The same biological process that causes more miscarriages in the mates of older men, cause de novo autism, schizophrenia, cancers, autoimmune disorders and single gene defects etc.
Genetic clock ticks for menArticle from: Font size: Decrease Increase Les Sheffield
June 12, 2008 12:00am
MOST men would have been surprised to read that overseas researchers had found the death rate of young adults was higher if they had been born to older fathers.
This is no surprise to me. It has been scientifically established that genetic changes occur more often in the sperm of older fathers than younger fathers.
As men age there is a higher chance of changes in the genes in the sperm.
These changes can cause genetic conditions in their offspring, such as birth defects, autism and schizophrenia.
Their partners can also have an increased risk of miscarriages.
The presumed reason for the increase occurrence of all of these conditions is that they are all due to a new genetic change in the sperm of the older father.
Genetic changes are occurring all the time. Sometimes they have a beneficial effect, such as making the individual stronger, taller or smarter.
This is part of the concept of "survival of the fittest".
Sometimes, when the gene change is in a non-coding part of the genome, they have no effect. At other times, they can be harmful.
The problem is that these harmful effects are extremely varied because they can affect any one of the 20,000 or so human genes.
For example, they often change the structure of the body. One example is dwarfism, where the arms and legs are short due to a genetic change. The commonest type of dwarfism is achondroplasia.
An individual with this condition will have a 50 per cent risk of having an affected child themselves.
Indeed, about 20 per cent of the parents of achondroplastic babies have one of the parents with this condition, but the remaining 80 per cent do not.
If you look at the parents of babies with achondroplasia, who do not have the condition themselves, you find their average age is older than other people having babies in the population.
Significantly, statistics show it is the father's age which is important and not the mother's.
Achondroplasia is rare and it is only one of the many genes that can go wrong. Collectively, any of the 20,000 genes can change and this causes an increase in risk from about the age of 40.
The risk in men for any single gene change is one in 200 at age of 40, 20 at age 50 and rises steeply after that.
This increase in risk with paternal age is no surprise to me, but it is a surprise to practically everyone else.
The increase risk for older mothers for Down syndrome is well-known.
As part of my work as a clinical geneticist, I see couples every week who come to ask about the risk of having babies because of the age of the mother.
We talk about this and often, as the male partner is also older, we talk about the risk of his age. Most of the partners are quite surprised and even taken aback with this news.
In today's society, delaying pregnancy until later is often done for career and other purposes but usually only the age of the mother is taken into account in planning when to start a family. Why is the increased risk in relation to a father's age not widely known?
There are many possible reasons. Some of the information - such as increased death rates of adults - is new.
But information about single gene changes, such as achondroplasia, has been around for many years.
I think the real reason for the lack of knowledge is the conditions that can be caused are varied and can't really be prevented by a screening program like the one offered for Down syndrome.
In fact, most of the conditions, such as achondroplasia, can't even be picked up by the normal ultrasound scan for abnormalities done at 18-20 weeks of a pregnancy.
So, if you're a male, the only way not to be exposed to this increased risk of genetic defects in your offspring is to plan your children early and regard the increasing risks of the woman in her late 30s and early 40s as also applying to you.
In other words, stop your child bearing at the same sort of age that women stop child bearing. This may not be what older men want to hear, but they need to seek information about what the risks actually are before making child-bearing decisions.
We hear about the positive sides of parenthood in some older celebrity fathers but the story last week about the increase in death rates of the offspring brings out the hidden risks associated with fathering children at an older age.
Associate Professor Les Sheffield is a clinical geneticist with the Victorian Clinical Genetics Services
Expert calls for vigilance on IVF problems
Friday, 13 June 2008 Anna Salleh
As men age the DNA of their sperm gets damaged and this can cause disease in their children later in life (Source: iStockphoto)
Infertility, ABC Health and Wellbeing
Male biological clock probed
IVF: who's pushing who?
Map: Newcastle 2300
As humans become more dependent on reproductive technologies, an Australian reproductive biologist say we must remain vigilant to avoid the spread of genetic or epigenetic defects.
The warning comes in an editorial by Professor John Aitken, of the University of Newcastle, in the current issue of Expert Review of Obstetrics and Gynecology.
"People shouldn't be too confident that just because the baby looks normal there is no damage there that won't appear later in life," he says.
"People underestimate how much genetic damage they're passing onto the embryos."
Aitken says 1 in every 35 babies born in Australia are a result of IVF.
"In some countries it's more like 1 in 20 and there are models that predict it will be 1 in 10 before too long," he says.
Aitken says because IVF allows infertile men to reproduce, the more we use it the more it will be needed in the future.
"So we better make sure it's safe because a large proportion of the population will be generated in this way," he says.
Aitken says a number of factors are known or suspected to cause genetic damage to sperm, that don't necessarily cause defects obvious at birth.
For example, Aitken says the sperm of ageing males is thought to contribute to conditions such as autism, schizophrenia and epilepsy.
He says there is strong evidence linking sperm DNA damage to smoking, which can lead to the development of childhood cancers.
Epigenetic changes to sperm DNA that can affect fertility through several generations have also been reported.
For example, several recent papers have shown that infertile men have a dramatically altered DNA methylation profile.
