The dangers of postponing parenthood: why it poses risks to children’s physical and mental health | Reproduction

W.When we think about the effects of age on making babies, we tend to focus on women. That overwhelming supply of eggs. Those chromosomal problems. Sterility. But men are also affected by age. There is now a substantial (and growing) body of evidence suggesting that delaying parenthood may have its own consequences. They are rarely talked about: how often, for example, are men told to “pay more attention” to their biological clocks?

Fertility services are also generally discouraged for older men who want to become fathers, as some countries do for older women who want to be mothers. In England and Wales, for example, the National Institute for Clinical Excellence recommends that the NHS does not offer IVF to women over 42, but paternal age is not mentioned in its guidelines. There is also no agreed-upon definition of “old” when it comes to parents.

However, we know that around age 40, men’s sperm start to slow down. Conception becomes more difficult. And children born to older parents face higher rates of diseases such as autism, schizophrenia and leukemia.

In many countries, men are becoming fathers at older ages. In the United States, for example, in 1980 around 43 out of every 1,000 babies were born to men between 35 and 49 years old; for 2015 this I had jumped approximately 69 out of every 1,000 babies.

Age affects the sperm itself. A great systematic review published in 2015, which analyzed 90 separate studies involving 93,839 subjects, found that a man’s age negatively affected measures of sperm quality: the appearance of the sperm, how well they moved, and how many were damaged.

The physical attributes of sperm can be important when conceiving a child. Research suggests that older men’s conception rates are lower than younger men’s. in a study of 2,112 UK couplesMen over 45 were almost five times more likely to take more than a year to conceive compared to men under 25, and this held true even when the female partner was young.

The results of in vitro fertilization (IVF) for older men also appear worse. An article this year. in it Journal of Assisted Reproduction and Genetics examined the results of 11 studies and 10,527 egg donation cycles (egg donors tend to be young) and found that increasing male age was associated with a slight decrease in the live birth rate.

The conceptions of older men are also more likely to end in miscarriage or stillbirth. And babies born to older fathers are more likely than those conceived by younger men to be born premature (32 to 37 weeks pregnant) or very premature (28 to 32 weeks pregnant).

“People assume that if there is a swimming sperm that can penetrate an egg, everything is fine,” says Bernard Robaire, a professor at McGill University in Montreal who specializes in the aging male reproductive system, “but that’s not the case.” “. .” And it’s not just the general public that hasn’t noticed. Robaire says that last year he gave a presentation on the subject to doctors specializing in obstetrics and gynecology. Many were unaware of the link between male age and poor reproductive outcomes.

in a review article published last year in Frontiers of endocrinologyRobaire and his McGill colleague Peter Chan also highlighted numerous epidemiological studies that have linked late fatherhood to health problems in their children.

Older parents are more likely, for example, to have children with birth defects such as a cleft lip or a hole in the diaphragm, and the odds increase with each year of paternal age. Some cancers also become more common. a birth record study of almost 2 million children In Denmark they discovered that a certain type of childhood leukemia increases its probability by 13% for every five years older than the father. The risk of brain cancer and breast cancer is also elevated in people born to older parents.

There are also neurological effects. Children whose parents are over 40 years old at birth are almost six times more likely to have autism than those whose parents are under 30 years old. according to a study. Babies born to parents over 50 face up to five times greater risk increased risk of schizophrenia. Obsessive-compulsive disorder, ADHD, and bipolar disorder are more likely, research indicates, if the father is older.

Robert De Niro and his partner Tiffany Chen.
Robert De Niro had his seventh child at the age of 79 with his partner Tiffany Chen. Photograph: Stéphane Cardinale/Corbis/Getty Images

But how can this be, you ask, with more and more older parents in the news? Didn’t Mick Jagger at 73, Robert De Niro at 79 and Al Pacino at 83 have a son? Isn’t sperm renewed approximately every 74 days? Don’t male humans ever run out of those things? Yes, yes and yes.

There is a lot of talk about the fact that a woman is born with all the eggs she will ever have; That in your mid-30s they start to break down and, before you know it, they’re gone. At approximately 50 years of age, a woman faces a complete cessation of her reproductive capacity. The same does not happen with males, who can reproduce practically until the end of their lives. But research now shows that the longer the sperm factory operates, the more likely it is that faults will be introduced during the manufacturing process.

