The Male Biological Clock

Columbia University urologist Dr. Harry Fisch is one of the high-profile experts speaking out about the risks of geriatric fatherhood. He's appeared on the Today show and written a book called The Male Biological Clock, as well as an article in the medical journal Geriatrics. There he warns "couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome."

"Probably Like Females, Males Have a Reproductive Age"

"And that's How We Should Start To Think About It", Craig Newschaffer, professor and chairman of the department of epidemiology and biostatistics, Drexel University School of Public Health in Philadelphia

Father's Age May Play Role in Autism Risk
by Jon Hamilton
All Things Considered, September 5, 2006 · A study of children born in Israel finds that, as a man's age increases, so does his risk of fathering a child with autism.
Until a few years ago, scientists who study childhood disorders tended to focus on risks related to a mother's age. Their research showed, for example, that older moms were more likely to have a child born with a problem such as Down syndrome.
Then a few scientists started asking whether a father's age mattered, too. Abraham Reichenberg, an assistant professor of psychiatry at the Mount Sinai School of Medicine in New York, says they soon found evidence that it did. A series of studies showed an association between paternal age and schizophrenia.
"It made us wonder if there was something in autism," says Reichenberg.
Both conditions have a genetic component and appear to involve subtle changes to a child's developing brain.
So Reichenberg led a team of scientists that studied more than 300,000 children born in Israel. One set of government records showed the age of each father when a child was born, and usually the age of the mother. Another set of records showed whether a child was later diagnosed with autism.
The analysis of the information showed a clear trend.
"The older the age of the father at the time of birth, the higher the chances of the offspring to have autism," Reichenberg says. "In fathers who were 40 years or older, the risk for autism was almost six times higher than in the offspring of fathers who were younger than 30 years of age."
The mother's age didn't seem to matter.
There was another intriguing finding. Most studies show that autism is at least three times more common in boys than in girls. But that didn't hold true for the children of older fathers.
"The ratio of male to female was almost one to one," Reichenberg says, "which makes you think that some of the mechanisms might be a little bit different."
In other words, autism in children of older fathers may have a different cause than autism in children with younger dads.
It's not clear why older men are more likely to father children with autism. But there are at least two possibilities, suggests Craig Newschaffer, professor and chairman of epidemiology and biostatistics at the Drexel University School of Public Health in Philadelphia. One theory is that as men age, there is a greater chance of new mutations in their sperm. When combined with the egg, the sperm's mutations could have adverse health consequences – such as autism.
Another possibility is that older men who carry genes associated with autism are, for some unknown reason, more likely to pass along the risk from those genes.
It is tempting to ask whether the apparent rise in the number of children with autism is partly the result of a growing number of older fathers. But there's no ready answer. The study doesn't give a reliable indication of exactly how much the risk rises with age.
"If the magnitude of that effect truly were large," Newschaffer says, "I might be more inclined to say, perhaps the aging of dads in general could explain a piece of that trend."
The study also isn't clear enough to help parents decide whether it's too risky to have children based on the father's age, Newschaffer says. But he believes that this study and other studies of older fathers do offer a message: "Probably like females, males have a reproductive age." And that's how "we should start thinking about it."
Newschaffer's study appears in the September issue of the Archives of General Psychiatry.Father's Age May Play Role in Autism Risk

'NEW POINT MUTATIONS IN HUMANS ARE INTRODUCED THROUGH THE MALE LINE" THE NUMBER OF MUTATIONS IN SPERM INCREASE AS MEN AGE

Paul D. Thacker


Genetic Defects Linked to Sperm of Older Fathers
McGillivray, Katrina katrina at beststart.org
Wed Apr 14 10:00:40 EDT 2004

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Biological Clock Ticks for Men, Too
Genetic Defects Linked to Sperm of Older Fathers
Paul D. Thacker

JAMA. 2004;291:1683-1685.

Women approaching middle age have long been aware that the consequences of a
ticking biological clock include not only decreased fertility but also a
sharp increase in the odds of delivering a child with Down syndrome. Older
men, seemingly untouched by such biological constraints, felt free to father
children as they entered middle, and even old, age.

But now it is becoming increasingly clear that the biological clock ticks
for men as well as women, as researchers turn up evidence that as would-be
fathers get older, they have an increased chance of passing on genetic
defects to their children.

"New point mutations in humans are introduced through the male line," says
Dolores Malaspina, MD, professor of clinical psychiatry at Columbia
University and the New York State Psychiatric Institute. Furthermore, she
adds, the number of mutations in sperm increases as men age.

"This has been known since the 50s," said Malaspina. "What is intriguing is
why society chooses to ignore this."

