Covid kills many more men than women. Despite a year of research on the virus, it is still unclear why. Older age is known to be one of the main risk factors, but mortality among older men is twice that of women of the same age. This happens with many other diseases and is due in part to external behavioral and lifestyle factors. But still the difference is so brutal that there has to be something more. And there is: biological sex.
The differences between the sexes go far beyond the sexual organs. Biological sex has a decisive influence on the functioning of the immune system, something observed in both animals and humans. In general, females have more effective immune systems than males. For example, women generate more immunity against influenza than men after being vaccinated, while men with HIV tend to have a higher viral load than infected women, recall today Takehiro Takahashi and Akiko Iwasaki, immunologists from Yale University (USA). UU), in an article published in Science. This immune strength occurs from the first months of life: young girls are much more resistant than boys to infections, wars, hunger and other calamities.
All this is important because death from covid is not so much due to the coronavirus as to the dysfunctional reaction of the patient himself. Days after infection, there are people who begin to produce large amounts of inflammatory proteins that in theory should alert elite bodies to the immune system. But that inflammatory overload ends up collapsing the defenses and dynamiting the functioning of the lungs. It is the now famous cytokine storm, the name of the inflammatory molecules that can aggravate the disease to death.
It is as if the male immune system in old age is hindering itself
The most interesting thing is that the production of these molecules is much more common among men than in women, especially in advanced ages. In addition, older men generate fewer T lymphocytes capable of identifying and destroying infected cells. And just a few months ago a study showed that some covid patients generate defective antibodies that worsen their condition and can cause death. 95% of the known cases were men. It is as if the male immune system in old age is hindering itself.
From a biological point of view, a man is characterized by having a single X chromosome, inherited from his mother, and a Y chromosome, from the father, while a woman has two copies of the X chromosome, one from each parent. Chromosomes – humans have 23 pairs – are like the atoms into which the whole of our genome is divided, the unique sequence with more than 3,000 million genetic letters that contain all the information that configures a person and that allows him breathe, move, reproduce, live. The X chromosome contains several fundamental genes for the proper functioning of the immune system. A few months ago, a team of doctors from the Netherlands analyzed pairs of brothers, all men, young people in their twenties, who fell ill with serious covid and even one of them died. Genetic analysis uncovered a defect in the TLR7 gene. “This gene produces very important proteins to detect the entry of a virus into the body,” he highlights Anna Planas, from the Barcelona Institute for Biomedical Research (CSIC). “This gene is located on the X chromosome.” The affected men had only one copy of the gene and it was defective. On the other hand, women have an important advantage in this regard.
Although normally only one of its two copies of the X chromosome is active, it is not always the same. “This phenomenon means that more or less 50% of a woman’s cells will use the copy of the X chromosome that her father passed to her and the other 50% will use that of the mother,” explains José Luis Labandeira, professor of Human Anatomy at the University of Santiago de Compostela. “If a woman has a defect in one of the genes of the immune system on the X chromosome, it could be corrected because not all her cells will use the damaged copy,” he details.
The immune system of men ages earlier than that of women
On the X chromosome there are also other genes that can allow women to mount a more balanced immune response than men, especially in advanced ages. Like the rest of the body, the immune system ages, but not at the same rate. Men experience a weakening of their defenses from the age of 63. One of the most striking changes is that the inflammatory function of the immune system becomes stronger while the adaptive immunity is weakened, which is the second and most sophisticated line of defense, as it includes specialized cells to make antibodies against new viruses and also cells memory that will remember and destroy them if they appear again. This senescence of the immune system happens in women too, but it comes about five years later.
Estrogen – a female hormone – regulates the functioning of many types of cells of the immune system. One of the forms of this hormone contributes to lower levels of inflammatory proteins, something that can be key when one is on the verge of the cytokine storm. Estrogen also increases the production of ACE2, the cell surface protein that the coronavirus uses as a gateway to our cells. “At first it was thought that producing more ACE2 would be harmful, but we have seen that it is not,” explains Labandeira. “This protein also has other anti-inflammatory effects. If women produce more of this protein it can have positive effects. This is something that we have also shown with drugs that increase ACE2, such as ibuprofen. They do not have harmful effects ”, he details. There are also indications to the contrary: therapy that reduces the production of male sex hormones reduces the risk of SARS-CoV-2 infection, highlights the Science work.
In any case, the protective effect of female hormones would last only until menopause, so it cannot be very decisive in explaining mortality by sex in ages 70 or 80, warns Vicente Rubio, researcher at the Institute of Biomedicine of Valencia (CSIC). “Mortality from covid is multiplied by eight from 55 years of age and in people over 65 it is 64 times higher,” he explains. “The great unknown is understanding why such a brutal rise happens with age. We still cannot fully explain it, nor can the higher mortality in men, although it is probably due to this unbridled inflammatory reaction to the infection ”, he highlights.
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