Health differences between men and women have traditionally been linked largely to sex hormones such as estrogen and testosterone. However, new research highlights that genes located on the X and Y chromosomes also directly influence health, acting independently as well as in combination with hormones.

A 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, examines how sex chromosomes affect immunity, metabolism, brain ageing, cancer and cardiovascular disease. The findings also point to potential implications for diagnosis, treatment and the design of clinical trials.

Rather than being simple determinants of biological sex, the X and Y chromosomes contain genes that can influence how cells age and how the body responds to disease. The review brings together evidence from human studies, animal models and genomic research to explore these effects across the lifespan.

In women, one of the two X chromosomes is largely inactive from early development, but some genes escape this process and others may become active again with age. This can give female cells additional copies of certain genes. Research in mice also suggests that the parental origin of the active X chromosome may influence ageing-related outcomes, including brain ageing and memory.

Sex chromosome loss can also occur as people age. In women, the loss of an X chromosome has been associated with an increased risk of leukemia, although its wider effects are still being investigated. In men, loss of the Y chromosome, particularly in blood cells, has been associated with conditions including cancer, cardiovascular disease, severe infections and Alzheimer's disease. Researchers are studying whether sex chromosome loss could serve as both a marker and a possible contributor to age-related disease.

Theodorescu noted that X and Y chromosomes actively participate in health and disease throughout life. In cancer research, his laboratory has found that tumors that lose the Y chromosome may be better able to evade immune responses while potentially showing greater sensitivity to immunotherapy. Understanding these mechanisms could eventually help researchers develop more individualized treatment strategies.

The review grew out of discussions from the 2025 National Institute on Aging Workshop on sex differences affecting human health across the lifespan. The researchers hope the work will encourage further investigation into the role of sex chromosomes in cancer and other diseases and highlight their potential diagnostic and therapeutic importance.

Theodorescu's earlier research has examined how Y chromosome loss in T cells and cancer cells may help tumors evade the immune system and contribute to poorer outcomes. More recent work from his group suggests that Y chromosome loss in apparently normal tissues could serve as an early indicator of genetic changes associated with future cancer risk.

The review also included contributions from Fabrisia Ambrosio of the Schoen Adams Research Institute at Harvard Medical School and Michael B. Stout of the Oklahoma Medical Research Foundation.

Source: https://news.arizona.edu/news/study-sex-chromosomes-drive-how-bodies-deal-cancer-heart-health-and-longevity