Older Men and Fertility
DNA mutation in older men:
These mutations could reflect the differences in male and female
reproduction, notes Jabs. By the time females reach their teen
years, their eggs have already been formed-just one new egg matures
each month. Men, on the other hand, produce millions of sperm cells
every time they ejaculate. After each ejaculation, they must
literally replicate those cells, and each replication multiplies
the chance for a DNA "copy error"-a genetic chink in the sperm DNA.
The more ejaculations a man produces, the greater the chance for
chinks to arise, leading to increased point mutation and thus
increased infertility and birth defects. While a woman's
reproductive capacity halts more or less abruptly after all her
eggs have been used up somewhere in their forties or fifties, men
experience a longer, more gradual winnowing and disintegration. "We
believe that something in men's DNA replication machinery keeps
becoming less efficient and less accurate with age, and the
problems accumulate," says Jabs.
"Researchers found that as a man gets older he loses his natural
ability to weed out unhealthy sperm cells through a process known
as apoptosis. This means that there is a greater chance that a
damaged sperm cell will successfully fertilize the female egg. This
could mean that the risk of miscarriage is increased or, at the
other end of the scale, that children have a greater chance of
developing mild abnormalities such as uneven teeth, or asymmetrical
limbs. Lead researcher Dr Narendra Singh told the BBC: "We found
there is a significant change by the age of 35."
Sperm quality : Dr Singh's team examined sperm quality in 60 men
aged between 22 and 60. All had healthy sperm counts. The
researchers found that men aged 35 and older had higher
concentrations of sperm with broken strands of DNA, and that the
damage was greater."
Early Show medical correspondent Emily Senay explains that the
study in the Journal of Urology suggests older fathers have similar
risks as older mothers of producing children with greater chances
of birth defects, such as Down syndrome, and they also lose their
ability to conceive. The report found men over 40 years of age were
twice as likely to have a child with down syndrome than those less
then 20 years old.It was always thought in the past that a woman's
age was the sole determining factor in birth defects, such as Down
syndrome, says Dr. Senay. But the new report adds to the growing
body of evidence that late fatherhood is a factor when it comes to
the health of a baby.
Previous studies have shown a link between paternal age and
schizophrenia; and paternal age and a birth defect known as
Achondroplasia;the most common cause of dwarfism, or significantly
abnormal short stature. Achondroplasia is characterized by abnormal
bone growth that results in short stature with disproportionately
short arms and legs, a large head, and characteristic facial
features with frontal bossing and mid-face hypoplasia. In infancy,
hypotonia is typical, and acquisition of developmental motor
milestones is often delayed. Intelligence and life span are usually
normal, although compression of the spinal cord and/or upper airway
obstruction increases the risk of death in infancy.
Researchers in this latest study were able to look at a large
number of births to older women in New York State over a 14-year
period. They found a dramatic increase in the number of older
parents in general, and saw the greatest increase in the number of
Down syndrome cases where the father and mother were both over
40.
Currently, Dr. Senay explains, the emphasis is on counseling
parents only if the woman is older. But the idea that sperm quality
decreases as a man ages underlines the importance of older couples
being aware of that possibility, and the risk of birth defects.
Screening can be done at a very early stage to detect genetic
abnormalities. The researchers say that prenatal counseling, if
either parent is over 40, is probably a good idea.
A study published in 2001 in the Archives of General Psychiatry
found the risk of schizophrenia in children was associated with
older paternal age. For instance, children of fathers over 50 were
almost three times more likely to have schizophrenia than children
born to the youngest fathers, the research found. The database
included nearly 90,000 people.
In another study, more than 3,400 cases of Down syndrome were
studied. The researchers found that the father's age played a
significant role when both parents were over 35 at the time of
conception. The effect was most pronounced when the woman was over
40. In those cases, the researchers "found the incidence of Down
syndrome is related to sperm approximately 50 percent of the time."
These findings appeared in the June 2003 issue of The Journal of
Urology.
"The message to men is: 'Wake up and smell the java,' " said
Pamela Madsen, executive director of the American Fertility
Association, a national education and advocacy group. " 'It's not
just about women anymore, it's about you too.' "
"I think what we're saying is that men, too, need to be
concerned about their aging," Dr. Eskenazi said. "We don't really
know what the complete effects are of men's age on their ability to
produce viable, healthy offspring."
Geneticists have been aware for decades that the risk of certain
rare birth defects increases with the father's age. One of the most
studied of these conditions is a form of dwarfism called
achondroplasia, but the list also includes neurofibromatosis, the
connective-tissues disorder Marfan syndrome, skull and facial
abnormalities like Apert syndrome, and many other diseases and
abnormalities. Apert syndrome is a form of Craniostenosis
characterized by oxycephaly and syndactyly of the hands and feet.
Facial manifestations include exophthalmos, high prominent
forehead, small nose, and malformation of the mandible and
mouth.
