mLOY: The genetic defect that explains why men live less than women | Science

Men live about five years less on average than women and the causes are unclear. Now, a study suggests that after age 60, the biggest culprit is a genetic defect: the loss of the Y chromosome, which determines sex at birth.

“It’s clear that men are more fragile, the question is why?”, explains Lars Forsbergresearcher at the University of Uppsala (Sweden).

For decades, the male Y chromosome was thought to be a “genetic dump” whose sole function is to generate sperm that determines 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 generate a new cell. is. In 2014, Forsberg looked at the life expectancy of older men based on whether or not they lost blood cells from their Y chromosome, a mutation called mLOY. The recorded effect was “enormous”, 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 kept this part of the genome. Three years later, Forsberg discovers that this mutation triples the risk of suffering from Alzheimer’s. What is most disturbing is the enormous prevalence of this defect. 20% of men over 60 have this mutation. The rate rises to 40% among those over 70 and 57% among those over 90, according to previous studies by this geneticist. “It’s probably the most common mutation in humans,” he says.

Until today, no one knew if the progressive disappearance of the chromosome in the blood had a causal role in diseases related to aging. In a study published today in the magazine Sciencea benchmark of the best science in the world, Forsberg, in collaboration with scientists from Japan and the United States, 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 common cardiovascular conditions in humans – and die earlier than normal mice. The authors then analyzed the recorded life expectancy of nearly 15,700 patients with cardiovascular disease whose data is stored in the UK public biobank. Their analysis shows that the 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”, explains the biochemist Kenneth Walsh, 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 stems from a previous study in which men with a high mLOY load 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 age 60, genetics becomes the main culprit in the deterioration of health; “It seems that men age faster than women,” says Walsh.

Study reveals molecular keys to damage associated with mLOY mutation. Within the large group of blood cells are the white blood cells of the immune system responsible for defending the body against viruses and other pathogens. The loss of the Y chromosome triggers aberrant behavior of macrophages, a type of white blood cell, in a way that causes more scarring in heart tissue, which increases the risk of heart failure. The researchers showed that the damage can be reversed if the mice are given pirfenidonea drug approved in humans to treat idiopathic pulmonary fibrosis.

“It seems that men age faster than women”

Three risk factors increase the effects of the loss of the Y chromosome. The first is unavoidable: aging. The more years one lives, the more cell divisions occur in the body and the greater the likelihood that mutations will occur during 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 quit smoking, healthy cells come back in the majority,” Walsh sums up. The third is also unavoidable: there are other inherited genetic mutations that multiply by five the progressive loss of the Y chromosome in the blood, explains Forsberg.

The two scientists believe that this study opens up a “huge” field of research, even if for the moment these are only the first steps. There is a need to investigate whether men with this mutation also have cardiac fibrosis and whether this is the cause of their heart attacks and other heart conditions. We also need to better understand why the loss of the Y chromosome is detrimental to health. “So far, we’ve shown that the Y chromosome is not genetic junk that’s only used for reproduction, but is important for health,” says Forsberg. The next step is to identify the genes responsible for this phenomenon.

Loss of this chromosome has been detected in all 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 it 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, this mutation on the Y chromosome was shown to disrupt 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 essential components of the immune system, in men with prostate cancer and Alzheimer’s disease respectively.

There are virtually no tests for mLOY at present. The team of scientists designed a PCR test that measures the level of this mutation in the blood which could be easily scaled and would be used to determine which levels of this mutation are harmful to health. “Right now we’re seeing people in their 80s who have 80% of their blood cells mutated, but we don’t know what impact that has on their health,” Walsh says.

Another unanswered question for now is why men lose the male genetic mark with age. The evolutionary logic, argue the book’s authors, is that humans are biologically designed to bear offspring as soon as possible and live 40 or 50 years at most. The dramatic increase in life expectancy over the past century has caused men and women to live to very old ages — 80 and 86 in Spain, respectively — making the effect of these mutations. Another fact may be related: the vast majority of people who reach 100 years of life They are women.

“To turn all of these discoveries into treatments, we need to better understand this phenomenon,” Forsberg points out. “Men aren’t meant to live forever, but maybe we can increase our life expectancy by a few more years,” he adds.

the biochemist Jose Javier Fuster studies pathological mutations in blood cells at the National Center for Cardiovascular Research. The specialist emphasizes the importance of work. “Until now, it was unclear whether the loss of Y was the cause of cancer, Alzheimer’s disease and heart failure or just an occasional marker,” he explains. “This is the first demonstration in animals that it has a causal role.” The human Y chromosome is different from that of the mouse, so the priority now is to accumulate more data in humans. “This is an important first step in understanding this new mechanism at the origin of age-related diseases,” he adds.

Cells in 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 symmetrical partner with which to adapt: ​​it does so with an X chromosome; and often the whole Y chromosome is lost, says Luis Alberto Pérez Jurado, of Pompeu Fabra University in Barcelona. “So far, six genes have been identified within the Y chromosome that are believed to be responsible for health impacts. All of them are linked to the proper functioning of the immune system,” he points out. This would also partly explain the greater vulnerability of men to viral infections, including covid.

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