X and Y Chromosomes: More Than Just Sex Determinants
A recent review in Science reveals that the X and Y chromosomes play a substantial role in influencing cell function, aging, and disease response, beyond their traditional role in determining biological sex.
Historically, differences in male and female health have been primarily attributed to sex hormones like estrogen and testosterone. However, genes located on the X and Y chromosomes also have a direct impact, either independently or in conjunction with these hormones.
The review, spearheaded by Dr. Dan Theodorescu of the University of Arizona Cancer Center and Dr. Dena B. Dubal from the University of California, San Francisco, examines how sex chromosomes influence various health aspects, including immunity, metabolism, brain aging, cancer, and cardiovascular diseases. This understanding could revolutionize diagnostic and treatment strategies, as well as the structuring of clinical trials.
“X and Y chromosomes are often thought of as simple determinants for biological sex, but their role in human health is much larger,” remarked Theodorescu, highlighting that these chromosomes carry genetic instructions vital for cellular aging and disease defense.
The review emphasizes that the X and Y chromosomal genes, rather than just hormone levels, crucially determine disease risk, progression, and response to treatment, affecting areas like aging, cancer, neurological and immune function, and cardiometabolic health.
Utilizing data from human studies, animal models, and genomic technologies, the review details how cellular processes influenced by these chromosomes impact health throughout life. In women, although one X chromosome is mostly inactivated early in development, some genes remain active or can reactivate with age, offering potential genetic advantages. The origin of the active X chromosome—whether maternal or paternal—also plays a role, with research indicating that brain aging and memory decline are affected by the maternal X in mice.
Age-related chromosomal loss also has implications. Women are at increased leukemia risk with X chromosome loss, while men face higher risks for cancers, heart disease, severe infections, and Alzheimer’s with Y chromosome loss. Such losses are under investigation as biomarkers and potential contributors to age-related diseases.
Theodorescu noted, “When we look inside human cells, we see that X and Y chromosomes are participants in health and disease throughout a person’s life,” underscoring the potential for tailored cancer treatments based on Y chromosome loss.
Originating from discussions at the 2025 National Institute on Aging Workshop, this review aims to promote further research into the X and Y chromosomes’ roles in disease, with hopes for diagnostic and therapeutic advancements.
Theodorescu’s earlier research indicated that Y chromosome loss in T cells and cancer cells allows tumors to evade the immune system, explaining the link to increased mortality in cancer. His group’s recent studies also suggest that Y chromosome loss in normal tissues may signal an underlying risk for cancer development.
Co-authors of this review include Fabrisia Ambrosio of the Schoen Adams Research Institute of Harvard Medical School and Michael B. Stout from the Oklahoma Medical Research Foundation.
This research was supported by National Institutes of Health grant Nos. R01AG079176, R01AG068325, R01AG070035, R33AG072137, R01AG089455, R01AG087565, and R35CA294022, as well as the U.S. Department of Veterans Affairs under Grant No. I01BX006239.
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