A new review published in Science brings together growing evidence that the X and Y chromosomes do much more than determining biological sex. They also shape how cells function, age and respond to disease.
Differences in health between men and women have long been attributed mainly to sex hormones such as estrogen and testosterone. However, genes on the X and Y chromosomes also play a direct role, working both on their own and alongside hormones.
The review was co-led by University of Arizona Cancer Center physician-scientist Dr. Dan Theodorescu 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 the design 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," said Theodorescu, one of the study's corresponding authors and Nancy C. and Craig M. Berge Chair and Director of the Cancer Center. "Our review shows that these chromosomes carry genetic instructions that shape how our cells age and how our bodies defend against major diseases throughout our lives."
The study shows that the genes on the X and Y chromosomes, rather than circulating hormone levels alone, determine disease risk, progression and therapeutic responses across key heath areas including aging, cancer, neurological conditions, immune system functions and cardiometabolic disease.
The review, which evaluated and synthesized existing evidence from human studies, mouse models and genomic technologies, describes several processes inside cells that shape health across the lifespan.
In women, one of the two X chromosomes is largely switched off early in development, but some of its genes stay active and others can switch back on with age, giving female cells extra doses of certain genes. Studies in mice suggest it also matters whether a cell's active X came from the mother or the father. Men inherit their only X chromosome from their mother, while in women each cell uses either the mother's or the father's copy. In mice whose cells relied mostly on the mother's X, faster brain aging and memory decline was observed.
With age, some cells lose a sex chromosome. In women, loss of an X is linked to higher leukemia risk, though its broader effects remain largely unknown. In men, loss of the Y, most often measured in blood, is linked to cancers, heart disease, severe infections and Alzheimer's disease. The loss of these chromosomes is being explored as both a biomarker of and potential contributor to age-related disease.
"When we look inside human cells, we see that X and Y chromosomes are participants in health and disease throughout a person's life," said Theodorescu, who is also a professor at the U of A College of Medicine – Tucson . "In cancer, for example, our laboratory has found that tumors that lose the Y chromosome can evade the immune system, yet may respond better to immunotherapy. Understanding this biology could help us tailor treatment."
The review originated from discussions at the 2025 National institute on Aging Workshop: Sex Differences Impacting Human Health Across the Lifespan, especially with Francesca Duncan of the Northwestern University Feinberg School of Medicine.
"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," said Theodorescu. "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."
Theodorescu's previous related research focused on how the loss of the Y chromosome in T cells and cancer cells in men gave tumors the ability to evade the immune system, providing an explanation why the loss of the chromosome has been linked to increased mortality from carcinomas. Other recent Theodorescu group research showed how loss of the Y chromosome in normal-appearing tissues acts as an early warning sign and may mark a hidden zone of genetic risk for cancer to develop.
The new review study's co-authors included Fabrisia Ambrosio of the Schoen Adams Research Institute of Harvard Medical School and Michael B. Stout of the Oklahoma Medical Research Foundation.
This review study was funded in part by National Institutes of Health grant Nos. R01AG079176, R01AG068325 R01AG070035. R33AG072137 R01AG089455, R01AG087565 and R35CA294022; and the U.S. Department of Veterans Affairs under Grant No. I01BX006239.
