Background We constructed a new proteomic aging clock (PAC) and computed the published Lehallier’s PAC to estimate biological age. We tested PACs’ associations with mortality in longer-term cancer survivors and cancer-free participants.

Methods ARIC measured 4,712 proteins using SomaScan in plasma samples collected at multiple visits, including Visit 5 (2011-13), from 806 cancer survivors and 3,699 cancer-free participants (aged 66-90). In the training set (N=2,466 randomly selected cancer-free participants), we developed the new PAC using elastic net regression and computed Lehallier’s PAC. Age acceleration was calculated as residuals after regressing each PAC on chronological age after excluding the training set. We used multivariable-adjusted Cox proportional hazards regression to examine the associations of age acceleration with all-cause, cardiovascular disease (CVD), and cancer mortality.

Results Both PACs were correlated with chronological age [r=0.70-0.75]. Age acceleration for these two PACs was similarly associated with all-cause mortality in cancer survivors [hazard ratios (HRs) per 1 SD=1.40-1.42, p<0.01]. The associations with all-cause mortality were similar in cancer survivors and cancer-free participants for both PACs [p-interactions=0.20-0.62]. There were also associations with all-cause mortality in breast cancer survivors for both PACs [HRs=1.54-1.72, p<0.01] and colorectal cancer survivors for the new PAC [HR=1.96, p=0.03]. Additionally, the new PAC was associated with cancer mortality in all cancer survivors. Finally, HRs=1.42-1.61 [p<0.01] for CVD mortality in cancer-free participants for two PACs but the association was insignificant in cancer survivors perhaps due to a limited number of outcomes.

Conclusion PACs hold promise as potential biomarkers for premature mortality in cancer survivors.

The authors have declared no competing interest.

The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute; National Institutes of Health; Department of Health and Human Services, under Contract nos. (75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). SomaLogic Inc. conducted the SomaScan assays in exchange for the use of ARIC data. This work was supported in part by NIH/NHLBI grant R01 HL134320. Cancer data in ARIC are also supported by the National Cancer Institute (U01 CA164975 and NU58DP007114). Cancer incidence data have been provided by the Maryland Cancer Registry, Center for Cancer Surveillance and Control, Department of Mental Health and Hygiene, 201 W. Preston Street, Room 400, Baltimore, MD 21201. We acknowledge the State of Maryland, the Maryland Cigarette Restitution Fund, and the National Program of Cancer Registries (NPCR) of the Centers for Disease Control and Prevention (CDC) for the funds that helped support the availability of the cancer registry data. The authors thank the staff and participants of the ARIC study for their important contributions. This research was also supported by 1UM1TR004405 and R01CA267977. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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The ARIC datasets are available through BioLINCC, with appropriate study approvals consistent with NIH policies. Data request forms through BioLINCC can be accessed at https://biolincc.nhlbi.nih.gov/studies/aric/.

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Data Availability Statement The ARIC datasets are available through BioLINCC, with appropriate study approvals consistent with NIH policies. Data request forms through BioLINCC can be accessed at https://biolincc.nhlbi.nih.gov/studies/aric/.

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