Researchers Shed Light on Underestimated Factor That Could Shape How We Age

Scientists have found that X and Y chromosomes may do much more than decide a person's biological sex. A new review of research, published in the journal Science on October 1, says these chromosomes could also affect how people age and how diseases develop. Experts from across the United States looked at studies on mice and humans to reach this conclusion. Their findings could one day change the way doctors treat serious illnesses like cancer, heart disease, and Alzheimer's disease.

For a long time, scientists believed that differences in health between males and females were mostly caused by hormones like estrogen and testosterone. But new research shows that the chromosomes themselves play a big role too. Dr. Dan Theodorescu, one of the review's authors and director of the Cancer Center at the University of Arizona, explained that X and Y chromosomes can directly affect how cells work, how the immune system responds, and how diseases grow. He said that today, the best understanding is that hormones and sex chromosomes work together.

Chromosomes are tiny, thread-like structures inside our cells that are made of DNA. Most humans have 23 pairs of chromosomes, and one of those pairs determines biological sex — the X and Y chromosomes. Everyone gets an X chromosome from their mother, while biological females get a second X from their father and biological males get a Y. This means most people are either XX or XY, though some people have other variations. The sex chromosomes, it turns out, keep doing important jobs long after a person is born.

One important discovery has to do with how the X chromosome behaves over time. In females, one of the two X chromosomes is mostly switched off early in life to keep the body from getting too much activity from X-linked genes. But as people get older, that silencing doesn't always hold, and some genes on the inactive X chromosome can turn back on — a process called X chromosome reactivation. Scientists found that this reactivation improved memory and thinking in older mice, which suggests it could someday be used as a treatment in humans.

Researchers also found that a gene called KDM6A, located on the X chromosome, was linked to better brain health in people with Alzheimer's disease. In mouse studies, this gene even reversed some of the damage caused by the illness. However, Dr. Theodorescu noted that reactivation is not always helpful. In some cases, turning certain X-linked genes back on could actually help diseases grow, so whether it helps or hurts depends on which genes are involved and at what point in life.

Having two X chromosomes comes with both benefits and risks for biological females. The X chromosome carries many genes that help cells stay healthy and strong, so having two copies may offer some protection against brain aging. However, women are still more likely to develop Alzheimer's disease than men, which shows these protections don't always work once a disease has already started. The two X chromosomes may also make the immune system stronger — helpful for fighting infections, but potentially risky if the immune system starts attacking the body's own tissues.

Heart health is also shaped by chromosomes in ways scientists are still learning. Men tend to have heart attacks at younger ages, but women are more likely to die from heart attacks or heart failure later in life. Researchers found that having two X chromosomes may drive some of this cardiac vulnerability, and has also been linked to weight gain and fatty liver disease. These findings suggest that the differences in heart health between men and women go beyond just hormones.

As men age, some of their cells can lose the Y chromosome, which is one of the most common genetic changes during normal aging in males. The Y chromosome isn't lost from every cell — it disappears from some cells, especially blood cells, while others keep it. Studies have linked this loss to heart disease, Alzheimer's disease, increased inflammation, and a higher risk of dying earlier. Dr. Theodorescu's lab also found that when cancer cells and immune cells lose the Y chromosome, cancers can grow more aggressively and shorten lifespans.

These discoveries could change how doctors approach treatment in the future. Right now, doctors consider whether a patient is male or female, but they don't usually check the status of X and Y chromosomes inside tissues or tumors. Scientists believe that testing for chromosome changes could one day help predict disease risk and guide treatment decisions, such as knowing whether a certain cancer therapy will work. Measuring Y chromosome loss in the blood, for example, might help identify men who are at higher risk for age-related illnesses.

Overall, this research challenges the old idea that X and Y chromosomes mostly just determine biological sex. Scientists now believe these chromosomes keep influencing health throughout a person's entire life, affecting everything from the brain to the heart to the immune system. Understanding how chromosomes work could lead to new ways to prevent disease and improve treatments for everyone. As Dr. Theodorescu put it, uncovering these mechanisms may ultimately lead to new approaches for preventing disease and improving treatment outcomes for both women and men.