Society is starting to pay attention. With many couples now deferring
childbearing until they are older, the issue of paternal age and increased
risk for birth defects is gaining a higher profile. It is also possible, say
some experts, that if current trends of older fatherhood continue, it could
someday become a public health problem as well as a personal one.

According to the latest birth statistics released in December by the Centers
for Disease Control and Prevention (CDC), the average age of motherhood is
at an all-time high of 25.1 years compared with 21.4 years in 1971. Although
some of this increase can be explained by the drop in teen births, another
reason was an increase in older women having children. Women in two age
groups-35 to 39 years and 40 to 45 years-now have children at the highest
levels in 3 decades. Statisticians find that women tend to marry men of
similar ages, so it can be surmised that the ages of fathers have also
increased.

Interestingly, while news reports on the CDC figures by various news outlets
mentioned the link between increased female age and disease risk to infants,
none reported the vulnerabilities posed by aging fathers that researchers
have turned up in recent years, such as the association between increased
paternal age and genetic diseases such as Apert syndrome (a disorder
characterized by craniofacial and limb abnormalities) and achondroplasia (a
skeletal disorder that causes dwarfism). Furthermore, studies show that 2%
of children born to men 50 years or older will have schizophrenia, three
times the incidence of schizophrenia in offspring born to fathers in their
early 20s.

Some experts in this field speculate that as the mean age of fathers
increases, the accumulation of mutations in the human gene pool could
heighten the risk of some recessive genetic disorders in future generations.


Malaspina notes that some European countries now ban men from becoming sperm
donors after reaching certain ages.

"I wouldn't discourage a man from having a child because the risk for many
of these diseases is quite small for an individual," she says. "But it's
quite meaningful at the population level." The Human Fertilisation and
Embryology Authority in the United Kingdom revised the upper age of sperm
donors downwards from 50 to 45 in 2000, based on the evidence that older men
are more likely to pass on genetic defects to offspring.


EARLY HINTS

The first hint of a link between paternal age and incidence of birth defects
was noted in 1912 by Wilhelm Weinberg, MD, who found that achondroplasia, an
inherited skeletal disorder occurred more often in younger siblings than
older ones, suggesting that as parents aged, the likelihood of the disorder
increased. Decades later, L. S. Penrose, MD, discovered that only the
father's age that correlated with de novo incidence of the autosomal
dominant disorder.

There are now approximately 20 different disorders that are correlated with
paternal age. The effect is quite prominent for de novo diseases such as
Apert, Crouzon, and Pfeiffer syndromes, for which frequency increases
rapidly with paternal age. Fathers of children with these syndromes are, on
average, 5 years older than the mean age of fathers in the population or
those of similarly affected children with familial forms of the same
diseases.

The increase in such genetic disorders probably has multiple causes,
including differences in how sperm are produced as well as environmental
factors. In 1955, Penrose hypothesized that mutations in sperm cause
disease. The copy-error hypothesis posits that mutations arise
disproportionately in the male germ line, because these cells undergo many
more replications than do the germ cells that give rise to eggs. Also,
because the number of replications leading to sperm formation increases as
men age, there are more possibilities for genetic mistakes.

Abnormal expression of paternally imprinted genes is another possible
mechanism linking advancing paternal age and offspring health, suggests
Malaspina. Imprinting is a phenomenon affecting certain genes that causes
such genes to be expressed differently in offspring, depending on whether
they are inherited from the mother or the father.

DNA DAMAGE IN SPERM
Men thus add more mutations to the gene pool than women simply because their
germ cells pass through more mitotic replications. Women have only about 24
divisions in the cells that give rise to their eggs, and these divisions all
occur before birth. In men, germ line cells have already passed through 30
rounds of mitosis before puberty, and then continue to divide every 16
days-a total of 23 replications per year.

By the time a man reaches age 30, the cells that create sperm will have
passed through 380 mitotic divisions. At age 40, the number has climbed to
610, and at age 50, it reaches 840 rounds of replication. Each round of
division creates another opportunity for an error to enter into the germ
line.

"When I worked in industry before [going to] medical school, women were
closely watched for their exposure to toxins in case they were pregnant,"
says Malaspina. Such an approach ignores the fact that men, with their
dividing germ cells, also should be protected from benzenes and other
chemicals, as well as radiation.

Multiple studies have examined aging's effect on sperm DNA. Narendra Singh,
MBBS, of the bioengineering department at the University of Washington, in
Seattle, and colleagues found in a study of 66 men aged 20 to 57 years,
there were significantly more breaks in the DNA of sperm from older men (="
src="/math/ge.gif" border=036 years) than from younger men (Fertil Steril.
2003;80:1420-1430).

"There is a gradual increase in DNA damage with age," Singh says. "But the
change was most remarkable at age 35."

