X and Y chromosomes shape how cells age and fight disease too

By Stephen Beech

Sex chromosomes drive how human cells respond to disease — including cancer, reveals new research.

The study brings together growing evidence that the X and Y chromosomes do much more than just determine biological sex.

It shows that they drive the risk of several diseases, independent of hormones.

The review, published in the journal Science, reveals that the X and Y chromosomes also shape how cells function and age.

Differences in health between men and women have long been attributed mainly to sex hormones such as estrogen and testosterone.

However, more recent research suggests that genes on the X and Y chromosomes also play a direct role, working both on their own and alongside hormones.

The review describes how sex chromosomes influence immunity, metabolism, brain aging, cancer and heart disease.

Study co-leader Dr. Dan Theodorescu said: "X and Y chromosomes are often thought of as simple determinants for biological sex, but their role in human health is much larger.

"Our review shows that these chromosomes carry genetic instructions that shape how our cells age and how our bodies defend against major diseases throughout our lives."

The study reveals that genes on the X and Y chromosomes, rather than circulating hormone levels alone, determine disease risk, progression and therapeutic responses across key heath areas.

These include aging, cancer, neurological conditions, immune system functions and cardiometabolic disease.

The review, which evaluated and synthesized existing evidence from human studies, mouse models and genomic technologies, describes several processes inside cells that shape health across the lifespan.

In women, one of the two X chromosomes is largely switched off early in development, but some of its genes stay active and others can switch back on with age, giving female cells extra doses of certain genes.

Studies in mice suggest it also matters whether a cell's active X came from the mother or the father.

Men inherit their only X chromosome from their mother, while in women each cell uses either the mother's or the father's copy.

In mice whose cells relied mostly on the mother's X, faster brain aging and memory decline were observed.

With age, some cells lose a sex chromosome. In women, loss of an X is linked to higher leukemia risk, although its broader effects remain largely unknown.

In men, loss of the Y, most often measured in blood, is linked to cancers, heart disease, severe infections and Alzheimer's disease.

The loss of those chromosomes is being explored as both a biomarker of and potential contributor to age-related disease.

University of Arizona physician-scientist Theodorescu said: "When we look inside human cells, we see that X and Y chromosomes are participants in health and disease throughout a person's life.

"In cancer, for example, our laboratory has found that tumors that lose the Y chromosome can evade the immune system, yet may respond better to immunotherapy.

"Understanding this biology could help us tailor treatment."

Theodorescu's previous related research focused on how the loss of the Y chromosome in T cells and cancer cells in men gave tumors the ability to evade the immune system, providing an explanation why the loss of the chromosome has been linked to increased mortality from carcinomas.

Other recent research by his group showed how loss of the Y chromosome in normal-appearing tissues acts as an "early warning sign" and may mark a hidden zone of genetic risk for cancer to develop.

Theodorescu added: "Our hope is that this review will stimulate further investigation and bring greater awareness to the significant potential of studying the X and Y chromosomes in cancer and other diseases, with far-reaching diagnostic and therapeutic implications.

"This would help ensure that treatments and diagnostics are tailored to match every patient's unique profile.

"When clinical trials are designed to be sex-aware, researchers can turn these cellular differences into personalized medical care."