The raw material for sperm is the spermatogonial stem cells found in the testicles. As part of the sperm production process, these immature cells are continually replenished through cell division. Only about half of the new cells will take the journey to become new sperm, while the other half will remain to maintain the pool of spermatogonial stem cells.

But replication involves copying the entire genome, which has about 3 billion letters. Although rare, a copying error is sometimes made. And if that happens, the sperm that will later emerge from that spermatogonial stem cell will forever carry that mutation.

The older a man is, the more times his spermatogonial stem cells have replicated. Has been My dear that sperm produced by a 25-year-old will have experienced 350 replications, while sperm from a 45-year-old will have had 750. Each replication creates more opportunities to make a mistake. Which means that children of older men are likely to have more genetic mutations than those born to younger men.

We are all born with new mutations: about 60 on average. But people born to older parents have more. In fact, researchers who have sequenced whole genomes or whole exomes (specific parts of the genomes) of mother-father-child trios have found that the number of new mutations in children it increases steadily with the father’s age: about one or two additional mutations for each year older than the father at the time of the child’s birth.

And since we can deduce which chromosome comes from which parent, we know that around 80% of these chromosomes “de novo” Mutations come from the father, whether younger or older.

The good news is that most acquired mutations are harmless. “The vast majority of these mutations will have no effect, because they will occur in a part of the genome that is not coding,” says Anne Goriely, professor of human genetics at the University of Oxford. But some will have effects, she says, and although they are rare, they are important contributors to genetic diseases. They affect approximately one in every 300 live births, she noted in a review document with his colleague, Katherine Wood, in Fertility and sterility last year.

Al Pacino had his last child at the age of 83 with his partner Noor Alfallah.
Al Pacino had his last child at the age of 83 with his partner Noor Alfallah. Photo: Gotham/GC Images

Goriely’s own interest is in a small subset of these disorders, known as “paternal age effects disorders,” long associated with older fathers. They include conditions such as achondroplasia, which causes dwarfism, and Apert syndrome, which causes a deformed skull and fused fingers and toes. However, unlike many conditions caused by de novo mutations, these paternal age-effect disorders do not simply show a linear increase with age, but rather their prevalence increases considerably as the father’s age increases, occurring very frequently. more frequently than would be expected by chance.

But de novo mutations alone may not explain the higher frequency of complex conditions like autism and schizophrenia that we see in people born to older parents.

Could the modification of epigenetic marks play a role? “What is passed on to a child is not simply the base sequence (of the DNA),” says Robaire, who is studying epigenetic alterations in the sperm of older men, “but a lot of other messages that are included to allow some genes become turned on or not turned off.” These messages, or epigenetic marks, control expression of genes. The very act of living, says Robaire, exposes man to stresses, toxins, chemicals and experiences that will modify the epigenetic marks in his spermatogonial stem cells. Those modified marks will be copied into any sperm produced from them.

In 2020, Robaire and his colleagues published an article in Clinical epigenetics demonstrating that there are age-dependent alterations in the epigenetic marks found in human sperm DNA. He says you can look at the patterns of epigenetic marks and “predict a man’s age within two years.”

The researchers expected to find that epigenetic changes were related to sperm development, but this was not the case. Interestingly, the sites that showed the greatest age-related epigenetic change were sites associated with neurological development. “I have no idea why those sites are selectively affected,” Robaire says.

Men produce a large number of sperm: about 2,000 with each heartbeat, he says. It’s several million a day. “It’s an amazing machine to be able to produce so many cells.”

But problems accumulate as a man ages. Stem cells acquire more mutations. Epigenetic marks are modified. Human life experiences, including environmental exposures, cause stress and oxidative damage. These things, and more, may act together to cause the effects that researchers are seeing in children born to older parents.

What is clear is that paternal age matters and that more and more men are becoming older fathers. As Robaire and Chan write, a series of factors including delayed marriages, second marriages, assisted reproduction, treatments like Viagra for erectile dysfunction, and famous men modeling older fatherhood “have provided the makings of a perfect storm.”


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