Older stem cells might simply be creating more damaged sperm. Another
possibility is that protection from free radicals, which damage DNA, might
decrease with age. The researchers also found that both motility and the
rate of apoptosis, or programmed cell death, in sperm also fell. Apoptosis
is one mechanism to keep damaged sperm from fertilizing an egg.

"This is the first study showing that apoptosis goes down as a function of
age," notes Singh. "This finding is troubling because it shows that aging
predisposes the offspring for transmission of damaged DNA." Future research
might uncover strategies for either selecting healthy sperm or helping the
body to cull the sperm with damaged DNA, he says.

Other studies have found high rates of point mutations in the genes
associated with disease in offspring. Ethylin Jabs, MD, a professor of
pediatric genetics at Johns Hopkins University, in Baltimore, found that 99%
of the Apert syndrome cases were caused by mutations from the male germ line
(Am J Hum Genet. 2003;73:939-947). The incidence of these mutations
increases as men age, but the higher predicted incidence of Apert syndrome
in society suggests that some other process may be at work.

"It's more complex than just the number of mutations in the sperm," said
Jabs. "There may be some sort of selection process for sperm with mutations
that we can't yet explain."

A similar trend has been found by Norman Arnheim, PhD, professor of
molecular and computational biology at the University of Southern
California, Los Angeles. Achondroplasia closely correlates with male age,
but its incidence is higher than can be accounted for by the frequency of
mutated sperm (Proc Natl Acad Sci U S A. 2002;99:14952-14957). He has
posited a number of theories to explain why sperm selection might be
occurring.

"There's a big field on sperm competition and we know that it happens in a
number of animals," he says. Some scientists suggest, for example, that it
is possible that a mutation that increases the odds of a birth defect will
also allow the particular sperm possessing that mutation to outcompete other
sperm to fertilize the egg. "Some think it might have to do with the
mitochondria that power the sperm's flagella. I don't know if that's the
right hypothesis, but it's one that's out there."

A PUBLIC HEALTH THREAT?
Although researchers have attempted to conduct epidemiological studies to
look for correlations of disease with paternal age, such studies can be
difficult to perform. For one thing, data sets often lack information about
paternal age. Statistics from the CDC, for example, indicate that 13.4% of
birth certificates from 2002 did not list the father's age.

This lack of information makes it difficult to ask questions about paternal
age and birth defects, says Mathias Forrester, a data consultant for the
Hawaii Birth Defects Program. "We've looked at maternal age, but we've never
even asked the question about paternal age because it's difficult to get
good denominators out of birth certificates."

Even when information about the father's age is provided on a birth
certificate, birth defects might be missed; they are often underreported
because they are sometimes identified after the birth certificate is filled
out, notes Thomas Mathews, a CDC demographer. In some cases, conditions with
a genetic component have a late onset, which further complicates linking
paternal age to a disorder in offspring.

To overcome this problem in a study that found a strong association between
paternal age and risk of developing schizophrenia, Malaspina anonymously
linked data from a population-based birth cohort to the records of the
Israeli Psychiatric Registry (Arch Gen Psychiatry. 2001;58:361-367).
"Ours was the first study to show this," she says. "The problem is that
people never asked about paternal age."

CULTURAL RESISTANCE
There are many reason why paternal contribution to birth defects has a low
profile. James F. Crow, PhD, emeritus professor of genetics and medical
genetics at the University of Wisconsin in Madison, mentions that most of
these defects occur at low levels, on the order of 1 in tens of thousands.
In contrast, the odds of having a child with Down syndrome are about 1 in
350 when the mother is age 35 years and 1 in 100 at age 40 years. However,
some scientists hint that society may not be ready to hear that older men,
like older women, run the risk of passing on birth defects.

But the risk of having a child who later develops schizophrenia, Malaspina
notes, is about 1 in 110 when the father is age 40-similar to a 40-year-old
woman's risk of having a child with Down syndrome.

Malaspina says she believes her findings met resistance because of a
reluctance by men to accept that fathering children later in life poses
increased health risks to their children.

"Despite the fact that our paper received excellent reviews it was rejected
by two medical journals," she said, noting that the study results now have
been replicated five times with similar results. "And these biases really
hold us back from scientific advances."

PATERNAL AGE IS A DRAMATIC AND VERY ROBUST RISK FACTOR FOR AUTISM AND SCHIZOPHRENIA

LITTLE TIDBITS OF WHAT IS ON THIS BLOG You will find abstracts with citations for these quotes on the blog and many more abstracts

"The first mention in the historical literature suggesting a possible life-shortening effect on offspring of delayed parenting was made by the French naturalist Buffon(1826), who noted that when old men procreate "they often engender monsters, deformed children, still more defective than their father"(see Robine and Allard 1997).




Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors.

But you don't have to carry a genetic disease to pass one on — the trouble can start in your testicles. There, sperm-generating cells divide about 23 times a year, in the process slowly accumulating copying errors.


