Abstract 4772: Metabolic phenotype, age acceleration, and obesity-related cancer risk in Women's Health Initiative and Atherosclerosis Risk in Communities cohorts

Abstract Introduction: While normal physiologic aging causes metabolic decline, metabolic dysregulation owing to excess nutrient intake, physical inactivity, and obesity may drive accelerated aging. However, the relationship of accelerated aging with metabolic dysfunction across different levels of BMI (i.e., metabolic obesity phenotype) and whether it may mediate the relationship with obesity-related cancer (ORC) risk is not well established. Methods: To test this hypothesis, we are leveraging existing blood-based DNA methylation (DNAm) data within the Women’s Health Initiative (WHI) and the Atherosclerosis Risk in Communities (ARIC) cohorts. Weight, height and blood pressure were measured by trained technicians in the respective cohorts and fasting blood glucose, triglycerides and HDL cholesterol were quatified by standard clinican assays. Metabolic obesity phenotypes are classified as metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obese (MHO), and metabolically unhealthy overweight/obese (MUO) when defined by ATP III criteria. Age acceleration was measured as a residual from regressing pan-tissue Horvath’s DNAmAge on chronological age. Results: The mean baseline age was 64 ± 6.6 years and 54 ± 5.7 year among WHI and ARIC participants, respectively and the age acceleration was measured at an mean follow-up time of 16 years from baseline for WHI and 3.5 years from baseline for ARIC cohort. The outcome of interest, ORC incidence was observed among 474 participants of which 387 were women. The median time for cancer diagnosis from baseline was 25 year and from DNAm measurement was 18.6 years. Of the 4341 (70% women) participants included in the analysis, 23.9% were MHNW, 3.2% MUNW, 39% MHO, and 33.5% MUO. A 31.5% of MHNW, 40.4% of MUNW, 28.7% of MHO, and 35.2% of MUO showed age acceleration. MUNW (OR 1.47, 95% CI: 1.03-2.11) and MUO (OR 1.18, 95% CI: 1.00-1.40) individuals at baseline had increased odds of experiencing age acceleration at a follow-up visit. The risk of all ORC combined was significantly elevated among MUO (HR 1.63, 95% CI: 1.27-2.09) compared to MHNW. Age acceleration at the follow-up visit was not significantly associated with ORC risk (HR 0.91, 95% CI: 0.75-1.11). These analyses were not adjusted for confounders. Conclusions: MUNW and MUO individuals had increased odds of age acceleration at a follow-up visit. Furthermore, MUO individuals were at an elevated risk of ORC, compared to individuals with MHNW. Accelerated aging does not appear to mediate this association, as accelerated aging was not associated with ORC. Citation Format: Prasoona Karra, Garnet L. Anderson, Mary C. Playdon, Sheetal Hardikar, Aladdin Shadyab, Kari E. North, Anne E. Justice, Elizabeth A. Platz, Jan Bressler, Anna Prizment, Weihua Guan, Dominique S. Michaud, Eric A. Whitsel, Brock C. Christensen, Lucas A. Salas. Metabolic phenotype, age acceleration, and obesity-related cancer risk in Women's Health Initiative and Atherosclerosis Risk in Communities cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4772.