The Y chromosome degrades over time and men's health is paying for it

The Y chromosome can disappear over time in human males, which may introduce a number of health problems. While the exact trigger for such degeneration is unknown, environmental factors can play a significant role. New research on the topic hints that the human Y chromosome is evolutionarily unstable and could even become extinct in the future.

Chromosomal complications

Most people have 23 pairs of chromosomes, including a pair of sex chromosomes that can be either an X chromosome or a Y chromosome. Having two X chromosomes usually designates a human as biologically female, while having one X chromosome and one Y chromosome designates a human as male, though this is separate from a person's gender identity.

The Y chromosome is only about one-third the size of the X and contains far fewer genes. Now, scientists have found that this smaller chromosome can actually degrade over time. "The idea is that as men grow older, they lose this chromosome from many of their cells, which drives age-related disease," said New Scientist.

Specifically, the loss of the Y chromosome (LOY) has "important effects in shaping the activity of the immune system," and can open the door wider for several diseases, including "cancer, neurodegeneration, cardiovascular disease and acute infection," said a January 2025 study published in the journal Nature Reviews Genetics. "If you're a male, you do not want to lose your Y chromosome, it's definitely going to shorten your life," Kenneth Walsh, a professor at the University of Virginia, said to New Scientist.

When it comes to cancer, "tumors without the Y chromosome grew twice as fast as those with it," said New Scientist. This is largely because the "loss of the Y chromosome causes tumor cells to make proteins that exhaust T cells, a kind of immune cell that ordinarily recognizes and attacks cancers." In addition, research has shown that the risk of Alzheimer's disease greatly increases with LOY. Experts speculate that the "Y chromosome-deficient immune cells infiltrate the brain and may lead to increased inflammation or may be less able to regulate the inflammatory response," a symptom which is "characteristic of Alzheimer's disease," the study said.

Micro mistakes

Y chromosome loss is largely "due to cell division mistakes," said News Medical. This is "enormously common" and "not like some freakish accident," Lars Forsberg, a senior lecturer and associate professor at Uppsala University in Sweden, said to New Scientist. It likely happens to all males, but age increases the level of loss significantly. Additionally, there is "no data to suggest that men with loss of Y would feel it."

Other contributing factors include smoking and exposure to environmental toxins like air pollution, glyphosate herbicides and arsenic-contaminated water. Quitting smoking could reduce the risk, and "future research may identify specific mutations or factors that trigger LOY," said News Medical.

LOY is "increasingly viewed as a marker of genome instability and a biological indicator of environmental stress," said News Medical. It could also be a major reason why females tend to have longer lifespans. "Females seem to be the stronger sex from a genetic point of view, with a more stable and less disease-prone genome," said the study. While the Y chromosome degrades on the individual level, there is evidence that the chromosome may be going extinct on an evolutionary scale as well.

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Abstract

Loss of Y chromosome (LOY) is the most commonly occurring post-zygotic (somatic) mutation in male individuals. The past decade of research suggests that LOY has important effects in shaping the activity of the immune system, and multiple studies have shown the effects of LOY on a range of diseases, including cancer, neurodegeneration, cardiovascular disease and acute infection. Epidemiological findings have been corroborated by functional analyses providing insights into the mechanisms by which LOY modulates the immune system; in particular, a causal role for LOY in cardiac fibrosis, bladder cancer and Alzheimer disease has been indicated. These insights show that LOY is a highly dynamic mutation (such that LOY clones expand and contract with time) and has pleiotropic, cell-type-specific effects. Here, we review the status of the field and highlight the potential of LOY as a biomarker and target of new therapeutics that aim to counteract its negative effects on the immune system.