It’s been
known for more than a half-century that many men lose their Y chromosomes as
they age. But no one knew if it really mattered. The loss of Y could just be a
sign of aging, like gray hair, with no clinical relevance.
اضافة اعلان
Now, though,
researchers report that it can matter. Very much.
A new study using
male mice genetically engineered to lose their Y chromosomes provides insight.
The paper, published July 14 in the
journal Science, found that when the Y
chromosome was gone from blood cells in those mice, scar tissue built up in the
heart, leading to heart failure and a shortened life span.
Because there was a
direct cause-and-effect relationship between the loss of Y and ailments of
aging in the mice, the study bolsters the notion that the same thing can happen
in human males. Researchers have documented an increase in risk for
chronic diseases like heart disease and cancer-related to loss of the Y chromosome in
many studies over the years, including the new one, which used data from a
large genetic study of the British population. The loss of Y could even account
for some of the difference between the life spans of men and women, the authors
of the Science study say.
Other investigators
not associated with the work were impressed.
“The authors really
nailed it here,” said Dr Ross Levine, the deputy physician in chief for
translational research at Memorial Sloan Kettering Cancer Center in New York.
“It’s super important work.”
The inspiration for
the new research came when Lars Forsberg, a researcher at
Uppsala University,
ran into a former professor on a bus in Uppsala, Sweden, in 2013. They began
talking, and the professor told Forsberg that the Y chromosomes in fruit flies
were more important than previously appreciated.
Forsberg was
intrigued. He had never paid much attention to the loss of Y chromosomes. Males
have one X and one Y (females have two X’s), and nearly all the genes used by
male cells are genes on the X. Forsberg had shared the common view that the Y
chromosome was pretty much a genetic wasteland.
At least 40 percent
of males lose the Y chromosome from some of their blood cells by age 70. And by
age 93, at least 57 percent have lost some of it.
The chromosome is
lost sporadically from blood cells during cell division, when it is kicked out
of some cells and then disintegrates. The result is what researchers call a
mosaic loss of Y.
There is no way,
other than to stop smoking, to reduce the risk of losing the Y chromosome. And
the condition is unrelated to men having lower levels of testosterone in their
bodies as they age. Taking testosterone supplements would have no effect, nor
would it reverse the consequences.
Curious about the
idea his professor had proposed, Forsberg went back to his computer and looked
at data on 1,153 aging men in a large Swedish study, the Uppsala Longitudinal
Study of Aging Men.
“I had the data in
a few hours and I was like, ‘Wow,’” Forsberg said. “I saw that men with loss of
Y in a large proportion of their blood cells survived only half as long, 5.5
years versus 11.1 years.
“You can imagine my
surprise,” he said. “Of course I redid everything.”
The finding held
up, and he published a paper in the journal Nature Genetics in 2014, reporting
that increased death rates and cancer diagnoses were associated with a loss of
the Y chromosome in blood cells.
He quickly founded,
and became a shareholder in, the company Cray Innovation to test men for loss
of Y.
Other researchers
began publishing similar analyses. Soon, about 20 independent papers showed
associations between loss of the Y chromosome in blood cells and heart disease,
shortened life spans, and various age-related diseases like solid tumors and
blood cancers.
At that point,
Forsberg heard from Kenneth Walsh, director of the Hematovascular Biology
Center at the
University of Virginia School of Medicine. Walsh had become
interested in the loss of Y chromosomes because of his work on a different type
of genetic loss that occurs with aging: an increase in cancer mutations in
blood cells called CHIP. People with CHIP have a greater risk of heart disease
and cancer, which prompted Levine to set up a CHIP clinic at Sloan Kettering.
In January, Dr
Pradeep Natarajan, director of preventive cardiology at
Massachusetts General Hospital, and others formed a company, TenSixteen Bio, to develop a
cost-effective test for CHIP and to study treatments to prevent its
consequences.
But, Walsh noted,
CHIP mutations are only a small part of the genetic alterations that occur with
aging.
“What’s the rest of
this pie?” he asked. He wondered about Y chromosomes and began planning a way
to see if there was a direct cause and effect between loss of Y in blood cells
and diseases. That led to his study with mice.
At first the mice
seemed fine, Walsh said, but “they aged poorly.” Their life spans were
shortened and they developed scar tissue in their hearts, kidneys, and lungs,
including non-ischemic heart failure, a type that is not the result of a heart
attack and whose cause is poorly understood. The animals’ mental abilities also
were diminished.
Working with
Forsberg, Walsh then examined data from the UK Biobank involving 223,173 men.
Men with mosaic
loss of Y had a 41 percent increased risk of dying from any cause during a
seven-year follow-up and a 31 percent increased chance of dying from any
cardiovascular disease. The more cells that lost Y chromosomes, the greater the
risk.
It is too soon to
say what men should do — other than to stop smoking — to protect themselves
from losing their Y chromosomes or to alleviate the consequences.
Those in Walsh’s
group found they could protect the hearts of the mice without Y chromosomes by
blocking TGF-beta, a key molecule involved in the production of scar tissue.
Dr Stephen Chanock,
director of the division of cancer epidemiology and genetics at the National
Cancer Institute, said the mouse study was “really cool.” But he noted that
there was no evidence yet that drugs to block TGF-beta would be effective in
men who lost their Y.
And, for now, there is little point in testing men for loss
of Y, Chanock said, adding that “the over-interpretation of these data for
monetary purposes worries me deeply.”
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