PhenoAgeAccel mediates the association between metabolic syndrome and cancer risk in males: a cross-sectional NHANES study

Background The relationship between metabolic syndrome (MetS) and cancer risk, and the potential mediating role of biological aging as measured by Phenotypic Age Acceleration (PhenoAgeAccel), remains insufficiently characterized.Methods We conducted a cross-sectional study of 12,664 participants from the National Health and Nutrition Examination Survey (NHANES, 1999–2010, 2015–2020). MetS was defined according to established criteria, cancer status was self-reported, and PhenoAgeAccel was derived from clinical biomarkers. Weighted multivariable logistic regression and formal causal mediation analysis were employed.Results After full adjustment, MetS was significantly associated with increased cancer prevalence (OR = 1.338, 95% CI: 1.074–1.666, p = 0.010). This association was more pronounced in males (OR = 2.383, p < 0.05) and adults aged 20–65 years (OR = 1.573, p < 0.05). Mediation analysis revealed that PhenoAgeAccel significantly accounted for 16.5% of the total effect of MetS on cancer (Average Causal Mediation Effect = 0.00352, p < 0.001). Gender stratification indicated a statistically significant mediating effect in males (proportion mediated = 10.9%, p = 0.002) but not in females (proportion mediated = 10.9%, p = 0.086). The direct effect of MetS remained significant (OR = 1.265, p = 0.050).Conclusion MetS is associated with elevated cancer risk, with PhenoAgeAccel serving as a significant mediating pathway, particularly among males. These findings identify younger males as a high-risk subgroup for targeted preventive strategies.