Accelerated Biological Aging Links Unhealthy Lifestyles to Colorectal Cancer Risk
A large UK Biobank study reveals biological aging mediates up to 27% of lifestyle-driven colorectal cancer risk, with DNA methylation changes at 15 CpG sites as key mechanisms.
Summary
Researchers analyzed 322,640 UK Biobank participants to examine how biological aging connects unhealthy lifestyles to colorectal cancer (CRC). Accelerated aging measures—particularly PhenoAge acceleration and homeostatic dysregulation score—were associated with increased CRC risk, especially early-onset CRC. Biological aging mediated up to 27% of the harmful effect of unhealthy lifestyles on CRC. Using Mendelian randomization, epigenetic aging clock GrimAge was genetically linked to higher CRC risk. A three-step MR analysis identified 15 aging-related CpG sites and four key genes (TNF, BICC1, NCF2, DIP2B) whose altered methylation and expression help explain how aging drives CRC development. Healthy lifestyle adherence may delay biological aging and reduce CRC risk.
Detailed Summary
Colorectal cancer (CRC) is the world's third most common cancer, and while chronological aging is a well-known risk factor, individual variation in biological aging may better explain cancer susceptibility. Researchers set out to clarify whether accelerated biological aging mediates the link between unhealthy lifestyles and CRC, and to identify the molecular mechanisms involved.
Using 322,640 participants from the UK Biobank (5,448 incident CRC cases; 317,192 controls), the team measured five biological aging indicators: leukocyte telomere length (LTL), PhenoAge acceleration, Klemera-Doubal method biological age (KDM-BA) acceleration, homeostatic dysregulation (HD) score, and frailty phenotype. Cox regression models evaluated associations with overall CRC and subgroups including early-onset CRC (EOCRC, diagnosed <50 years) and late-onset CRC (LOCRC). Mediation analyses quantified how much of the lifestyle-CRC association was explained by biological aging.
PhenoAge acceleration and HD score were positively associated with CRC risk. Notably, associations were substantially stronger for EOCRC than LOCRC: hazard ratios were 1.29 (95% CI: 1.07–1.55) and 1.35 (1.08–1.69) for PhenoAge acceleration and HD score in EOCRC, versus 1.06 (1.03–1.09) and 1.05 (1.02–1.08) in LOCRC. Accelerated biological aging mediated between 0.18% and 27.00% of the adverse effects of unhealthy lifestyle components—including smoking, alcohol consumption, unhealthy diet, and physical inactivity—on CRC risk.
Mendelian randomization analyses from an epigenetic perspective showed that genetically determined DNAm GrimAge acceleration was positively associated with CRC risk. A further three-step MR combined with colocalization analysis identified 15 aging-related CpG sites significantly associated with CRC. Four genes were highlighted: TNF, BICC1, NCF2, and DIP2B. Lower expression of TNF, NCF2, and DIP2B mediated the adverse effect of methylation at specific CpGs on CRC risk, while higher BICC1 expression mediated the effect of methylation at four other CpGs. These findings point to immune dysregulation and inflammatory signaling as plausible biological pathways linking aging to CRC.
The study suggests that healthy lifestyle behaviors—avoiding smoking, limiting alcohol, maintaining a healthy diet, and exercising adequately—may reduce CRC risk partly by slowing biological aging. The identification of specific CpG sites and their downstream gene targets offers potential directions for therapeutic intervention and biomarker development in CRC prevention and treatment.
Key Findings
- PhenoAge acceleration raised early-onset CRC risk by 29% (HR 1.29) vs. only 6% for late-onset CRC.
- Accelerated biological aging mediated 0.18%–27% of the CRC risk attributable to unhealthy lifestyles.
- Genetically determined DNAm GrimAge acceleration was causally linked to higher CRC risk via Mendelian randomization.
- 15 aging-related CpG sites were associated with CRC risk, implicating altered methylation as a mechanistic bridge.
- Four genes—TNF, BICC1, NCF2, DIP2B—mediated CpG-methylation effects on CRC through altered expression.
Methodology
A longitudinal cohort study of 322,640 UK Biobank participants used Cox regression to assess five biological aging measures against CRC incidence, with mediation analyses for lifestyle factors. Mendelian randomization was applied to evaluate epigenetic aging clocks and CRC risk, followed by a three-step MR and Bayesian colocalization analysis linking aging-related CpG methylation to gene expression and CRC.
Study Limitations
The cohort was restricted to white UK Biobank participants, limiting generalizability to other ethnicities. Biological aging measures were assessed at a single baseline timepoint, potentially missing dynamic changes over time. Mediation proportions were relatively modest for most lifestyle-aging-CRC pathways, indicating other mechanisms also contribute substantially.
Enjoyed this summary?
Get the latest longevity research delivered to your inbox every week.