X and Y Chromosomes Drive Aging and Protect the Body Through Their Own Genes, Independent of Hormones: a Science Review Identifies Three Specific Mechanisms

X and Y Chromosomes Drive Aging and Protect the Body Through Their Own Genes, Independent of Hormones: a Science Review Identifies Three Specific Mechanisms

Biologists from the University of California, San Francisco, Harvard, the University of Arizona, and the Oklahoma Medical Research Foundation have published a review in Science showing that the sex chromosomes X and Y directly control cellular aging, immunity, and cancer risk, independent of estrogen and testosterone. Published on October 1, 2026, the review synthesizes mouse experiments and human data into three mechanisms.

For decades, differences in health between men and women were attributed to hormones. This review demonstrates that genes on the X and Y chromosomes themselves govern cellular aging and disease response through dosage: how many copies of a gene are active in a given cell and whether the cell reactivates silenced copies as it ages.

In women, one of the two X chromosomes is silenced during embryonic development, but 15–30% of its genes in humans remain active (3–7% in mice), giving female cells a double dose of those genes. One is KDM6A, an enzyme that removes protective packaging from DNA. To separate the gene's effect from that of ovarian hormones, researchers created mice with two X chromosomes but testes instead of ovaries, and modeled Alzheimer-like brain damage in them: these mice lost less memory and died less often, despite being hormonally male. In humans, a KDM6A variant with higher brain expression is associated with slower cognitive decline in Alzheimer's disease.

With age, some genes on the silenced X reactivate. The myelin gene Plp1 turns back on in the aging mouse brain, and boosting its expression improves memory in old animals of both sexes. The same phenomenon appears in immune cells: memory immune cells from old female mice reactivate such genes at twice the rate of other cell types. In some women, nearly all cells use only one parental copy of the X chromosome throughout life. In one experiment, mice expressing only the maternal X copy performed worse in a maze, and the memory gap widened with age. The hippocampus, the brain region responsible for memory, aged faster in these mice according to DNA methylation clocks, even though their blood aged at the normal rate. The cause was that several genes on the maternal X had gone silent in hippocampal neurons; when researchers reactivated them with CRISPR, memory in old females improved.

A parallel fate awaits the Y chromosome in men: with age, blood cells increasingly lose it altogether, making this the most common chromosomal loss in aging males, detectable by around age sixty. In bladder cancer tumors, loss of Y depletes the T-cells that attack those tumors, making the cancer more aggressive. The same loss appears in healthy tissue adjacent to the tumor and in T-cells surrounding it; when Y loss occurs in both locations simultaneously, the prognosis is worse than when it is found in only one, suggesting that Y loss can propagate between neighboring cells of different types and jointly shape disease outcome.

"In oncology, our lab has found that tumors that have lost the Y chromosome can evade the immune system but may respond better to immunotherapy. Understanding this biology could help tailor treatments more precisely," Dan Theodorescu, director of the University of Arizona Cancer Center and co-author of the review, told MedicalXpress.

The review grew out of a 2025 National Institute on Aging seminar on sex differences in health and brings together two previously separate lines of research: the neurobiology of brain aging and the oncoimmunology of Y chromosome loss. The authors flag as an unresolved problem the near-total absence of these markers from diagnostics and clinical trials: Y chromosome loss, expression from the "silenced" X, and skewed X-inactivation favoring one parental copy.