Associations of Combined Phenotypic Aging and Genetic Risk with Incident Cancer: A Prospective Cohort Study

Background Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer. Methods Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and 9 biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs). Results Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18-1.27) in men, 1.26 (1.22-1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10-2.51) for men and 1.94 (1.78-2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = -1.01 in men, P < 0.001; Beta = -0.98 in women, P < 0.001). Conclusions Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by National Natural Science Foundation of China (82230110, 82125033 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study used (or will use) ONLY openly available human data that were originally located at:UK Biobank Resource() (Application Number: 60169) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.