastrointestinal cancers, while metabolomic age gap was associated with increased risk of early-onset lung and endometrial cancers.
The investigators examined organ-specific aging using plasma proteomic data from 19,874 UK Biobank participants. Immune-system aging was associated with early-onset lung cancer, while adipose-tissue aging was associated with early-onset colorectal cancer. These associations remained following adjustment for systemic aging measures, suggesting organ-specific aging may contribute independently to cancer development.
A separate analysis in the All of Us cohort yielded similar results. The investigators found that each 1–standard deviation increase in PhenoAge-defined age gap was associated with a 22% higher likelihood of early-onset solid cancer. The cohort also demonstrated increased biological age gaps across more recent birth cohorts.
The investigators noted that accelerated biological aging may reflect the cumulative effects of multiple exposures and physiologic changes that are difficult to measure individually across the life course. They suggested that biological aging could serve as an integrative measure for studying factors contributing to rising rates of early-onset cancers.
Several limitations should be considered. The study was observational and cannot establish causality. Residual confounding remained possible despite adjustment for established risk factors. Some cancer-specific and organ-specific analyses were limited by relatively small numbers of cases, and the findings may not generalize beyond UK and US populations. The investigators also noted that the organ-specific aging analyses require independent validation.
"[P]rospective UK and US data show rising age gap across birth cohorts, potentially associated with increased risk of several early-onset solid cancers," wrote lead study author Ruiyi Tian, of the Department of Surgery in the Division of Public Health Sciences at the Washington University School of Medicine in St. Louis, and colleagues. The investigators added that uncovering the mechanisms and life-course factors underlying these patterns will be important for understanding early-onset cancer risk.
Full disclosures of the study authors can be found in the study.
Source: Nature Medicine