A new study reveals that Y chromosome loss may explain why men usually die younger than women. According to the research, the eventual death of the male sex chromosome can lead to heart muscle scarring. In some cases, this may cause fatal heart failure.

University of Virginia School of Medicine researcher Kenneth Walsh, Ph.D., said Y chromosome loss affects about 20% of 60-year-old men and 40% of 70-year-olds. While aging plays the most significant role in genetic changes, smoking, and genetic predisposition can increase the risk of Y chromosome loss.

Walsh added that men experiencing Y chromosome death might greatly benefit from a medicine that alleviates harmful heart scarring. He suggested the drug could help offset other male sex chromosome loss complications. These maladies may impact men’s health in various body parts besides the heart.

On average, women outlive men in the U.S. by five years. Walsh estimates the new research may explain almost four of the five-year disparity.

“Particularly past age 60, men die more rapidly than women. It’s as if they biologically age more quickly,” said study author Kenneth Walsh in a press release. “The years of life lost due to the survival disadvantage of maleness is staggering. This new research explains why men have shorter lifespans than women.”

Male Versus Female Chromosomes

In humans, each cell usually possesses 23 pairs of chromosomes. Twenty-two of these cells, called autosomes, express themselves the same in both men and women. The 23rd pair consists of the sex chromosomes, which differ between males and females. Women have two X chromosomes while men have one X and one Y.

However, many men lose their Y chromosome in some cells as they age, with smokers at an elevated risk. Y chromosome loss doesn’t impact male reproductive cells, so children don’t inherit it. This process seems to occur at an exceptionally high rate in frequently replaced cells, such as blood cells.

Previous studies have discovered that men with Y chromosome loss tend to die younger. They also suffer from age-related neurodegenerative diseases such as Alzheimer’s more often. Walsh’s study is the first to prove that chromosome loss directly impacts men’s health.

The findings appeared on July 14, 2022, in the journal Science.


The Study Showing Why Men Die Younger Than Women

Researchers used innovative CRISPR gene-editing technology to create a specialized mouse model. They wanted to gain more insight into how Y chromosome loss affects the blood. So, they removed the Y chromosome from the bone marrow cells of male mice.

The experiment resulted in accelerated rates of age-related diseases in the mice. It also made them more vulnerable to heart scarring and caused them to die much younger than average. The research team concluded that inflammation by itself didn’t cause these issues. They determined that the Y chromosome loss triggered a cascade of immune system responses. In turn, this caused tissue scarring, or fibrosis, in the mice.

Researchers believe this immunological reaction could cause rapid disease development. The authors added that tissue fibrosis could also accelerate aging, contributing to an estimated 45% of deaths in Western nations.

The researchers concluded that Y chromosome loss likely caused fibrosis in the mice. To investigate how chromosome loss impacts human men, they analyzed from the U.K. Biobank. Not surprisingly, it revealed that Y chromosome death contributed to cardiovascular disease and heart failure. It also found that chromosome loss could cause men to die younger.

Walsh explained how an entire chromosome could disappear: “The DNA of all our cells inevitably accumulate mutations as we age. This includes the loss of the entire Y chromosome within a subset of cells in men. Understanding that the body is a mosaic of acquired mutations provides clues about age-related diseases and the aging process itself.”

“Studies that examine Y chromosome loss and other acquired mutations have great promise for the development of personalized medicines that are tailored to these specific mutations,” he added.

Potential Treatment for Heart Scarring Due to Y Chromosome Loss

Even though it sounds terrifying, researchers also had good news to share from the study. When they gave mice an antibody that inhibits white blood cell activity, it reversed cardiac dysfunction. This finding provides hope that drugs formulated to treat fibrosis could prevent early death from heart disease.

Walsh noted that the FDA already approved one drug, pirfenidone, to treat idiopathic pulmonary fibrosis, a type of lung scarring. The drug may also cause fewer men to die from heart failure and chronic kidney disease, though tests haven’t yet determined this. Further studies are needed to determine whether the medication could attenuate the impact of Y chromosome loss.

The authors believe that antifibrotic drugs may have a pronounced effect on men with Y chromosome loss. However, the research team noted that few tests currently detect chromosome loss.

Walsh’s collaborator, Lars A. Forsberg of Uppsala University in Sweden, developed an inexpensive polymerase chain reaction (PCR) test to solve this problem. While it detects Y chromosome loss, researchers haven’t yet tested it outside Walsh’s labs.

Walsh foresees a bright future for the PCR test: “If interest in this continues and it’s shown to have utility in terms of being prognostic for men’s disease and can lead to personalized therapy, maybe this becomes a routine diagnostic test,” he said.


Final Thoughts on Research Revealing Why Males Die Younger Than Females

A new study by the University of Virginia and Uppsala University found that Y chromosome loss causes men to die younger. On average, women outlive men by about five years. The researchers believe that male sex chromosome loss can explain most of this difference. They removed the Y chromosome from the blood cells of male mice and observed tissue scarring as a result. The team noted the same effects in human men.

While fibrosis contributes to 45% of deaths in industrialized nations, the researchers provided some positive news. Antifibrotic drugs have shown promise in reversing age-related diseases like heart failure and cardiovascular disease. Hopefully, treatments will improve so men won’t die of a largely unavoidable illness.