Abstract P029: Proteomic age acceleration associated with cancer risk in the Atherosclerosis Risk in Communities (ARIC) study
Authors: Wang Shuo , Blaes Anne H. , Coresh Josef , Joshu Corinne E. , Pankow James S. , Thyagarajan Bharat , Platz Elizabeth A. , Guan Weihua , Prizment Anna 
Published: January 2023

Background: Individuals of the same chronological age may have a different pace of physiological dysregulation, so chronological age is not a perfect measure of the aging process. A measure of physiological aging – aging clock – has been proposed, including a novel proteomic aging clock (PAC). The deviation of PAC from chronological age is called proteomic age acceleration. PACs have been linked to age-related diseases, but, to our knowledge, no studies tested their association with cancer risk. We examined the associations of proteomic age acceleration for two PACs – a newly created PAC in ARIC (so called, “new” PAC) and the published 491-protein PAC by Lehallier et al [2020]) with cancer risk in the ARIC study. Methods: ARIC is a prospective cohort of White and Black women and men initiated in 1987, followed for cancer until 2015 (median follow-up=17.89 yrs). At Visit 2 (1990-92), about 5000 plasma proteins were measured in 10834 participants: 3347 who developed cancer during follow-up and 7487 who stayed cancer-free, using an aptamer-based assay SomaScan. Using elastic net regression (alpha=0.5), we constructed a new PAC in the training set of two-thirds randomly selected cancer-free participants. This PAC included 1282 proteins and was internally validated in the remaining one-third cancer-free participants (test set). We also constructed Lehallier’s PAC using weights estimated in ARIC. We calculated proteomic age acceleration as residuals after regressing PAC on chronological age. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for overall cancer risk per 1 standard deviation (SD, ~2.7 yrs for age acceleration for both PACs) increase in age acceleration in participants after excluding the training set. HRs were adjusted for chronological age, sex, race, center, education, BMI, smoking status, alcohol intake, eGFR, diabetes, and aspirin use. We also estimated HRs for the most common cancers (breast, prostate, colorectal, and lung cancer). Results: In the test set, both PACs were correlated with chronological age [Pearson correlation coefficient (r): new PAC=0.82; Lehallier’s PAC=0.76] and with each other [r=0.90]. For both PACs, those with higher age acceleration were more likely to be White, aspirin users, and have diabetes and a lower eGFR. Age acceleration of the new PAC was significantly associated with overall cancer risk [per 1 SD: HR (95% CI)=1.04 (1.00-1.08)] but not Lehallier’s PAC. This association was not modified by sex, race, or smoking status. Age acceleration for both PACs were associated with lung cancer risk [HRs: new PAC=1.23 (1.12-1.36); Lehallier’s PAC=1.20 (1.09-1.32)] and remained among never smokers [HRs=1.40-1.42]. Age acceleration of the new PAC was also associated with colorectal cancer risk [HR=1.15 (1.02-1.30)]. Neither of age accelerations was associated with breast or prostate cancer risk. Conclusion: PAC holds promise as a potential biomarker for cancer risk. Funding: NHLBI, NCI, NPCR

Citation Format: Shuo Wang, Anne H. Blaes, Josef Coresh, Corinne E. Joshu, James S. Pankow, Bharat Thyagarajan, Elizabeth A. Platz, Weihua Guan, Anna Prizment. Proteomic age acceleration associated with cancer risk in the Atherosclerosis Risk in Communities (ARIC) study. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P029.