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UVA Health Research Reveals Causal Relationship Between Y Chromosome Loss & Heart Failure

It’s well established that women outlive men by several years. Many factors contribute to this disparity, but we now know a significant reason why: loss of the Y chromosome (LOY) leads to heart disease.

This finding comes from a UVA Health-led global collaboration — and could open the door to extending male longevity.

UVA Health researcher Ken Walsh, PhD, working with colleagues in Sweden and Japan, identified a causal relationship between Y chromosome loss and cardiac fibrosis, dysfunction, and mortality in men. They published their findings in the journal Science.

“Men live 6 years less than women in industrialized countries,” Walsh says. “Most of this mortality occurs past age 50. It appears that men biologically age faster. Our ongoing studies focus on understanding the underlying basis of biological age.”

Mouse Models, Biobank Analysis Confirm Findings

The research team includes:

  • Walsh, a professor and member of the Robert M. Berne Cardiovascular Research Center at UVA Health
  • Soichi Sano, a prior fellow at the Berne Center, and now an associate professor at the Cardiovascular Research Center in Osaka
  • Lars Forsberg, a geneticist at Uppsala University in Sweden

For years, differences in aging rates were attributed to behavior and hormones, Walsh says. Then, in 2014, Forsberg and colleagues found the loss of the Y chromosome in men’s blood cells increases the chance of dying from any cause. It also contributes to the development of cancer and the incidence of Alzheimer’s disease.

However, it was unclear whether loss of the Y chromosome was only a biomarker of biological age, such as gray hair, or whether it was directly responsible for the accelerated mortality and morbidity. Thus, Walsh, Forsberg, and Sano later tested for a causal connection between the loss of the Y chromosome and cardiovascular disease.

The group established a mouse model of Y chromosome loss, as occurs in the white blood cells of some males.

When the team studied the hearts of LOY mice, they found:

  • Cardiomyopathy and other diseases of aging got worse as the mice aged.
  • The mice with Y chromosome loss had shorter lifespans.
  • Focusing on the heart, they found more fibrosis that appeared to be contributing to cardiac dysfunction.

The team then examined the relationship between Y chromosome loss and heart disease in humans by analyzing survival data of more than 200,000 men in a United Kingdom biobank.

Their key finding: Men with loss of the Y chromosome in more than 40% of their white blood cells showed a 31% increased risk of cardiovascular disorders when compared to men without LOY.

How & Why Do Men Lose Their Y Chromosome?

The Y chromosome controls much more than sex characteristics. It also plays an important role in immunity. Recently, the genetic sequencing of the Y chromosome was completed. The Y chromosome is unique in that it contains many repeat sequences or palindromes. This sequence complexity likely makes it prone to loss due to mistakes that occur when cells divide.

“If a cell messes up replication of the Y, it can lose this chromosome during cell division,” Walsh says. “Cells probably get it right more than 99.9% of the time, but over 60 or 70 years, a lot of mistakes can accrue, leading to a lot of cells that lack the Y chromosome.”

By age 70, more than 40% of men have lost a detectable amount of Y chromosome. Over time, all men lose some of their Y, but this occurs at different rates in different individuals.

Antifibrotic Medications Could Help Extend Male Longevity

In the mouse studies, the team treated the LOY mice with an antibody targeting a protein called TGFβ1. The antibody blocks the signaling pathway for the TGFβ1 protein. This treatment reduced the formation of fibrosis in the LOY mice hearts, reversing the heart dysfunction.

Men might also respond to antifibrotic medicine, Walsh says. Hypothetically, a simple polymerase chain reaction (PCR) test can be used to test for loss of the Y chromosome in men. Depending on an individual’s symptoms, this could indicate that further testing is needed, such as cardiac magnetic resonance imaging (MRI) to check for fibrosis.

The FDA-approved drug pirfenidone, as well as other anti-fibrotic drugs currently under development, could be especially effective in men with notable loss of their Y chromosome, Walsh says. Pirfenidone treats idiopathic pulmonary fibrosis. It’s being tested to see how it works on fibrosis related to heart failure and chronic kidney disease.

Research Goals: Understanding Age-Related Pathologies

Future studies hope to improve understanding of how loss of the Y chromosome contributes to age-associated pathology as well as the process of biological aging in men, Walsh says.

The research team hopes to define the role of genes on the Y chromosome and study how their loss impacts disease conditions.

“We think this can reveal features of the disease process and the biological aging process,” Walsh says. “And it could someday lead to designing a new class of drugs.”

Researchers plan to use blood samples from a large, diverse patient population to help pinpoint the genes lost on the Y chromosome.

This may help explain why men seem to age faster and die earlier than women.

  • At age 50, there are 100 men for every 100 women.
  • Past the age of 80, there are 50 men for every 100 women.

In 30 years, mortality doubles for men, Walsh says.

“As our work becomes more clinical, we hope to improve health span and longevity,” Walsh says.

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