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“Historically, most sex differences in disease were attributed to estrogen, testosterone, and other hormones. However, a growing body of research shows that the X and Y chromosomes can directly influence how cells function, how the immune system responds, how tissues age, and how diseases develop. The most accurate conclusion today is that hormones and sex chromosomes work together.”
“Our hope is that this review will stimulate further investigation and bring greater awareness to the significant potential of studying the X and Y chromosomes in cancer and other diseases, with far-reaching diagnostic and therapeutic implications. This would help ensure that treatments and diagnostics are tailored to match every patient's unique profile. When clinical trials are designed to be sex-aware, researchers can turn these cellular differences into personalized medical care.”
“The review is rich in examples that show the importance of understanding the mechanisms of X and Y chromosome regulation.”
Review reveals sex chromosome complement drives distinct aging and disease trajectories in humans and animal models, highlighting novel targets for sex-informed precision medicine.
Sex differences have traditionally been attributed to gonadal hormones, but accumulating evidence shows that sex chromosomes exert distinct, cell-autonomous effects on health, aging, and disease. XX and XY complements alter gene dosage, epigenetic programming, immune signaling, metabolism, and cellular stress responses, which shape aging and disease trajectories in women and men. This Review integrates mechanistic advances in sex chromosome biology—including escape from X chromosome inactivation, X reactivation, parent-of-X-origin, X-skew, X- and Y-linked gene functions, and Y loss—with aging, neurologic disease, immunity, cancer, and cardiometabolic disease. We highlight insights from mouse models, human studies, and emerging technologies that disentangle hormone-driven effects from chromosome-mediated effects and discuss translational implications for diagnostics, biomarkers, therapeutics, and clinical trial design, emphasizing the integration of sex chromosome biology into precision medicine.
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Dubal et al. (2026) studied this question.
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