Learn about the genetic biological clock and teach everyone you know, it has been kept under the radar

Men manufacture new sperm continuously throughout life, with each one living about 74 days. Scientists once thought that defective sperm were doomed to die with the roughly 40 million unrequited suitors in every ejaculation. But now it seems that some kinds of damage do not hinder sperm in their race to fertilization. The result can be embryos with high vulnerability to problems including autism and cancer.

Men's reproductive health is most robust in their twenties, and after that it's downhill. Each year after puberty, a man's spermmaking cells divide about 23 times. By age 40, these vital human building blocks have gone through about 610 rounds of replication, each with a chance for genetic error.

In the human, the contribution of the sexes to the genetic load is dissimilar the Male Germline is Dominant

1: Hum Mol Genet. 2008 Jul 1;17(13):1922-37. Epub 2008 Mar 18.
Links
DNA double-strand break repair in parental chromatin of mouse zygotes, the first cell cycle as an origin of de novo mutation.
Derijck A, van der Heijden G, Giele M, Philippens M, de Boer P.
Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
In the human, the contribution of the sexes to the genetic load is dissimilar. Especially for point mutations, expanded simple tandem repeats and structural chromosome mutations, the contribution of the male germline is dominant. Far less is known about the male germ cell stage(s) that are most vulnerable to mutation contraction. For the understanding of de novo mutation induction in the germline, mechanistic insight of DNA repair in the zygote is mandatory. At the onset of embryonic development, the parental chromatin sets occupy one pronucleus (PN) each and DNA repair can be regarded as a maternal trait, depending on proteins and mRNAs provided by the oocyte. Repair of DNA double-strand breaks (DSBs) is executed by non-homologous end joining (NHEJ) and homologous recombination (HR). Differentiated somatic cells often resolve DSBs by NHEJ, whereas embryonic stem cells preferably use HR. We show NHEJ and HR to be both functional during the zygotic cell cycle. NHEJ is already active during replacement of sperm protamines by nucleosomes. The kinetics of G1 repair is influenced by DNA-PK(cs) hypomorphic activity. Both HR and NHEJ are operative in S-phase, HR being more active in the male PN. DNA-PK(cs) deficiency upregulates the HR activity. Both after sperm remodeling and at first mitosis, spontaneous levels of gammaH2AX foci (marker for DSBs) are high. All immunoflurescent indices of DNA damage and DNA repair point at greater spontaneous damage and induced repair activity in paternal chromatin in the zygote.
PMID: 18353795 [PubMed - indexed for MEDLINE]

Sperm several paternal risk factors such as age, various drugs, lifestyles, and various environmental and occupational exposures

1: Methods Mol Biol. 2008;410:241-71.
Laboratory methods for the detection of chromosomal structural aberrations in human and mouse sperm by fluorescence in situ hybridization.Marchetti F, Cabreros D, Wyrobek AJ.
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

The father, like the mother, can transmit genetic defects that are detrimental for development and genetic health for his children, but the mechanisms for paternally mediated abnormal reproductive outcomes remain poorly understood. A battery of sensitive methods has been developed for detecting genetic damage associated with infertility, spontaneous abortions, as well as inherited defects in children such as aneuploidy syndromes, translocation carriers, and certain genetic diseases directly in sperm. Among these, fluorescence in situ hybridization (FISH) sperm-based assays for measuring numerical abnormalities and structural chromosomal aberrations are now available for an expanding number of species including humans, rodents, and several domesticated animals. This new generation of sperm FISH methods has identified several paternal risk factors such as age, various drugs, lifestyles, and various environmental and occupational exposures. These sperm FISH assays provide new opportunities to identify and characterize male reproductive risks associated with genetic, lifestyle, and environmental factors. This chapter outlines the laboratory methods for the detection of sperm with chromosomal structural aberrations in humans (ACM assay) and mice (CT8 assay) that have been validated for detecting environmental germ cell mutagens.

PMID: 18642604 [PubMed - in process]

Men Have a Biological Clock too.