So for a man, the older you get, the less your child's genetic endowment will resemble your own.


Absolute Mutation Rate
JAMES F. CROW

"The total mutation frequency,as inferred from evolutionary studies,44), is something in the order of 100 new mutations per generation. This seems utterly frightening. Surely the overwhelming majority of these must be essentiallt neutral. More relevant is the frequency of new deleterious mutations, which is more than one per zygote.45)That is still high. WHY AREN'T WE EXTINCT


Our results indicate a linear increase in structural aberrations and disomy for chromosome 9 in sperm with respect to age.



Table II. Long-term effects of paternal ageing on offspring from table on page 2373 of Long –term effects of delayed parenthood by J.J. Tarin, J. Brines, and A. Cano

Dominant disorders
Wilms tumour, thanatophoric dysplasia, retinitis pigmentosa, osteogenisis imperfecta type IIA, acrodysostosis, achondroplasia, Apert’s disease, fibrodysplasia ossificans progressiva, aniridia, bilateral retinoblastoma, multiple exostoses, Marfan’s, Lesch-Nyan’s, Pfeiffer’s, Wardenburg’s, Treacher-Collins, Soto’s, and Crouzon’s syndromes, basel cell nevus, cleidocranial dysostosis, polyposis coli, oculodentodigital syndrome, Costello syndrome , progeria, Recklinghausen’s neurofibromatosis, tuberous sclerosis and renal polycystic kidney disease.

X-linked recessive diseases
Haemophilia A and Duchenne’s muscular dystrophy

Non-cytogenetic congential defects
Congential cataracts, reduction defects of the upper limb, nasal aplasia, pulmonic and urethtal stenosis, perauricular cyst, cleft palate,1 neural tube defects

Athetoid /dystonic cerebral palsy and congenital hemiplegia

Psychotic disorders

Decreased learning capacity and/or mental retardation




FRANCIS COLLINS


"Almost all cases of HGPS (Progeria) studied so far turn out to be new mutations of paternal origin. Consistent with this, the age of fathers of children with HGPS is on the average slightly older than the general population of fathers. You can read more about this in the entry on progeria in GeneClinics.org"

paternal age effect is present as the father's age is significantly increased by about five years on average. There is no increase in consanguinity.


"De novo point mutations in such genes could explain the advanced paternal age association that has been reported for autism13. There is no evidence, however, that the risk of a de novo CNV is related to the age of either parent."


"The optimal time for a man to father a healthy child is the same as for a woman — 25 or so," says Dolores Malaspina, a psychiatry professor at New York University and coauthor of the study.


Advanced Grandparental Age as a Risk Factor for Autism


The paternal age distribution of the AGRE fathers, whose first child is autistic differs significantly from that of the 'control' sample (P=0.005). A 2 goodness-of-fit test with 2 degrees of freedom was conducted using percents in the 'control' group age categories to calculate the expected values in the AGRE sample. The shift toward higher paternal ages in those with an affected first-born is seen most dramatically in the group of AGRE fathers who are 30–39 years inclusive, which is 54.7% of the distribution compared with the 41.9 % that is expected. We interpret this shifted age distribution to provide support for the recently reported finding by Reichenberg and co-workers that autism risk is associated with advancing paternal age.



The results of this review show that 3 of the 4 population-based studies28-29,32 to examine paternal age reported a significant association with risk of autism and ASDs. The fourth study31 also found that paternal age was older in fathers of case patients with autism compared with fathers of controls, although this relationship was statistically weaker in the adjusted analysis. Thus, advancing paternal age is consistently associated with increased risk of autism and ASDs.
Advanced paternal age has been associated with several congenital disorders, including Apert syndrome,40 craniosynostosis,41 situs inversus,42 syndactyly,43 cleft lip and/or palate,44-45 hydrocephalus,44 neural tube defects,46 and Down syndrome.47 In addition, advanced paternal age has been associated with schizophrenia15 and decreased intellectual capacities in the offspring.48 The most widely proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose.49 After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals.



The most irrefutable finding is our demonstration that a father’s age is a major risk factor for schizophrenia. We were the first group to show that schizophrenia is linearly related to paternal age and that the risk is tripled for the offspring of the oldest groups of fathers.7 This finding has been born out in every single cohort study that has looked at paternal age and the risk for schizophrenia. The only other finding that has been as consistently replicated in schizophrenia research is that there is an increased risk associated with a family history of schizophrenia. Since only 10% to 15% of schizophrenia cases have a family history, family history does not explain much of the population risk for schizophrenia. However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose in the 1950s. He hypothosized that this was due to errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children. In the 1960s, an excess of schizophrenia in last-born children was also reported.



Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors