mLOY: The genetic defect that explains why men have shorter lives than women

We have long been baffled as to why men live around five years less than women, on average. But now a new study suggests that, beyond the age of 60, the main 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 Forsberg, a researcher at Uppsala University in Sweden.

For decades it was thought that the male Y chromosome’s only function was to generate sperm that determine the sex of a newborn. A boy carries one X chromosome from the mother and one 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 happens when the mother cell divides to produce a daughter cell. In 2014, Forsberg analyzed the life expectancy of older men based on whether their blood cells had lost the Y chromosome, a mutation called mLOY. The effect recorded was “mindblowing,” the researcher recalls.

Men with fewer Y chromosomes had a higher risk of cancer and lived five and a half years less than those who retained this part of the genome. Three years later, Forsberg discovered that this mutation makes getting Alzheimer’s three times as likely. What is most worrying is the enormous prevalence of this defect. Twenty percent of men over the age of 60 have the mutation. The rate rises to 40% in those over 70 and 57% in those over 90, according to Forsberg’s previous studies. “It is undoubtedly the most common mutation in humans,” he says.

Until now, nobody knew whether the gradual disappearance of the Y chromosome in the blood played a pivotal role in diseases associated with aging. In a study just published in the journal Science, Forsberg and scientists from Japan and the US demonstrate for the first time that this mutation increases the risk of heart problems, immune system failure and premature death.

The researchers have created the first animal model without a Y chromosome in their blood stem cells: namely, mice modified with the gene-editing tool CRISPR. The study showed that these rodents develop scarring of the heart in the form of fibrosis, one of the most common cardiovascular ailments in humans, and die earlier than normal mice. The authors then analyzed the life expectancy recorded in nearly 15,700 patients with cardiovascular disease whose data are stored in the UK public biobank. The 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 the age of 60,” explains biochemist Kenneth Walsh, a researcher at the University of Virginia in the US and co-author of the study. In other words, this mutation would explain “four of the five years lower life expectancy in men.” Walsh’s estimate links to a previous study in which men with a high mLOY load live about four years less than those without it.

It is well known that men die earlier than women because they smoke and drink more and are more prone to recklessness. But, beyond the age of 60, genetics becomes the main culprit in the deterioration of their health: “It seems as if men age earlier than women,” Walsh points out.

The study reveals the molecular keys to the damage associated with the mLOY mutation. Within the large group of blood cells can be found the immune system’s white blood cells responsible for defending the body against viruses and other pathogens. The loss of the Y chromosome triggers aberrant behavior in macrophages, a type of white blood cell, causing them to scar heart tissue, which in turn increases the risk of heart failure. Researchers have shown that the damage can be reversed if they give mice pirfenidone, a drug approved to treat humans with idiopathic pulmonary fibrosis, a condition in which the lungs become scarred and breathing becomes increasingly difficult.

There are three factors that increase the risk of Y chromosome loss. The first is the inevitable ageing process. The longer one lives, the more cell divisions occur in the body and the greater the likelihood of mutations occurring in the genome copying process. The second is smoking. “Smoking causes you to lose the Y chromosome in your blood at an accelerated rate; if you stop smoking, healthy cells once again become the majority,” says Walsh. But the third is also inevitable: other inherited genetic mutations can increase the gradual loss of the Y chromosome in the blood by a factor of five, explains Forsberg.

Both Forsberg and Walsh believe that this study opens up an “enormous” field of research. Still to be studied is whether men with this mutation also have cardiac fibrosis and whether this is behind their heart attacks and other cardiac ailments. We also need to better understand why losing the Y chromosome damages health. “For now, we have shown that the Y chromosome is not just there for reproduction, but is is also important for our health,” says Forsberg. The next step is to identify which genes are responsible for the phenomenon.

The 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 60. It is abundant in the blood because this is a tissue that produces millions of new cells every day from blood stem cells. Healthy stem cells produce healthy daughter cells and mutated ones produce daughter cells with mLOY.

A previous study showed that this mutation of the Y chromosome disrupts the function of up to 500 genes located elsewhere in the genome. It has also been shown to damage lymphocytes and natural killer cells, evident in men with prostate cancer and Alzheimer’s disease, respectively.

There are hardly any tests for mLOY at present. But Forsberg and his colleagues have designed a PCR test that measures the level of this mutation in the blood and could serve to determine which levels of this mutation are harmful to health. “Right now, we see people in their 80s with 80% of their blood cells mutated, but we don’t know what impact this has on their health,” says Walsh.

Another unanswered question is why men lose the genetic mark of the male with age. The evolutionary logic, argue the authors of the paper, is that men are biologically designed to have offspring as soon as possible and to live 40 to 50 years at most. The spectacular increase in life expectancy in the last century has meant that men and women live to an advanced age – 80 and 86 years in Spain, respectively – which makes the effect of these mutations more evident. Another fact which possibly has some bearing on the issue: the vast majority of people who reach 100 are women.

“To transform all these discoveries into treatments, we first need to better understand this phenomenon,” says Forsberg. “We men are not designed to live forever, but perhaps we can increase our life expectancy by a few more years.”

Biochemist José Javier Fuster, who studies pathological mutations in blood cells at the National Center for Cardiovascular Research, stresses the importance of the work. “Until now it was not clear whether the loss of Y was the cause of cancer, Alzheimer’s disease and heart failure,” he explains. “This is the first demonstration in animals that it has a causal role.” The human Y chromosome is different from the mouse chromosome, so the priority now is to accumulate more data in humans. “This is a great first step in understanding this new mechanism behind aging-linked diseases,” he adds.

The cells of the human body group their DNA into 23 pairs of chromosomes that pair up one by one when a cell copies its genome to generate a daughter cell. The Y is the only one that does not have a symmetrical partner to pair up with: instead, it does so with an X chromosome; and the entire Y chromosome is often lost, explains Luis Alberto Pérez Jurado from Pompeu Fabra University in Barcelona. “For now, six genes have been identified within the Y chromosome that would be responsible for an impact on health,” he says. “All of them are related to the proper functioning of the immune system.” In part, this would also explain the greater vulnerability of males to viral infections, including Covid-19.