Grant Number:	1R21CA301160-01A1 Interpret this number
Primary Investigator:	Prizment, Anna
Organization:	University Of Minnesota
Project Title:	Circulating Senescent Proteins and Their Trajectories in Relation to Age-Related Outcomes in Cancer Survivors
Fiscal Year:	2026

ABSTRACT Cancer survivors experience multiple age-related diseases that occur at earlier age than in cancer-free persons. Thus, cancer survivors age faster than those without cancer, and the accelerated aging is driven by prolonged cellular senescence. The detrimental role of senescence is mainly explained by the proteins that comprise senescent-associated phenotype (SASP). These SASP proteins may be released into blood. The central hypothesis of our proposed R21, responsive to PAR-23-255, is that, in cancer survivors, circulating post- diagnosis SASP proteins are associated with an increased risk of mortality, increased risk of cardiovascular death (CVD), and greater changes in frailty and kidney function. To assess circulating proteins after cancer diagnosis, we will use proteomic data measured by highly sensitive SomaScan assay in a large population- based cohort study – Atherosclerosis Risk in the Community (ARIC) of white and black participants. Using ~5000 SomaScan proteins measured three times over 20 years, we will create cross-sectional (Aim 1) and longitudinal SASP indexes (Aim 2) that will include 133 functional, biologically meaningful proteins that were identified in the published atlas of soluble SASP proteins. The unique feature of our novel longitudinal SASP index is that it will combine the characteristics of the cross-sectional index and rate of change in each SASP protein, and may better reflect the aging process than the cross-sectional metrics. The indexes will be created in the training set of cancer-free participants, internally validated in the remaining cancer-free participants, and then applied to cancer survivors to examine associations with all-cause mortality including mortality from cancer and from other causes, as well as the CVD risk and changes in frailty and kidney function. We will also explore whether associations of SASP indexes with outcomes differ in those with cancer and in cancer-free participants. Our multi-disciplinary study team is well-prepared to lead this work, with complementary expertise in cancer and molecular epidemiology, cancer survivorship and oncology, chronic disease, aging biomarkers, biostatistics, and proteomics analysis. The use of existing well-characterized ARIC data will enable a quick and cost-efficient testing of our hypothesis. The proposed study will have a significant impact because SASP indexes are biologically meaningful, and understanding their role in cancer survivors will not only inform risk-stratified cancer care and surveillance for age-related diseases, but may also serve as a potential target for anti-senescence drugs that are currently in clinical trials or under development.