Epigenetic aging as a driver of racial disparities in early onset prostate cancer

Prostate cancer (PrCa) shows significant racial disparities, especially impacting African American (AA) men, who have a 1.4 times higher risk of PrCa diagnosis, and a double risk of PrCa-related mortality compared to European American (EA) men. AA men are also more frequently diagnosed with early-onset PrCa (≤55-years) than other

racial/ethnic groups. Despite these disparities, we have limited knowledge about how ancestry/race influences epigenetic age and whether early-onset PrCa is linked to accelerated epigenetic aging due to genetic or environmental factors. This study builds on prior research that suggests ribosomal DNA (rDNA) methylation is a

reliable marker of biological aging, with direct links to aging, longevity, and cancer We hypothesize that accelerated rDNA methylation (rDNAm) age is linked to early-onset PrCa (EO) in African American (AA) patients, potentially explaining their higher risk. By studying the rDNA methylation-EO PrCa relationship in AA men, we

aim to uncover factors contributing to racial disparities. This insight may lead to targeted interventions for reducing the increased risk of EO PrCa in AA men. In the first aim, we investigate whether African American (AA) prostate cancer patients have a higher rDNA methylation age at diagnosis compared to age-matched

European American (EA) prostate cancer patients. The second aim explores if AA men with prostate cancer exhibit an increased rDNA methylation age at diagnosis in comparison to age- and race-matched non-cancer controls. In the third aim, we assess the performance of the rDNA methylation clock in AA prostate cancer

patients within their age range, relative to alternative metrics of epigenetic aging. Our hypothesis is that the rDNAm clock's age prediction will rival or surpass other measures like the Horvath, Hannum, PhenoAge, and GrimAge clocks in both prostate cancer patients and non-cancer controls. This cross-platform validation

strengthens study rigor, advancing clock performance evaluation in the context of health disparities, ultimately progressing the field. Our main objective is to uncover the reasons behind racial disparities in prostate cancer among AA patients. In the short term, we expect the rDNA clock to emerge as a valuable tool for assessing the

risk of early-onset prostate cancer in African American patients. In the long term, our research aims to provide strong evidence supporting the widespread adoption of the rDNA clock as a biomarker for monitoring age-related diseases in this unique group of cancer patients. Most importantly, this proposal lays the groundwork for future

research to establish rDNA methylation epigenetic age as a fundamental baseline for epigenetic aging measurements in studies involving exercise, dietary, or other interventions for individuals at risk of prostate cancer, especially those of African descent.