| Sumario: | Background & Significance: Postmenopausal women with breast cancer commonly experience cognitive decline. Area deprivation and acceleration of DNA methylation-based epigenetic age are independently associated with cognition. In contrast, aerobic exercise may improve cognition. Purpose: To characterize the relationships among aerobic exercise, area deprivation, epigenetic age acceleration, and cognition, and to examine whether area deprivation and epigenetic age acceleration modify aerobic-exercise effects on cognition. Methods: This study capitalized on existing data from a randomized controlled trial which examined effectiveness of a six-month aerobic-exercise intervention on cognition in postmenopausal women with breast cancer (NCT02793921). Variables included 1) group assignment (Aerobic-exercise vs Usual-care), 2) Area Deprivation Index (ADI); national percentile [1 to 100]; higher values indicate greater area deprivation), 3) epigenetic age acceleration (residual epigenetic age adjusted for chronological age) based on six blood-derived methylation-based clocks (Horvath1, Horvath2, Hannum, PhenoAge, GrimAge, and BrainAge), and 4) objectively-measured cognition (composite scores for seven domains; higher scores indicate better performance). We applied ANCOVA and linear mixed-effects modeling adjusted for age (year), body mass index (kg/m2), and education (year). Findings and Interpretations In 116 women (mean age 62.40±7.06; 90% White; 61% stage I), the mean ADI was 42.27±22.25 and higher ADI was associated with greater epigenetic age acceleration (PhenoAge, p = .006; BrainAge, p = .025) at pre-randomization. Aerobic exercise did not produce benefits in epigenetic age acceleration compared with usual care overall, however, it appeared more beneficial in epigenetic age acceleration among those living in lower-ADI neighborhood (BrainAge, p = .004). Mental flexibility was positively associated with pre-randomization epigenetic age acceleration (GrimAge, p = .016), and epigenetic age acceleration changes (PhenoAge, p = .019). With greater pre-randomization epigenetic age acceleration (Horvath1, p = .033; Grim-Age, p = .017), the aerobic-exercise group showed less improvement in verbal memory. Conversely, with greater pre-randomization epigenetic age acceleration (Horvath1, p = .010; Horvath2, p = .009; Hannum, p = .004), the aerobic-exercise group showed greater improvement in attention. Discussion: These findings indicate that area deprivation and epigenetic age acceleration are associated and jointly shape cognitive responses to aerobic exercise, with effects varying across epigenetic clocks and cognitive domains among postmenopausal women with breast cancer. Cancer- and treatment-related physiological stress may accelerate biological aging and alter individuals' capacity to benefit from aerobic exercise. Identifying these mechanisms responsive subgroups will advance precision cognition care in cancer populations.
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