Men Have a Biological Clock too.
By Sue Leonard.
Published by The Irish Examiner ‘Feelgood,’ 18th July 2008.

We all know that women have a biological clock. And that its ticking becomes louder the older that she gets. But did you know that men have a biological clock too?

A new French study has found that the chance of a successful pregnancy recedes when a man is over 35; and falls significantly when he is over 40.

French researchers at the Eylau Centre for Assisted Reproduction conducted a study of over 12,000 couples undergoing Intrauterine Insemination- IUI. They examined the man’s sperm, checking its quantity, motility and its size and shape. Then they recorded the couple’s rates of pregnancy, miscarriage and birth.

The team found that where the father was in his late 30’s, the rate of miscarriage increased. And if the man was over 40 the chances of a successful pregnancy were even lower.

Presenting the research, Dr Stephanie Belloc told a conference in Barcelona that such couples should be offered ICSI. (Where a sperm is injected directly into an egg.)

Dr Edgar Mocanu of HARI; the infertility clinic attached to the Rotunda Hospital, sees an increasing number of males coming forward for ICSI.
“What was perceived as a female problem is now recognised more as a couple issue,” he said. “And thus the investigation and treatment of the male has now a recognised place in the practise of infertility.”

Dr David Walsh of the SIMS clinic, whilst always aware that infertility is a ‘couple’ issue,’ is surprised by the degree of the problem as highlighted by the research.
“We knew that age matters, and that under 35 is a better time to have a baby, but with men, the talk was always of the risks for much older men; those in their fifties and sixties.

“There was, for example, an increased risk of achondroplasia (dwarfism), in their children. We now see that in men beyond 35 there is an increase in quite a lot of abnormalities; in things like autism, schizophrenia and cleft lip.

Apert

Sporadic genetic defects may spring from germ cell selection
By John Timmer | Published: July 16, 2008 - 09:01AM CT

Apert syndrome, which causes craniofacial defects and fusion of the digits, is somewhat oddly behaved as a genetic disease. It can be inherited as an autosomal dominant disorder, but many of the cases are sporadic. Almost all of these sporadic cases can be traced back to mutations at two specific bases in the gene. Estimates based on the general rate of mutation that occurs throughout the human genome suggest that these two mutations are occurring somewhere between 100 and 1,000 times more often than would be expected. A paper that will be released by PNAS this week attempts to provide an explanation for this unexpected behavior, as its authors suggest that the same mutations that cause so many problems for developing infants actually help the germ cells in which they originated.
As predicted, the frequency of the Apert-specific mutations increased with age; men in their 60s had two orders of magnitude more of these mutations than men in their 20s.

The theory behind this behavior is several decades old, and is based on applying evolutionary principles to the behavior of the male germline. Unlike in females, the precursors of the male germ cells proliferate throughout their carrier's life. As a result, any mutation that causes them to divide faster than their peers should result in an excess of these mutations, and one that grows as the person ages. The authors speculate that the two mutations that cause Apert syndrome may represent this theory in action.

To test this, they obtained the testes of several healthy adults who died at a research hospital, and checked for the presence of the two Apert mutations, as well as changes in a nearby DNA base that acted as a control. As predicted, the frequency of the Apert-specific mutations increased with age; men in their 60s had two orders of magnitude more of these mutations than men in their 20s.

This sort of behavior could occur through a mutational hotspot mechanism, but the authors also showed that the occurrence of the mutations was clustered, as would be predicted by a population expansion from a single, ancestral mutation. The control base, in contrast, displayed a pattern of rare mutations that were distributed randomly about the testes.

The gene affected in Apert syndrome is a receptor for fibroblast growth factors, or FGFs, and these genes frequently control the proliferation of cells, suggesting an obvious mechanism for its promotion of germ cell expansion. But the authors note several other sporadic genetic diseases that show similar patterns of inheritance, and suggest this behavior may be involved in other syndromes.

