That women live longer than men is well known by all. In Spain, for example, one only has to consult the National Institute of Statistics (INE) to corroborate that the life expectancy of women in our country continues to be higher than that of men. The latest available data indicates that the life expectancy of people born in Spain in 2021 was 80.24 years for men and up to 85.83 for women. A difference of just over five years.
If we look at the data available from the INE since 1975, we will discover that life expectancy at birth has been growing over the years, along with improvements in quality of life, diet and medical care. In 1975, the life expectancy of women at birth was 76.25 years (almost ten years less than in 2021), while that of men was 70.53 years (also ten years less than now). However, the difference of around five years between men and women has remained. Amazing.
It is clear, with the data on the table, that men live less than women. That is why there are more widows than widowers. Now, how do we explain this difference?
It is not due to differences in occupational risks
In the past, hackneyed explanations were resorted to, and surely erroneous, related to the supposed efforts in the working day that (some) men made compared to the supposed lack of effort in the working day by the majority of women. From which it was deduced that men faced more dangers than women and hence they ended up dying earlier. But that didn’t seem like a reasonable explanation.
The search continued to point to chromosomal differences. Males have one X chromosome and one Y chromosome (XY), while females have two X chromosomes (XX), although one of the two X chromosomes must be inactivated in each cell to maintain cell viability. Well, there was research suggesting that having two copies of the same chromosome was, in the long run, more efficient than having two different copies for the sex chromosomes.
This protective effect not only appeared in the human species, but the Australian study confirmed it in no less than 229 animal species. On average, the homogametic (XX) sex lived 17.6% longer than the heterogametic (XY).
However, the discovery still did not explain why XY individuals live less, five years less for the human species. Is it due to a greater propensity of men to be affected by infectious diseases compared to women, whose immune system would be more prepared to fight against these infections, as some propose? This and other speculations without scientific basis have proliferated in recent years.
The missing Y chromosome
Beyond speculation, there is scientific observation, the collection of data for analysis. This is the origin of a recent study published in the journal Science in which the loss of the Y chromosome by some blood cells is pointed out as the reason why men live less than women.
Spontaneous loss of the Y chromosome in males (XY) appears to be relatively common in hematopoietic cells, the blood cells, such as lymphocytes. Technically, this loss is known as mLOY (mosaic loss of Y chromosome), the mosaic loss of the Y chromosome. It is called mosaic because it does not occur in all blood cells. This mLOY is detected in 40% of 70-year-old men and 57% of 93-year-old men.
The loss of the Y chromosome is associated with worse prognosis in blood cancers and a shorter life expectancy. Also to a higher probability of developing solid tumors, Alzheimer’s, cardiac disorders and cardiovascular diseases.
However, these are all just descriptive correlations, and we already know that a correlation does not indicate causality. Nothing indicates unequivocally that the cause of all these pathologies is the loss of the Y chromosome. Experiments have to be done. And that’s what a team of researchers from a Japanese, Swedish and American consortium did by deleting the Y chromosome from blood cells in CRISPR-Cas9 mice.
The experiment is easily explained in two steps. They employed a CRISPR-Cas9 strategy in mice using RNA guides complementary to the repeat sequences around the Y chromosome centromere. They thus favored the loss of the Y chromosome in certain blood cells, taking advantage of the hematopoietic stem cells of a mouse that constantly expressed the Cas9 nuclease.
Experiment carried out by Sano et al., published in Science (2022) to eliminate the Y chromosome in mice using CRISPR-Cas9 technology, directing the RNA guides to the repeated sequences of the centromere. /
Then, these cells were transfected with lentiviruses carrying the RNA guides and fluorescent markers to verify the process. And finally, they transplanted the cells that had lost the Y chromosome with very high efficiencies (80 to 95%) into the bone marrow of irradiated mice that had had their own hematopoietic stem cells removed.
From that moment on, the mice did show similarities to what happens in humans, in men. To begin with, they lost the Y chromosome in mosaic circulating lymphocytes, between 49 and 81% of the cells, with values similar to those detected in elderly men. And these values were maintained by the CRISPR-edited mice for more than 12 months.
Did that missing chromosome have consequences? Without a doubt, yes. Among other things, they lived less than mice with the intact Y chromosome. They also developed cardiomyopathies more frequently, with a slight but significant increase in heart size, which did not correlate with an increase in body weight. Furthermore, it increased fibrosis in the myocardium of these edited mice and lowered blood pressure.
Fibrosis was also seen in the lungs and kidneys of the gene-edited mice, along with significant memory loss. All of them were symptoms previously described in patients in whom the loss of the Y chromosome was detected in a significant number of their lymphocytes.
The application of the scientific method had made it possible to verify that the experimental elimination of the Y chromosome in hematopoietic cells shortened the life expectancy of the mice and led to the appearance of symptoms of cardiovascular alterations. Exactly the same as in older men.
The work published in Science contains many more revelations. For example, experimentally compressing the aorta of CRISPR-edited mice with no Y chromosome in their blood cells increases macrophage infiltration of the immune system. This causes fibroblasts to proliferate (fibrosis), which eventually leads to heart failure. The good news is that treating these mice with a monoclonal anti-TGFbeta antibody (a cytokine) can reverse this fibrosis. Therefore, it could serve as a treatment for elderly men with Y chromosome loss.
small but relevant
The Y chromosome is the smallest of all our chromosomes, also in the mouse. But it contains essential genes. On the one hand, the SRY, which directs the development of the embryo towards men, with the sexual characteristics and male sexual organs. On the other, genes that have to do with the functioning of the immune system.
That is why its loss has important, negative consequences, which would lead to fibrosis that would end up causing death in men before women.
Now we know why there are more widows than widowers.
This article has been published in ‘The Conversation‘.
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