Abstract 3452: Senescence-associated secretory phenotype (SASP) aging index is associated with cancer risk in the Atherosclerosis Risk in Communities (ARIC) Study

Abstract Background: The accumulation of senescent cells, which release SASP proteins damaging neighboring cells, contributes to aging and age-related diseases, such as cancer. Therefore, SASP proteins could be used as biomarkers for individuals’ aging process, but no studies have tested if SASP protein-based aging index is associated with cancer risk. We created a SASP-aging index based on the 72 SASP proteins reported in Tanaka et al. [2018] and examined its association with cancer risk in the ARIC study. Methods: ARIC is an ongoing cohort of White and Black females and males initiated in 1987, followed for cancer until 2015 (median follow-up=17.3 yrs). At Visit 2 (1990-92), 5000 plasma proteins were measured using SomaScan – an aptamer-based assay in 10,834 participants (aged 46-70 yrs, 55% female, 76% White): 3,347 participants developed cancer during follow-up and 7,487 participants stayed cancer-free. In the training set of 67% randomly selected cancer-free participants, we constructed the SASP-aging index by applying Ridge regression to train the 72 SASP proteins against chronological age. The SASP-aging index was validated in the remaining 33% of cancer-free participants (test set). We calculated age acceleration as residuals after regressing the SASP-aging index on age in participants after excluding the training set. We used Cox proportional hazards regression to estimate hazard ratio (HR) and 95% confidence intervals (CI) for the risk of any type of cancer per 5 years increase in age acceleration, employing Barlow’s method [1994] to account for the exclusion of the training set. HR was adjusted for age, sex, race, center, education, BMI, smoking status, alcohol intake, aspirin use, diabetes, and eGFR. We also estimated HRs for obesity-related, smoking-related, and the most common cancers (breast, prostate, colorectal, and lung). Results: In the test set, Pearson correlation coefficient between the SASP-aging index and age was 0.50. Age acceleration was significantly associated with the risk of any type of cancer [HR (95% CI) per 5 years=1.21 (1.08-1.36)]. There was a suggestion of a higher HR for any type of cancer in females [1.26 (1.07-1.48)] than males [1.18 (1.00-1.39)] [p-interaction=0.08], but HRs were similar across race and smoking status [p-interaction>0.50]. Age acceleration was significantly associated with the risk of obesity-related cancers [1.36 (1.20-1.54)]. A significant association was also found with smoking-related cancers [1.43 (1.24-1.65)] and this association remained significant even among never smokers [1.39 (1.07- 1.82)]. Age acceleration was also significantly associated with colorectal [1.34 (1.03-1.75)] and lung cancer risk [1.63 (1.31-2.02)] but not with breast or prostate cancer risk. Conclusion: SASP protein-based aging index shows promise as a potential biomarker for cancer risk. Funding: NHLBI, NCI, NPCR Citation Format: Shuo Wang, Zexi Rao, Anne H. Blaes, Josef Coresh, Corinne E. Joshu, James S. Pankow, Bharat Thyagarajan, Peter Ganz, Elizabeth A. Platz, Weihua Guan, Anna Prizment. Senescence-associated secretory phenotype (SASP) aging index is associated with cancer risk in the Atherosclerosis Risk in Communities (ARIC) Study [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 3452.