Sex chromosomes influence immunity, cancer, aging and disease risk

A new review published in Science brings together growing evidence that the X and Y chromosomes do much more than determine biological sex. They also shape how cells function, how they age and how they respond to disease.

Health differences between men and women have long been attributed primarily to sex hormones such as estrogen and testosterone. However, genes on the X and Y chromosomes also play a direct role, acting both alone and in parallel with hormones.

The review was co-led by Dr. Dan Theodorescu, a physician-scientist at the University of Arizona Cancer Center, and Dr. Dena B. Dubal of the University of California, San Francisco. It describes how sex chromosomes influence immunity, metabolism, brain aging, cancer and heart disease, and what this could mean for diagnosis, treatment and clinical trial design.

The X and Y chromosomes are often thought of as simple determinants of biological sex, but their role in human health is much more important. Our examination shows that these chromosomes carry genetic instructions that shape how our cells age and how our bodies defend against major diseases throughout our lives. »

Mr. Dan Theodorescu, one of the corresponding authors of the study and Nancy C. and Craig M. Berge president and director of the Cancer Center

The study shows that genes on the

The review, which assessed and synthesized existing evidence from human studies, mouse models and genomic technologies, describes several processes inside cells that shape health throughout life.

In women, one of the two Studies in mice suggest that it is also important whether a cell’s active X comes from the mother or father. Men inherit their single X chromosome from their mothers, while in women, each cell uses either the mother’s or the father’s copy. In mice whose cells relied primarily on the mother’s X, more rapid brain aging and memory decline were observed.

With age, some cells lose a sex chromosome. In women, loss of an X is linked to a higher risk of leukemia, although its broader effects remain largely unknown. In men, loss of Y, most commonly measured in the blood, is linked to cancers, heart disease, serious infections and Alzheimer’s disease. The loss of these chromosomes is being studied as both a biomarker and a potential driver of age-related diseases.

“When we look inside human cells, we see that the X and Y chromosomes are involved in health and disease throughout a person’s life,” said Theodorescu, also a professor at the University of Tucson School of Medicine. “In cancer, for example, our lab has discovered that tumors that lose the Y chromosome can evade the immune system, while still responding better to immunotherapy. Understanding this biology could help us tailor treatment.”

The review grew out of discussions at the National Institute on Aging’s 2025 Workshop: Sex Differences Impacting Human Health Across the Lifespan, specifically with Francesca Duncan of Northwestern University’s Feinberg School of Medicine.

“Our hope is that this review will stimulate further research and increase awareness of the important potential of studying the X and Y chromosomes in cancer and other diseases, with far-reaching diagnostic and therapeutic implications,” Theodorescu said. “This would ensure that treatments and diagnostics are tailored to each patient’s unique profile. When clinical trials are designed to take gender into account, researchers can translate these cellular differences into personalized medical care.”

Theodorescu’s previous related research focused on how loss of the Y chromosome in T cells and cancer cells in men gave tumors the ability to evade the immune system, explaining why loss of the chromosome was associated with increased mortality from carcinoma. Other recent research from Theodorescu’s group has shown how loss of the Y chromosome in normal-appearing tissue acts as an early warning sign and can mark a hidden area of ​​genetic risk for cancer development.

Co-authors of the new review study included Fabrisia Ambrosio of the Schoen Adams Research Institute at Harvard Medical School and Michael B. Stout of the Oklahoma Medical Research Foundation.