"We have counseled for quite a long time that as paternal age
increases, there is an increased frequency in new mutations," said
Dr. Joe Leigh Simpson, president-elect of the American College of
Medical Genetics.
Some studies suggest that the risk of sporadic single-gene
mutations may be four to five times higher for fathers who are 45
and older, compared with fathers in their 20s, Dr. Simpson said.
Even grandchildren may be at greater risk for some conditions that
are not expressed in the daughter of an older father, according to
the American College of Medical Genetics. These include Duchenne
muscular dystrophy, hemophilia and fragile-X syndrome. Duchenne is
the most common form of muscular dystrophy, in which fat and
fibrous tissue infiltrate muscle tissue, causing eventual weakening
of the respiratory muscles and the myocardium. The disease, which
almost exclusively affects males, begins in early childhood and
usually causes death before adulthood.
A recent study on autism attracted attention because of its
striking findings about a perplexing disorder. Researchers analyzed
a large Israeli military database to determine whether there was a
correlation between paternal age and the incidence of autism and
related disorders. It found that children of men who became a
father at 40 or older were 5.75 times as likely to have an autism
disorder as those whose fathers were younger than 30. Studies
elsewhere had similar findings, she said: a threefold increase in
schizophrenia among offspring of older fathers. Another study on
schizophrenia found that the risk of illness was doubled among
children of fathers in their late 40s when compared with children
of fathers under 25, and increased almost threefold in children
born to fathers 50 and older.
Another study by Fisch has found that when both parents are over
35, paternal aging may be responsible for as many as half of all
cases of Down syndrome, formerly thought to be inherited from the
mother. And recent studies show that half a dozen or more rare but
serious birth defects appear to be inherited exclusively from the
father, including Apert syndrome, Crouzon syndrome, and Pfeiffer
syndrome (all characterized by facial abnormalities and the
premature fusion of skull bones) as well as achondroplasia (the
most common form of dwarfism).
"But what we're finding now is that in humans as well as in
other mammals, when there's a new genetic change-called 'de novo or
sporadic point mutation'-it almost always happens in the male
parent," says Dolores Malaspina, chair of psychiatry at New York
University Medical Center. And these de new mutations increase in
frequency with the age of the male parent.
The biggest news - the father's role in brain disorders - has
come to light largely because of research from Israel, where birth
records routinely include the age of the male parent. The first
unsettling finding linked paternal age and schizophrenia.
"In our first study, looking at every pregnancy in Jerusalem
from 1964 to 1976, we found that increased age in the father
predicted increased cases of schizophrenia in the children,"
explains Malaspina, who was on the team doing the work. "In our
second study we found that when the cases arose from new
mutations-not familial inheritance-it almost always could be traced
to the genetics of the father. Somewhere between a quarter and a
third of the cases could be explained only by the age of the
father-a threefold risk linked to fathers older than 50 compared
with those in their 20s." Studies in Sweden and California produced
almost identical results.
The autism findings are even more disturbing: Men 40 and older
in the Israeli study were almost six times as likely to have
offspring with autism than men under 30. Some researchers believe
that older fathers may hold a clue to the vast upsurge in autism
cases in the past decade. "With older and older couples having
children-in the past two years, for the first time, more babies are
being born to women over age 30 than under age 30, and on average,
male partners tend to be older than female partners-it's very
feasible that paternal age is a major predictor of autism," asserts
Fisch.
Perhaps the worst aspect of the new findings is that a little
genetic damage in men's sperm may actually be worse than a lot of
damage. "When we started doing the research, our first concern was
fertility, and these new studies do show that fertility maybe
compromised by DNA damage. But that's not the most important
thing," declares Charles Muller, lab director of the Male Fertility
Clinic at the University of Washington in Seattle.
The greater threat to offspring is the less flagrant DNA damage
that gets passed on. Experts like Muller believe that a substantial
amount of the damage is caused by free radicals-the destructive,
highly reactive particles produced by our body's energy factories,
the mitochondria, as we metabolize oxygen. "One of the scariest
things we're finding is that sperm DNA is damaged by even low
levels of free radicals. Whereas high levels of damage lead to
infertility, miscarriages, or spontaneous abortions, low levels
chew up the DNA but the sperm can still fertilize," Muller states.
Damage may then be passed from one generation to the next.
"In short, the biggest genetic threat to society may not be
infertility but fertile old men," says University of Wisconsin in
Madison geneticist James F. Crow.
The new findings have profound implications for any potential
parent. Women may increasingly feel they share the onus of
potential infertility and birth defects with men. Older women,
focused though they are on their own reproductive timetable, may
increasingly view their partner's age with a wary eye. When both
parents are aging, the risks to offspring multiply. "If women are
under age 35, the father's age may not matter that much, but if the
mother is over 35, advanced male age can be a real problem." says
Jabs.