Abstract A022: Proteomic age acceleration associated with all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study. [R]
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: Longer lifespan and improved cancer treatment led to a rapid rise in the number of cancer survivors. However, many cancer survivors have physiological dysregulations at earlier chronological ages than those without cancer, suggesting that cancer survivors’ biological age is higher than their chronological age, i.e., they have accelerated aging. Cancer survivors’ biological age may be estimated by a novel proteomic aging clock (PAC). The deviation of PAC from chronological age is called proteomic age acceleration (PAA). To our knowledge, no studies examined whether PAA in cancer survivors is associated with increased all-cause mortality. We studied PAAs of two PACs – a newly created clock in ARIC (so called, “new” PAC) and the published 491-protein clock by Lehallier [2020] in relation to all-cause mortality in cancer survivors. Methods: ARIC is a prospective cohort of White and Black women and men, followed in 1987-2019. In 2011-13 (Visit 5), 5000 plasma proteins were measured using SomaScan, an aptamer-based assay. Using elastic net regression (alpha=0.5), we constructed a new PAC in a training set of two-thirds randomly selected cancer-free participants (N = 2466). This clock included 619 proteins and was internally validated in the remaining 1233 cancer-free participants (test set). We also computed Lehallier’s PAC using weights estimated in ARIC. We calculated PAA 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 all-cause mortality per 1 standard deviation (SD, ~2.6 yrs for PAAs for both PACs) increase in PAA in 806 survivors of all cancer at Visit 5, and survivors of breast, prostate, and colorectal cancer. HRs were adjusted for chronological age, sex, race, center, education, BMI, smoking status, alcohol intake, eGFR, physical activity, time since cancer diagnosis, diabetes, and aspirin use. Results: 272 deaths were identified in 4963 person-yrs (median follow-up=6.98 yrs). In the test set, both PACs were correlated with chronological age [Pearson correlation coefficient (r): new PAC=0.75; Lehallier’s PAC=0.70] and with each other [r=0.89]. For both PACs, those with higher PAA tended to be White and have lower physical activity and a lower eGFR. Both PAAs were significantly associated with all-cause mortality in cancer survivors [per 1 SD: HR (95% CI): new PAC=1.42 (1.24-1.62); Lehallier’s PAC=1.40 (1.22-1.61)]. The HRs were not modified by sex or race. Both PAAs were significantly associated with all-cause mortality in 169 breast cancer survivors [HR: new PAC=1.54 (1.05-2.25); Lehallier’s PAC=1.72 (1.13-2.64)]. PAA of the new PAC was also associated with all-cause mortality in 78 colorectal cancer survivors [HR=1.96 (1.19-3.22)]. PAA for each PAC was not associated with all-cause mortality in 255 prostate cancer survivors. Conclusion: Proteomic aging clocks hold the promise as a potential biomarker for premature mortality in cancer survivors. 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 all-cause mortality in cancer survivors in the Atherosclerosis Risk in Communities (ARIC) Study. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A022.