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A review published in Science synthesizes human, animal and genomic research on how X and Y chromosome genes may influence immunity, cancer, brain aging and cardiometabolic disease. The authors argue that chromosome biology deserves more attention alongside hormones, but many associations—especially those involving chromosome loss—need further study before they can guide care.
A review published in Science examines evidence that X and Y chromosome genes help shape immunity, cancer, aging and other disease risks, rather than health differences being explained by sex hormones alone. The review, co-led by researchers Dan Theodorescu of the University of Arizona Cancer Center and Dena B. Dubal of the University of California, San Francisco, synthesizes findings from human studies, mouse models and genomic research.
The authors describe chromosome-linked processes that may affect health across the lifespan, including immune function, metabolism, brain aging, cancer and heart disease. Their central argument is that genes on the X and Y chromosomes can act directly and in interaction with hormones, influencing disease risk, progression and responses to treatment. The review brings together prior evidence; it is not a new clinical trial or a single experiment demonstrating that chromosome differences cause all of these outcomes.
In people with two X chromosomes, one X is largely inactivated in each cell early in development. Some genes escape that inactivation, and the review discusses evidence that other X-linked genes can become active again with age. This may give some cells different doses of particular genes. Findings in mice also suggest that whether a cell uses the X inherited from the mother or the father could matter. In one reported mouse model, greater reliance on the maternal X was associated with faster brain aging and memory decline; that result does not establish the same effect in people.
The review also addresses age-related loss of sex chromosomes in some cells. Loss of an X chromosome in women has been linked to higher leukemia risk, while loss of the Y chromosome in men—often measured in blood—has been associated with cancer, heart disease, severe infections and Alzheimer’s disease. Researchers are studying chromosome loss as a possible marker of age-related risk and as a potential contributor to disease. The review does not establish that chromosome loss causes each associated condition.
Why Chromosome Biology Matters
The review’s practical significance is its call to treat sex chromosomes as part of the biological picture in research on disease and treatment. If chromosome-linked gene activity changes how disease develops or how tumors respond to therapy, hormone levels alone may not capture relevant differences between patients. The authors say this biology could inform diagnosis, treatment choices and clinical trial design, with the longer-term aim of tailoring care to individual profiles.
Theodorescu cited earlier work from his laboratory suggesting that some tumors that lose the Y chromosome can evade immune defenses, while potentially responding better to immunotherapy. That is a research finding discussed in the review, not evidence that Y-chromosome loss currently predicts an individual patient’s response in routine care. Further studies would be needed to establish how such findings should affect treatment decisions.
Greater attention to chromosome-related biology could also improve how studies account for differences among participants. The authors argue for sex-aware clinical research that investigates mechanisms rather than treating sex as a simple category or relying only on hormone explanations. Whether this approach will produce new clinical tests or treatments remains to be determined.
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From Hormones to Chromosomes
Health differences between men and women have often been discussed in relation to hormones such as estrogen and testosterone. The review adds another layer: the X and Y chromosomes carry genes that can influence cellular functions, and those effects may interact with hormone signaling. The authors frame the chromosomes not only as determinants of biological sex but also as active participants in health over time.
The review grew out of discussions at a 2025 National Institute on Aging workshop on sex differences in human health across the lifespan, including conversations with Francesca Duncan of Northwestern University. Its co-authors also include Fabrisia Ambrosio of Harvard Medical School’s Schoen Adams Research Institute and Michael B. Stout of the Oklahoma Medical Research Foundation. The paper, titled “X and Y chromosomes as determinants of aging and disease,” appeared in Science.
““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.””
— Dan Theodorescu
Where the Evidence Falls Short
The review synthesizes research rather than reporting a clinical trial, and many findings describe associations rather than proven causes. The extent to which X- or Y-chromosome loss drives disease, as opposed to reflecting aging or other biological changes, remains unsettled. The review also does not establish how frequently these mechanisms meaningfully alter risk for a particular person.
Some evidence comes from mouse models, including findings on which parental X chromosome is active and brain aging. Whether those results apply to humans is unclear. More broadly, the clinical importance of genes that escape X inactivation, age-related changes in gene activity, and chromosome loss across different tissues needs further investigation. No new diagnostic test or treatment recommendation is established by this review.
Research Needed Before Clinical Use
The authors hope the review will prompt more work on the mechanisms linking sex chromosomes to aging and disease. Future studies will need to test the findings in larger human populations, distinguish causal effects from associations, and examine how chromosome-related changes vary by tissue and over time. Research will also need to determine whether these changes reliably predict disease or treatment response.
Theodorescu said the goal is to help make diagnostics and treatments better matched to individual patients. That remains a research direction, not an announced clinical program. For now, the next step is further investigation into whether chromosome biology can produce validated markers or improve decisions in trials and clinical care.
Key Questions
What did the Science review report?
It synthesized existing research suggesting that X and Y chromosome genes may influence immunity, cancer, aging, metabolism, brain health and heart disease, alongside the effects of hormones.
Does the review prove that losing a sex chromosome causes disease?
No. It describes associations between chromosome loss and several conditions and discusses possible biological roles. Whether chromosome loss causes particular diseases, or serves mainly as a marker of other changes, remains uncertain.
What does the review say about Y-chromosome loss and cancer?
It discusses research linking Y-chromosome loss in men to cancer and other health risks. Theodorescu also cited laboratory findings that some Y-loss tumors may evade immune defenses yet respond better to immunotherapy. This is not an established treatment guide for individual patients.
Could these findings change medical care now?
The review does not announce a new test or treatment recommendation. The authors say more research is needed to determine whether chromosome-related findings can improve diagnosis, clinical trials or treatment decisions.
Source: rss
