WWhen we think about the effects of age on baby making, we tend to focus on women. That devastating supply of eggs. Those chromosomal problems. Infertility. But men are also affected by age. There is now a substantial – and growing – body of evidence suggesting that delaying fatherhood can have its own consequences. This is rarely talked about – for example, how often are men told to ‘pay more attention’ to their biological clock?
Also, fertility services are generally not discouraged for older men who want to become fathers, as some countries do for older women who want to become 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 the guidelines make no mention of the father’s age. There’s also no agreed-upon definition of “old” when it comes to fathers.
Yet we know that men’s sperm starts to slow down somewhere around age 40. Conception becomes more difficult. And children of older fathers are more often confronted with conditions such as autism, schizophrenia and leukemia.
In many countries, men become fathers at an older age. In America, for example, in 1980, about 43 in 1,000 babies were born to men between the ages of 35 and 49; by 2015 this had jumped to about 69 in 1,000 babies.
Age affects the sperm itself. A big systematic review published in 2015, which looked at 90 separate studies involving 93,839 subjects, found that a man’s age had a negative impact on sperm quality: the way sperm looked, how well they moved and how many were damaged .
The physical characteristics of the sperm can be important when it comes to conceiving a child. Research shows that the conception rate is lower in older men than in younger men. In a study of 2,112 British couplesmen over 45 were almost five times as likely to become pregnant for more than a year compared to men under 25, and this was true even if the female partner was young.
The results of in vitro fertilization (IVF) for older men also appear to be worse. A newspaper this year in the Journal of assisted reproduction and genetics examined findings from 11 studies and 10,527 egg donation cycles – egg donors tend to be young – and found that increasing men’s age was associated with a slight decline in the number of live births.
Conceptions of older men are too It is more likely to end in miscarriage or stillbirth. And the babies of older fathers are more likely to be born prematurely (between 32 and 37 weeks of gestation) or very early (between 28 and 32 weeks of gestation) than those of younger men.
“People assume that if there are sperm that swim and can penetrate an egg, then everything is fine,” says Bernard Robaire, a professor at McGill University in Montreal who specializes in the aging of the male reproductive system, “but that’s not the case. .” And it’s not just the general public that hasn’t participated. Robaire says that last year he gave a presentation on this subject to doctors specialized 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 linking older fatherhood to health problems in their children.
For example, older fathers are more likely to have children with birth defects such as a cleft lip or a hole in the diaphragm, and the risk increases with each year the father is older. Some cancers are also more common. A birth register research among almost 2 million children In Denmark it has been shown that the risk of a certain form of leukemia in children increases by 13% for every five years the father is older. The risk of brain cancer and breast cancer is also increased in people with older fathers.
There are also neurological effects. Children whose fathers were older than 40 at birth are almost six times more likely to have autism than children whose fathers were younger than 30. according to one study. Babies born to fathers over 50 years old face a fivefold increase increased risk of schizophrenia. Obsessive-compulsive disorder, ADHD, bipolar disorder – all are more likely, research shows, when the father is older.
But how is this possible, you may ask, with more and more older fathers in the news? Didn’t Mick Jagger have a child at 73, Robert De Niro at 79 and Al Pacino at 83? Isn’t sperm made fresh every 74 days? Do male humans never run out of stuff? Yes, yes, and yes.
Much is made of the fact that a woman is born with all the eggs she will ever have; that they start to go bad in your mid-thirties, and before you know it, she’s gone. Around the age of about 50, a woman faces a complete cessation of her reproductive capacity. This does not apply to males, who can reproduce almost until the end of their lives. But research now shows that the longer the sperm factory runs, the more likely it is that malfunctions will occur during the production process.
The raw material for sperm are spermatogonial stem cells in the testicles. As part of the sperm production process, these immature cells continually replenish themselves through cell division. Only about half of the new cells will travel to become new sperm, while the other half will stay to maintain the spermatogonial stem cell pool.
But during replication, the entire genome, which is about 3 billion letters long, is copied. Although rare, a copying error is sometimes made. And when that happens, the sperm that will later arise from that spermatogonial stem cell will carry that mutation with it forever.
The older a man is, the more often his spermatogonial stem cells will have replicated. It has been estimated that the sperm produced by a 25-year-old will have undergone 350 replications, while the sperm from a 45-year-old will have had 750. Each replication creates more chance of an error. This means that the children of older men are likely to have more genetic mutations than children of younger men.
We are all born with new mutations – about 60 on average. But people with older fathers have more. Researchers who sequenced whole genomes or whole exomes (specific parts of genomes) of mother-father-child trios have found that the number of new mutations in children increases steadily with the age of the father – approximately one to two additional mutations for each year older the father is at the time of the child’s birth.
And because we can deduce which chromosome comes from which parent, we know that about 80% of these “de novo” mutations come from the father, regardless of whether he is 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 does not code,” says Anne Goriely, professor of human genetics at the University of Oxford. But some will have effects, she says, and while they are rare, they are important contributors to genetic diseases. They affect about one in 300 live births, she noted review paper with her colleague, Katherine Wood, in Fertility and sterility last year.
Goriely’s own interest is in a small subset of these disorders, known as “paternal age effect disorders,” which have long been associated with older fathers. They include conditions such as achondroplasia, which causes dwarfism, and Apert syndrome, which leads to a deformed skull and fused fingers and toes. However, unlike many conditions caused by de novo mutations, these paternal age-related disorders do not merely show a linear increase with age, but increase sharply in prevalence as paternal age increases – they become much more common than you would expect by chance.
But de novo mutations alone may not explain the higher frequency of complex disorders such as autism and schizophrenia that we see in people with older fathers.
Could modification of epigenetic marks play a role? “What is passed on to a child is not simply the sequence of (DNA) bases,” says Robaire, who studies epigenetic changes in sperm from older men, “but a whole host of other messages that are incorporated to allow some genes be converted or not be turned off.” These messages, or epigenetic marks, control over expression of genes. Just living, Robaire says, exposes a man to stresses, toxins, chemicals and experiences that will alter the epigenetic marks on his spermatogonial stem cells. These modified markers are copied to all sperm produced from them.
In 2020 Robaire and his colleagues published a paper in Clinical epigenetics showing that there are age-dependent changes in the epigenetic marks found on DNA in human sperm. He says you can look at the patterns of epigenetic marks and “predict a man’s age within two years.”
The researchers had expected to find that the epigenetic changes were linked to sperm development, but that was not the case. Intriguingly, the sites that showed the most epigenetic age-related changes were sites associated with neurodevelopment. “I have no idea why those sites are being selectively affected,” says Robaire.
Men produce a huge amount of sperm – about 2,000 with each heartbeat, he says. That’s several million a day. “It is an amazing machine to be able to produce so many cells.”
But the problems pile up as a man gets older. Stem cells acquire more mutations. Epigenetic marks are changed. Experiences in a man’s life, including environmental exposure, cause oxidative stress and damage. These things, and many more, may combine to cause the effects researchers see in children of older fathers.
What is clear is that the age of the father matters – and more and more men are becoming older fathers. As Robaire and Chan write, a number of factors, including delayed marriages, second marriages, assisted reproduction, treatments such as Viagra for erectile dysfunction, and famous men modeling older fatherhood have “provided elements for a perfect storm.”