How vanishing Y chromosomes could help explain men’s ill health
How vanishing Y chromosomes could help explain men's ill health | New Scientist.
BlockquoteThe enigmatic Y chromosome has a tendency to disappear from cells with age. Now, research is revealing the long-term impacts this can have on disease risk and life expectancy
WOMEN, on average, live longer than men. This trend can be seen as far back as records stretch, and is true of every country in the world today. Many explanations have been put forward: men take more risks or smoke more, oestrogen is protective against health conditions, two X chromosomes are better than one… the list goes on. Some of these can account for small fractions of the difference; many have been debunked. None are wholly satisfying.
Now, researchers have come up with an intriguing alternative explanation for much of this lifespan difference – that it all comes down to the Y chromosome. Specifically, the idea is that as men grow older, they lose this chromosome from many of their cells, which drives age-related disease.
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Losing your Y chromosome in this way isn’t something that you would notice happening. “As far as I know, there are no data to suggest that men with loss of Y would feel it,” says Lars Forsberg at Uppsala University in Sweden. However, it turns out that a significant fraction of older men are affected, and researchers are now uncovering long-term consequences for the immune system and the risk of developing cancer, heart disease and even Alzheimer’s.
“If you’re a male, you do not want to lose your Y chromosome, it’s definitely going to shorten your life,” says Kenneth Walsh at the University of Virginia. The growing recognition of the importance of the Y chromosome for general health is opening the door to potential new ways to keep men healthier as they age.
Most people have 22 pairs of chromosomes plus two sex chromosomes – a pair of Xs or an X and a Y. The Y holds the master switch for determining the sex of a fetus (though not an individual’s gender identity) and, in adults, it maintains sperm production. It is one of the smallest chromosomes, about a third the size of the X, and it contains few genes. That said, it also has a lot of features that make it challenging to analyse, which meant it was the last human chromosome to be fully sequenced in 2023, before which over half of its sequence was a mystery. Many of its functions still aren’t completely understood.
That some men permanently lose the Y chromosome in some of their cells came to light in genetic studies from the 1960s and 70s, but it was thought this was just a benign side effect of ageing. Then, in the 80s and 90s, cancer biologists reported that men’s tumours sometimes lacked Y chromosomes. But with little interest in the Y’s contribution to adult physiology beyond sperm production, this too never received serious attention.
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Things changed in 2014 when a long-term health study of 1153 Swedish men in their 70s and 80s yielded a fortuitous discovery. These participants had given blood samples for DNA analysis and Forsberg and his colleagues found the Y was missing from a significant fraction of blood cells in around 8 per cent of participants. Then the team saw something striking: the median lifespan of these men was five and a half years shorter than that of those who hadn’t lost the Y from their blood cells.
Forsberg and his then supervisor Jan Dumanski, at Uppsala University, also found that men with loss of Y get cancer more frequently and develop Alzheimer’s disease at starkly elevated rates. In one study, for instance, they found that men with loss of Y were almost seven times as likely to develop Alzheimer’s than men without.
Dumanski says this series of findings “was very controversial – nobody wanted to believe in this”. But many larger subsequent surveys confirmed the findings and uncovered links between loss of Y and various other conditions. Most prominently, in 2022, Walsh and his colleagues analysed data from over 200,000 participants in the UK Biobank study and found that loss of Y was linked to increased risks of several forms of heart disease.
To begin to unravel why loss of Y has these impacts, we need to first understand how it becomes lost. The adult body contains around 30 trillion cells, and each day around 300 billion of these are replaced by new ones. Around 90 per cent of these newcomers are blood cells derived from haematopoietic stem cells in the bone marrow, including nearly 100 billion white blood cells.
Loss of Y occurs during this replacement process, when cells divide. Forsberg says this “is enormously common – it’s not like some freakish accident”, and he suspects it happens to all men to some extent, but ageing increases it dramatically. A study from February of 25,000 males aged 3 to 95 found that, overall, 11.5 per cent displayed loss of Y in at least 5 per cent of their white blood cells. However, very few participants aged below 50 showed detectable levels, whereas around 6 per cent of 50-to-60-year-olds did and over 40 per cent of the 80-plus population were affected.
Beyond simply ageing, the second major known risk factor is smoking, but loss of Y has also been linked to exposure to air pollution, glyphosate herbicides and arsenic-contaminated water.
