mLOY: the genetic defect that explains why men live less than women

Men live about five years less on average than women and the causes are not clear.

Today, a study suggests that, after 60, the biggest culprit is a genetic defect: the loss of the Y chromosome, which determines sex at birth.

“It is clear that men are more fragile, the question is why?” explains Lars Forsberg, a researcher at Uppsala University (Sweden).

For decades it has been thought that the male Y chromosome is a "genetic garbage dump" whose only function is to generate sperm that determine the sex of a newborn.

A boy carries an X chromosome from the mother and a Y from the father, while a girl carries two Xs, one from each parent.

In 1963, a team of scientists discovered that as men age, their blood cells lose the Y chromosome due to a copying error that occurs when a stem cell divides to produce a

.

In 2014, Forsberg looked at the life expectancy of older men based on whether their blood cells had lost their Y chromosome, a mutation called mLOY.

The recorded effect was "huge", recalls the researcher.

Men with fewer Y chromosomes had a higher risk of cancer and lived five and a half years less than those who did retain this part of the genome.

Three years later, Forsberg discovered that this mutation tripled the risk of Alzheimer's.

What is most worrying is the enormous prevalence of this defect.

20% of men over the age of 60 have this mutation.

The rate rises to 40% in those over 70 and 57% in those over 90, according to previous studies by this geneticist.

"It is without a doubt the most common mutation in humans," he sums up.

Until today, no one knew if the gradual disappearance of the chromosome in the blood has a causal role in diseases associated with aging.

In a study published today in the journal

, a benchmark for the best world science, Forsberg, together with scientists from Japan and the US, demonstrates for the first time that this mutation increases the risk of heart problems, immune system failure and premature death. .

Researchers have created the first animal model without a Y chromosome in their blood stem cells: mice modified with the gene editing tool CRISPR.

The work shows that these rodents develop scars in the heart -fibrosis, one of the most frequent cardiovascular ailments in humans- and die earlier than normal mice.

The authors then analyzed the recorded life expectancy of almost 15,700 patients with cardiovascular disease whose data is stored in the UK public biobank.

Their analysis shows that loss of the Y chromosome in the blood is associated with a 30% increased risk of dying from cardiovascular disease.

"This genetic factor can explain more than 75% of the difference in life expectancy between men and women over 60 years," explains biochemist Kenneth Walsh, a researcher at the University of Virginia (USA) and co-author of the study.

In other words: this mutation would explain "four of the five years less than life in men".

Walsh's calculation follows from a previous study in which men with high mLOY burden live about four years less than those without.

It is well known that men die earlier than women because they smoke and drink more and are more prone to reckless acts, among other external risk factors.

But, after 60, genetics becomes the main responsible for the deterioration of health;

"It seems as if men age faster than women," says Walsh.

The study reveals the molecular keys of the damage associated with the mLOY mutation.

Within the large group of blood cells are the white blood cells of the immune system responsible for defending the body from viruses and other pathogens.

The loss of the Y chromosome triggers aberrant behavior in macrophages, a type of white blood cell, in a way that causes more scarring in heart tissue, which in turn increases the risk of heart failure.

The researchers have shown that the damage can be reversed if they give mice pirfenidone, a drug approved in humans to treat idiopathic pulmonary fibrosis.

“It seems as if men age faster than women”

There are three risk factors that increase the effects of Y chromosome loss. The first is unavoidable: aging.

The more years one lives, the more cell divisions occur in the organism and the greater the probability that mutations will occur in the process of copying the genome.

The second is smoking.

“Smoking causes you to lose the Y chromosome from the blood in an accelerated way;

and if you stop smoking, healthy cells become the majority again”, summarizes Walsh.

The third is also unavoidable: there are other inherited genetic mutations that multiply the gradual loss of the Y chromosome in the blood by five, explains Forsberg.

Both scientists believe that this study opens a "huge" field of research, although for the moment these are only the first steps.

It is necessary to study if men with this mutation also have fibrosis in the heart and if this is the cause of their heart attacks and other cardiac ailments.

It is also necessary to better understand why losing the Y chromosome harms health.

"So far we have shown that the Y chromosome is not a genetic garbage can that only served for reproduction, but that it is important for health," Forsberg argues.

The next step is to identify which genes are responsible for this phenomenon.

The loss of this chromosome has been detected in all the organs and tissues of the body and at all ages, although it is more evident after the age of 60. It is abundant in the blood because this is an organ that produces millions of new cells every day from blood stem cells.

Healthy stem cells produce healthy daughters, and mutated stem cells produce mLOY daughters.

In a previous study, it was shown that this mutation on the Y chromosome disrupts the functioning of up to 500 genes located in other parts of the genome.

It has also been shown to damage lymphocytes and natural killer cells, two critical components of the immune system, in men with prostate cancer and Alzheimer's, respectively.

There are hardly any tests for mLOY at present.

The team of scientists has designed a PCR test that measures the level of this mutation in the blood that could be easily scaled and would serve to determine what levels of this mutation are harmful to health.

"Right now we see people in their 80s who have 80% of their blood cells mutated, but we don't know what impact this has on their health," says Walsh.

Another unanswered question for now is why men lose the male genetic mark with age.

The evolutionary logic, argue the authors of the work, is that men are biologically designed to have offspring as soon as possible and live 40 or 50 years at most.

The spectacular increase in life expectancy in the last century or so has meant that men and women live to very old ages —80 and 86 years in Spain, respectively— which makes the effect of these mutations more evident.

Another possibly related fact: the vast majority of people who reach 100 years of life are women.

"To transform all these discoveries into treatments we need to better understand this phenomenon," Forsberg highlights.

"Men are not designed to live forever, but maybe we can increase our life expectancy a few more years," she adds.

Biochemist José Javier Fuster studies pathological mutations in blood cells at the National Center for Cardiovascular Research.

The specialist highlights the importance of work.

"Until now it was not clear whether the loss of Y was a cause of cancer, Alzheimer's and heart failure or just a chance marker," he explains.

"This is the first demonstration in animals that it has a causal role."

The human Y chromosome is different from the mouse one, so the priority now is to accumulate more data in humans.

“This is a great first step in understanding this new mechanism behind age-related diseases,” he adds.

The cells of the human body bundle their DNA into 23 pairs of chromosomes that pair up one by one when a cell copies its genome to generate a daughter.

The Y is the only one that does not have a symmetric partner with which to fit: it does so with an X chromosome;

and often the entire Y chromosome is lost, explains Luis Alberto Pérez Jurado, from Pompeu Fabra University in Barcelona.

“So far, six genes have been identified within the Y chromosome that would be responsible for the impacts on health.

All of them are related to the proper functioning of the immune system”, he highlights.

In part, this would also explain the greater vulnerability of men to viral infections, including covid.

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