Chronic stressors, biological age and deficit accumulation frailty in black breast cancer survivors

Introduction : Chronic social stressors contribute to disparities in population morbidity and mortality. One putative mechanism for these patterns is that stressors, which are differentially experienced by population sub-groups, result in cumulative wear and tear that increases biological aging via sustained release of stress hormones. However, these relationships have not been well studied in cancer survivors. Methods : This cross-sectional study included 258 Black women from the Detroit Research on Cancer Survivors study. Survivors were 12-60 months post-diagnosis of stage 1-3 breast cancer and had germline DNA available for methylation analyses. Biological age was assessed using the Illumina Infinium Methylation EPIC Array for GrimAge, PhenoAge, Extrinsic Age and Dunedin Pace of Aging. Social stressors included life stress (financial, housing and food insecurity, lack of transportation to medical care, area safety; 0-5 composite score), racial discrimination and neighborhood area deprivation. The outcome was a deficit accumulation frailty index score (0-1; <0.20=robust, 0.20-0.35=pre-frail and >0.35=frail; differences of 0.02-0.06 points are clinically meaningful). Separate linear regression models tested associations of each stressor and deficit accumulation, considering age, time from diagnosis and cytotoxic treatment (chemotherapy, radiotherapy). Mediation models explored whether the relationships between stressors and deficit accumulation were statistically mediated by biological age. Results : Survivors were an average of 58.8 years (range 30-83), were 21.1 (SD 14.6) months from diagnosis and 69.6% were pre-frail or frail. Between 55-78% had biological age greater than chronological age on one or more epigenetic clock and 88% had a faster pace of aging than expected based on chronological age. For each 1-point increase in life stress there was a 0.06 point increase in adjusted deficit accumulation (p<0.001) and life stress accounted for 67% of the explained variance in deficit accumulation. Biological age measured by GrimAge mediated 11.8% of the association between life stress and deficit accumulation (p<0.05) and there was similar but non-significant mediation by other epigenetic measures. Living in the most vs. least deprived area was also associated a large clinically meaningful increase in adjusted deficit accumulation (p=0.007), but discrimination had a smaller, non-significant effect. Conclusions : These findings demonstrate an association between experiencing social stressors and deficit accumulation frailty among Black breast cancer survivors and this association was partially driven by biological aging. Future studies are needed to identify aging pathways and possible modifiable factors that could be targeted by policy, behavioral and pharmacological interventions to reduce disparities and improve outcomes among cancer survivors.