Whether dividing cells are more likely to lose their Y over other chromosomes remains uncertain. Given that Y is small and has many repeating stretches of DNA, it may be easier to misplace than other chromosomes. But critically, a male cell that sheds its Y survives, whereas losing a non-sex chromosome “is so harmful, this cell will die”, says Dumanski.
In fact, Y-less haematopoietic stem cells appear to thrive, giving rise to a significant fraction of circulating blood cells. And these transformed cells – so the theory goes – promote major age-related conditions. (In females, loss of one of the X chromosomes can also occur, and perhaps as frequently as loss of Y, but the affected cells seem to become less abundant.)
Dumanski says that one of the big questions for this field is to establish what other cells in men are prone to losing their Y chromosomes. It is also worth clarifying that this phenomenon is distinct from the question of whether humans, over evolutionary timescales, could totally and permanently lose the Y chromosome (see “Will the Y completely disappear?”, below). It is also distinct from the very occasional loss of the Y chromosome from male reproductive cells, which can lead to intersex offspring. And it is important to point out that the vast majority of studies that have been conducted so far have been in cisgender men. While it’s likely that other people with Y chromosomes experience a similar loss of Y, it remains an open question exactly how they are affected.
A serious problem
Nevertheless, the discovery that many older men lose their Y in a significant fraction of blood cells and are also living shorter lives suggests something very serious is going on.
From the get-go, Forsberg and Dumanski hypothesised that disrupted immune function could be the link. In 2021, for instance, they and their colleagues found that loss of Y changes the expression of many genes in human immune cells. As a result, “the immune system of males is more fragile”, says Dumanski. This could have many knock-on effects, and is particularly notable following the increased recognition of the immune system’s role in maintaining overall health – not just in fighting infections – with immune dysfunction implicated in many conditions, not least cancer, heart disease and Alzheimer’s disease.
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But not everyone buys this idea. John Perry at the University of Cambridge, for instance, thinks that loss of Y and most diseases that are associated with it are parallel manifestations of the real problem: an age-related increase in genomic instability. “The two strongest determinants of whether or not you get Y loss – and the extent of it – are your age and smoking,” says Perry. Both are profound risk factors for genomic damage and for disease, so he suspects processes that cause DNA damage also drive loss of Y. “It’s not surprising that you see correlations between Y loss and just about everything bad,” he says.
A 2019 study by Perry and his colleagues looked at the genetics of the risk of Y loss in nearly a million men and uncovered 156 gene variants associated with an increased incidence. These genes are largely involved in DNA damage repair and regulating the division of cells, suggesting that loss of Y is an offshoot of disruption to these processes, not a causal link in the chain.
To test this, Perry’s team investigated whether women who have the same gene variants that predispose men to loss of Y also develop more age-related diseases. They do. “It was an absolute proof of principle that all you’ve got is a load of genes predisposing to genome instability – and it’s just that in men one of the manifestations is loss of the Y chromosome,” says Perry.
Forsberg agrees that this mechanism exists, but he says that it doesn’t negate the possibility that loss of Y also has direct health consequences. And more recent studies have supported its causal role in ill health, helping to overturn the long-held notion that, aside from its role in sex determination and reproduction, the Y chromosome is pretty much genetically inert.
Studies of the mechanisms behind this process began when Walsh – who had long studied how mutations in blood cells can lead to cardiovascular disease – shifted his attention to the Y chromosome. To find out whether loss of Y could be directly causing health issues, Walsh’s team turned to mice. First, they genetically modified mouse haematopoietic stem cells to lack Y chromosomes. Then, they took some otherwise normal mice, eliminated their haematopoietic cells and replaced them with the Y-free ones. These animals therefore have Y-less blood cells independently of all the factors that might normally lead to loss of Y.
As these mice grow old, they develop cardiac dysfunction and cognitive decline and “basically die earlier”, says Walsh. This showed that loss of Y from immune cells can directly cause health problems. It was this finding that inspired Walsh and his colleagues to investigate data from the UK Biobank, the large-scale, long-term study of genetics and health. Here, they found a link between the percentage of blood cells with loss of Y and the chance of dying of diseases of the circulatory system over the next 11 years. For instance, men with 40 per cent or more Y-less white blood cells experienced a 31 per cent increased risk.