Screening and monitoring
Aitken says genetic problems mean it is important that reproductive clinics do a good job at screening sperm samples for genetic damage.
He is presenting the latest evidence on one screening technique he is developing with biotech company NuSep at the Australian Research Council's Graeme Clark Research Outcomes Forum in Canberra next week.
But Aitken says long-term monitoring of children born through IVF and other reproductive technologies is also essential because such techniques can not pick up epigenetic damage.
"There are all kinds of things that can and could still go wrong," he says.
While he says IVF children are being monitored, he is concerned about complacency among clinics who celebrate their ability to produce normal looking babies from sperm with high levels of DNA damage.
Professor Michael Chapman of the Fertility Society of Australia, who also works for IVF Australia, says genetic damage is considered by IVF clinics.
"They're concerns that are shared within the IVF profession," he says.
Chapman says one rare epigenetic disease has shown up in IVF children - at a rate of 1 in 1500 versus 1 in 5000 in the general population.
But he says Aitken's "provocative" article overstates the problem since in the 20 years that IVF has been around, few long-term problems have arisen despite thousands of children being monitored.
"I'm sure that if something starts to turn up, it will jump out at us," he says.
Sandra Hill, CEO of ACCESS Australia, a group led by patients seeking IVF treatment, is confident that IVF is well-monitored, and she agrees this should continue.
But she says many of the concerns raised by Aitken also apply to natural conception and she thinks the use of IVF should not be singled out.
She says it could be useful to educate men in general about the concerns raised by Aitken - especially the need for men to have children before they get too old.
Aitken says this may be so, but IVF still presents a unique challenge.
"With IVF you are facilitating the fertilisation of eggs with sperm that would otherwise be unsuccessful," he says.
Aitken also says the rate of birth defects in IVF children are up to twice that of normally-conceived children, although he expects that to improve as techniques improve.
Tags: fertility-and-infertility, pregnancy-and-childbirth, reproductive-technology, biotechnology, inventions
June 26, 2008 in Biology | 5 comments | Post a comment
Fact or Fiction: Men Have a Biological Clock
Does male fertility have an expiration date?
By Anne Casselman
TICKING CLOCK: Male fertility declines just like female fertility.
The female biological clock—its tick-tock marking the decline of fertility that grows louder as a woman reaches middle age—is deeply ingrained in popular consciousness. Take this scene from the film Bridget Jones's Diary: Bridget's Uncle Geoffrey reminds her that as a career girl she "can't put it off forever," alluding to her declining fertility. His wife Una chimes in: "tick-tock, tick-tock," her finger wagging like a metronome.
The biological clock, although just a metaphor, refers to a real phenomenon: Women over 35 years of age are only half as likely to become pregnant in the most fertile part of their menstrual cycle than women younger than 26.
So do men suffer from the same thing?
"For women, a biological clock is a decline in fertility and an increased chance of having genetically abnormal babies as they age," says Harry Fisch, director of New York City's Male Reproductive Center and author of The Male Biological Clock: The Startling News About Aging, Sexuality, and Fertility in Men. "And that's exactly what's happening with men."
So how did Indian farmer Nanu Ram Jogi sire a healthy child at the age of 90 last year? Such a feat would be impossible for a woman, even in an age when Carmela Bousada, 67, gave birth to twins in January 2007 after lying about her age to the doctors who gave her in vitro fertilization. Whereas fertility declines along with testosterone levels as men age, it doesn't drop to zero.
Still, Jogi is definitely the exception rather than the rule. One study found that the odds of fatherhood for those under the age of 30 was 32.1 percent compared with 20 percent over the age of 50, signifying a 38 percent drop in male fertility across that age gap.
One study examined 97 men between the ages of 22 and 80 and found that as they aged their semen volume decreased by 0.001 ounce (0.03 milliliter) per year from an average total of 0.09 ounce (2.7 milliliters) and their "total progressively motile sperm count"—a rough index for the fertility potential of one's sperm based on its movement—decreased about five percent with each year they aged.
Fisch and his colleagues have also found that the children of women over 35 whose babies' fathers were also of that age were more likely to have Down's syndrome than offspring whose fathers were younger.
In other studies, older men were more likely to father children with mental illness or other deficits. Roughly 11 children out of a thousand conceived by men over age 50 developed schizophrenia compared with under three children out of a thousand for fathers under 20 in one study from the Archives of General Psychiatry. And the children of men 40 years or older were nearly six times more likely to have autism spectrum disorders than kids begot by men under 30.
So do men's sperm get staler over time? To maintain sperm levels, cells known as germ cells must continue dividing. After all, men find ways to dispose of sperm—ahem—and once ejaculated they only survive for several days. By the age of 50, these germ cells will have divided 840 times. Each one of those divisions is an opportunity for something to go wrong. "There's more of a chance to have genetic abnormalities the more the cells divide," Fisch says. In sperm these mutations dot the genes with changes in the basic structure of the DNA—and can lead to problems in the resulting offspring.
Labels: clinical geneticist les Sheffield speaks the truth, paternal age past 32, RJ AITKEN, Scientific American Magazine Fact or Fiction Men Have a Biological Clock