X and Y chromosomes could do a lot more than determine a person's biological sex—they may also influence aging and disease progression, research has found.
Experts from the across the U.S. reviewed mouse models, human studies, and emerging technologies to uncover how sex chromosomes could impact the human body, and brought together existing evidence which suggests that chromosomes could play a role in aging, neurological disease, immunity, cancer, and cardiometabolic disease.
The review was published in the journal Science on October 1.
"Historically, most sex differences in disease were attributed to estrogen, testosterone, and other hormones," Dr. Dan Theodorescu, review author and director of the Cancer Center at the University of Arizona, told Newsweek.
"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," he added. "The most accurate conclusion today is that hormones and sex chromosomes work together."
Commenting on the review, Christine Disteche, a professor of medicine at the University of Washington who was not involved in the review, told Newsweek that it "provides a comprehensive discussion of the various roles of the sex chromosomes in health and in diseases including neurological diseases, immune-related diseases, and cancer."
"The review is rich in examples that show the importance of understanding the mechanisms of X and Y chromosome regulation," she said, adding that this knowledge "would aid understanding and help better tailor treatment."
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What Are Chromosomes?
Chromosomes are threadlike structures made of DNA and typically humans have 23 pairs of chromosomes—one of which determines biological sex (the X and Y chromosomes.)
Every person gets an X chromosome from their mother, and biological women get an additional X chromosome from their father while biological men get a Y from their father.
This means typically a person has either an XX or XY chromosome make up, but there are some variations.
The Impact of X Chromosome Reactivation
Previous belief was that sex chromosomes were largely fixed after early development, Theodorescu said, however, experts now understand that "they are surprisingly dynamic."
"In women, one of the two X chromosomes is mostly switched off early in life to prevent an overdose of X-linked genes," he said, "but as people age, that silencing is not always perfectly maintained. Some genes on the normally inactive X chromosome can become active again, a process known as X chromosome reactivation."
This process can have important consequences, and in some cases, reactivation may be beneficial. For example, the review outlined evidence that X chromosome reactivation was found to improve cognition in aged mice, which they said could show its therapeutic potential.
The researchers also said that a higher expression of KDM6A—located on the X chromosome—was associated with greater cognitive resilience in Alzheimer's disease in humans. In mouse models, it even reversed cellular and cognitive impairments.
Which genes remain active has an impact too. In an animal-based study, it was found that mice with higher activation of their maternal X chromosome experienced improved cognition.
Although, in other situations, "increased expression of certain X-linked genes could potentially contribute to disease," Theodorescu said, meaning in other words, "reactivation is probably neither universally good nor bad; its effects depend on which genes are involved, in which tissues, and at what stage of life."
How Two X Chromosomes Can Impact the Body
Research has indicated that while two X chromosomes can increase survival and resilience to brain aging, women remain disproportionately affected by Alzheimer's disease, which the experts said suggests that mechanisms that promote longevity may not be protective once disease-related pathology develops.
The X chromosome "carries many genes involved in basic cellular maintenance and resilience, and women may benefit from having two copies of this chromosome as well as greater cellular diversity resulting from the way the second X chromosome is regulated," Theodorescu said.
However, as the X chromosome contains an "unusually large number of immune-related genes," having two X chromosomes may "contribute to stronger immune responses, which can be beneficial for fighting infections, but may also increase the risk that the immune system mistakenly attacks the body's own tissues," he added.
Additionally, while men were found to have a higher incidence of heart attacks at a younger age, women tend to experience worse cardiovascular outcomes later in life, such as higher mortality following heart attacks and heart failure.
The researchers said this could be because the two X chromosomes have been found to drive cardiac vulnerability, and promote weight gain, fatty liver and other conditions.
The Impact of Losing Y Chromosomes in Aging
The researchers also described how with aging, some Y chromosomes can be lost in male cells, which is "one of the most common genetic changes that occurs during normal aging in men," Theodorescu said.
"Rather than disappearing from every cell, the Y chromosome is typically lost in a subset of cells, especially blood cells, creating a mixture of cells with and without the Y chromosome," he explained. He added these changes are also seen in "microscopically normal tissues in organs that have cancer in them suggesting these loses are an early event in tissues that eventually get cancer."
He said that cells lacking the Y chromosome can behave differently. Studies have linked loss of the Y chromosome to "altered immune function, increased inflammation, cardiovascular disease, Alzheimer's disease, and higher overall mortality risk," which he said could be because "Y chromosome contains genes that help regulate immune responses, gene expression, and other cellular processes."
He added that in his lab, they have also uncovered evidence that "losing the Y chromosome can directly contribute to disease rather than merely serving as a marker of aging. For example, mice with Y chromosome loss in cancer cells and T-cells led to more aggressive cancers and shorter lifespans."
What This Means for Disease Intervention
Theodorescu said that the biggest implication of this research is that "sex chromosomes themselves may become useful biomarkers and therapeutic targets."
He said that, today, physicians "routinely consider a patient's sex, but they rarely assess the biological status of X and Y chromosomes within tissues or tumors. These studies suggest that such information could eventually help predict disease risk, prognosis, and treatment response."
For example, he said measuring loss of the Y chromosome in blood may help "identify men at elevated risk for certain age-related diseases. In cancer, determining whether a tumor has lost the Y chromosome could potentially help guide treatment decisions, particularly regarding immunotherapy."
"More broadly, these findings challenge a long-standing assumption that sex chromosomes mainly determine whether someone develops as male or female," he said. "The emerging picture is that X and Y chromosomes continue to influence health throughout life and across many different diseases. Understanding those mechanisms may ultimately lead to new approaches for preventing disease and improving treatment outcomes for both women and men."
Reference
Dena B. Dubal et al. (2026) X and Y chromosomes as determinants of aging and disease. Science. https://www.science.org/doi/10.1126/science.aeh0145
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