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A review in Science brings together human, animal and genomic research suggesting that X and Y chromosome genes influence immunity, cancer, aging and other health outcomes, in addition to the effects of sex hormones. The findings point to possible roles in diagnosis, treatment and clinical-trial design, but many mechanisms and clinical applications remain under study.
A review published in Science examines evidence that genes on the X and Y chromosomes influence immunity, cancer, aging and other disease risks, alongside the effects of sex hormones. The authors say the evidence could inform future diagnosis, treatment and clinical-trial design, although many proposed links still need further study.
The review, co-led by Dr. Dan Theodorescu of the University of Arizona Cancer Center and Dr. Dena B. Dubal of the University of California, San Francisco, evaluates findings from human studies, mouse models and genomic technologies. It considers how sex-chromosome genes may affect immune function, metabolism, brain aging, cancer and cardiometabolic disease.
One topic is X-chromosome inactivation. In most female cells, one of the two X chromosomes is largely switched off early in development, but some genes escape that process. The review describes evidence that some genes may become active again with age, potentially changing the amount of certain gene products in cells. Mouse research also suggests the parental origin of the active X may matter: in one study, mice whose cells relied mostly on the maternal X showed faster brain aging and memory decline. That finding is from animal research and does not establish the same effect in people.
The authors also discuss 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 cancers, heart disease, severe infections and Alzheimer’s disease. The review notes that chromosome loss is being investigated as both a possible marker of disease risk and a potential contributor to disease; the associations do not by themselves show cause and effect.
Implications for Treatment and Trials
The review challenges an account of sex differences in health that focuses mainly on circulating hormones. The authors argue that chromosome-linked biology may also affect disease risk, progression and response to treatment. If future research confirms particular mechanisms in people, chromosome-related information could help clinicians and researchers identify meaningful differences among patients.
The cancer findings illustrate both the promise and the limits. Theodorescu said his laboratory has found that tumors that lose the Y chromosome can evade immune defenses, but may also respond better to immunotherapy. That is a research finding, not a general treatment rule for patients. The broader review makes the case for studying sex chromosomes in clinical research so trial results can better account for biological variation. It does not establish a new diagnostic test or recommend changing current care.
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From Hormones to Chromosome Genes
Sex differences in disease have often been discussed through the effects of hormones such as estrogen and testosterone. The review adds chromosome genes as another area of investigation, describing effects that may operate independently of hormones or interact with them. Its central contribution is a synthesis of existing work across several fields, rather than a report of one new clinical trial.
The review grew out of discussions at the 2025 National Institute on Aging workshop on sex differences affecting human health across the lifespan, including discussions with Francesca Duncan of Northwestern University. It was also co-authored by Fabrisia Ambrosio of Harvard Medical School’s Schoen Adams Research Institute and Michael B. Stout of the Oklahoma Medical Research Foundation. The article is titled “X and Y chromosomes as determinants of aging and disease.”
““These chromosomes carry genetic instructions that shape how our cells age and how our bodies defend against major diseases throughout our lives.””
— Dr. Dan Theodorescu, review co-lead and corresponding author
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Which Links Are Causal?
The review brings together findings of different kinds and strengths. Many reported links—including associations between loss of the Y chromosome and several diseases—do not establish whether chromosome loss causes disease, results from aging or illness, or reflects other factors. The authors describe chromosome loss as a possible biomarker and potential contributor, with broader effects still being investigated.
It is also unclear how findings from mice, including those about which parental X chromosome is active, apply to human health. The review does not specify a validated test, a treatment decision that should be based on chromosome status, or when such information might enter routine care. The strength and relevance of each relationship may vary by tissue, disease and individual.
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Research Needed Before Clinical Use
The authors call for further investigation of sex-chromosome biology across the lifespan and for greater awareness of these factors in research. A next step is to test proposed mechanisms in human studies and determine whether chromosome-related measurements can reliably predict disease or treatment response. Researchers will also need to establish how such findings should be interpreted across different tissues and patient groups.
The review’s longer-term aim is to support sex-aware clinical trials and, eventually, more tailored diagnostics and treatment. No timeline for a clinical application is given, and the article does not announce a new trial or change in care. For now, the findings are a research framework that identifies questions for future studies.
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Key Questions
What does the Science review say about sex chromosomes?
It synthesizes evidence that X and Y chromosome genes may influence immunity, aging, cancer and other diseases, in addition to the effects of hormones. It reviews existing research rather than reporting a new clinical trial.
Does losing the Y chromosome cause cancer or heart disease?
The review describes associations between Y-chromosome loss and several conditions, including cancer and heart disease. Those links do not, on their own, establish that chromosome loss causes the conditions.
Could chromosome findings change cancer treatment now?
Theodorescu cited laboratory findings connecting Y-chromosome loss in tumors with immune evasion and possible immunotherapy response. The review does not set out a treatment recommendation or show that chromosome status can currently guide care for an individual patient.
Does the review show that the active X chromosome affects human brain aging?
It discusses mouse research in which the parental origin of the active X was associated with brain-aging and memory findings. Whether the same relationship applies to people remains unclear.
Source: rss
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