The researchers then used the genetically engineered mice to investigate exactly how loss of Y might cause cardiac problems. They found that the hearts of these mice – and, indeed, their lungs and kidneys – accumulate an excess of scar tissue, or fibrosis, which is likely to be driven by the activity of Y-less immune cells. When the team gave the mice an antifibrotic drug, it prevented the heart disease.
If this effect on fibrosis is confirmed in humans, too, Walsh thinks that doctors might one day be able to use prophylactic courses of antifibrotic drugs to ward off heart disease in those with loss of Y.
More recently, loss of Y has also been shown to play a role in cancer. At Cedars-Sinai Medical Center in Los Angeles, Dan Theodorescu was studying bladder cancer – a condition that affects men around four times as often as women – and wondered if the Y chromosome was contributing to the sex differences in the disease. To investigate, he and his colleagues created cancerous bladder cells that either had or lacked Y chromosomes, and injected them into mice. The results were dramatic: tumours without the Y chromosome grew twice as fast as those with it.
When Theodorescu’s team consulted human databases, they found that 10 to 40 per cent of men’s bladder tumours lack the Y chromosome, and when they do, death occurs considerably sooner than in men whose cancers retain the chromosome. However, when the researchers grew the Y-less tumour cells in Petri dishes, they found they multiplied at the same rate as tumour cells with a Y chromosome. This suggested that the increased growth rate observed in the body wasn’t due to Y-less cells replicating faster, but it perhaps had something to do with their ability to evade the immune system.
Later experiments supported this view, with Theodorescu and his colleagues finding that in bladder cancer, loss of the Y chromosome causes tumour cells to make proteins that exhaust T cells, a kind of immune cell that ordinarily recognises and attacks cancers. Suppressed much less by these T cells, the cancer is able to grow more aggressively.
This finding has major implications for treatment. Immune checkpoint inhibitors – drugs that have revolutionised cancer treatment over the past decade – work by blocking this exhaustion mechanism, enabling T cells to better attack many different cancers. Theodorescu’s team saw that in mice, the drugs worked more effectively against bladder tumours without a Y chromosome compared with those that had one. Again, the clinical data matched: people with loss-of-Y bladder cancer respond much better to checkpoint inhibitors than those whose bladder tumour contains the Y chromosome.
The culprit
Whether loss of Y is an important factor in cancers other than that of the bladder is now under investigation. A 2023 study led by Esther Rheinbay at Harvard University found that it is “extremely common” for tumour cells of many different types of cancer to lack the Y chromosome, suggesting a wide-reaching impact.
Studies by both Walsh and Theodorescu also pinpoint a possible culprit for these effects: a gene in the Y chromosome called UTY. This gene makes an enzyme involved in the regulation of other genes – not least, those expressed by immune cells – so its loss probably leads to widespread changes in gene expression, which the researchers suspect creates health problems.
Notwithstanding Perry’s caveats, the overall message is, as Theodorescu puts it: “Loss of Y is bad.” Quite how much of the difference in male and female lifespans this might account for isn’t yet pinned down, but Dumanski estimates that it might be more than half.
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Another key question – as yet unanswered – is whether lifestyle changes that promote healthier ageing, such as a better diet, improved sleep and avoiding too much stress and alcohol, might slow down the loss of Y.
The upshot of all this is that our views of the importance of the long-overlooked Y chromosome “are changing dramatically”, says Dumanski. “We’re just scratching the surface.”
Since mammalian X and Y chromosomes first evolved around 200 million years ago, the X has remained more or less the same, whereas the Y has lost 97 per cent of its original genes. In fact, the Y chromosome is the most rapidly changing human chromosome. This has led to concerns that it is irretrievably withering away and is set to be permanently lost.
At first glance, this would seem to have dire implications for the very existence of males. But there are a few species of mammals for which this has already happened – and these creatures still come in male and female forms. For instance, the Amami spiny rat is Y-less, but a gene located elsewhere in its genome has evolved to be a brand new way of determining sex.
The likelihood of humans undergoing similar changes seems low, according to Kenneth Walsh at the University of Virginia. He says that after some initially dramatic shrinkage, the Y chromosome in most species has stabilised in size over the past 25 million years. And with this chromosome potentially containing genes that serve important functions in immune cells and possibly elsewhere (see main story), its future in those species – including humans – looks assured.