PNAS, 2008. DOI: 10.1073/pnas.0801267105

A Great Explantion of the Paternal Age Effect

Male Biological Clock

Sheena Lewis Professor of Reproductive Medicine

Tuesday, July 15, 2008Timing is key to fathering children
In this section »
Doctors say women's age remains the major factorCan regular sex preserve potency?THERESA JUDGENew research suggests men's biological clocks are also ticking

FERTILITY EXPERTS have warned there is a growing body of evidence showing that the man's age is a significant factor affecting the chances of a couple conceiving and of having a healthy child.

A new study presented last week at the annual meeting of the European Society of Human Reproduction and Embryology in Barcelona found that miscarriage rates increased significantly when the man was older than 35, and that pregnancy rates dropped when the man was older than 40. The study was based on more than 12,000 couples attending a fertility clinic in Paris.

Professor of reproductive medicine at Queen's University Belfast, Sheena Lewis, who also presented a paper at the conference, said the Paris study "provided more data to add to an emerging picture" relating to the significance of the age of the father.

She said people needed to realise that they are taking a risk by waiting until they were 35 years or older to have children - as an increasing number of women and men are. "You cannot assume that it will happen, that it will not be a problem," she said.

Prof Lewis, who is a scientist at the Regional Fertility Centre at the Royal Victoria Hospital in Belfast, said there was a growing trend of people leaving it later to have children when their careers were established, and of people trying to start second families later in life. She said the clinic was seeing an increasing number of men in their 40s and 50s who wanted to have children, often in a second relationship.

People often mistakenly assume they will be able to have children later in life, she said. "What happens is that we are inclined to take anecdotal evidence and assume that it applies to the whole population - so people hear about Cherie Blair and Madonna having babies and assume that older mothers can have easy pregnancies.

"And they hear about Picasso fathering a child when he was 81, and they believe that every man can do it, and it becomes the accepted wisdom, but unfortunately it is not the case. We are perpetuating a myth and people often believe it until it is too late," Prof Lewis said.

She said there were now quite a number of studies showing that as a man ages, the likelihood of his sperm being damaged increases. "A sperm is a very specialised little cell - it is just DNA with a tail and it has one single function, to get the DNA to the egg to fertilise it. In order to do that, the cell gets rid of everything but DNA, so it gets rid of repair mechanisms that you find in other cells. So if it gets damaged it can't repair itself."

She said that after fertilisation, the DNA damage of the sperm becomes part of the genetic make-up of the embryo. "If a poor sperm fertilises an egg, and even if you get a pregnancy, there is quite often a miscarriage," Prof Lewis said. While one study had suggested that an egg could repair a damaged sperm, she said there was not a great deal of evidence to support this, and further research would be needed to test it. She said other studies had shown that when a man is older it takes longer for a couple to conceive.

Dr Stephanie Belloc, who led the study at the Eylau Centre for Assisted Reproduction in Paris, told the Barcelona conference: "Until now gynaecologists only focused on maternal age and the message was to get pregnant before the age of 35 or 38, because afterwards it would be difficult. But now gynaecologists must also focus on paternal age and give this information to the couple."

The study examined 12,236 couples who had decided to try intra-uterine insemination (IUI) after having difficulty conceiving. This procedure involves spinning sperm in a centrifuge to separate it from seminal fluid and then inserting it directly into the womb.

Pregnancy, miscarriage and delivery rates were recorded as were the quality, activity and shape of the men's sperm. The analysis separated out male and female factors.

As expected, women over the age of 35 were less likely to get pregnant but the man's age was also found to be a significant factor both in miscarriage rates and pregnancy rates.

For men aged 34, the miscarriage rate was 16.7 per cent, but for men aged between 35 and 39 it rose to 19.5 per cent, and by age 44 it had reached 32.4 per cent.

Pregnancy rates only began to change significantly when the men reached the age of 40. As the men's age rose from 39 to 44 the proportion of treatment cycles producing a pregnancy fell from 13.4 per cent to 10.9 per cent.

Dr Belloc said the study "proves for the first time that there is a strong paternal age-related effect on IUI outcomes" and she said the findings were relevant to all couples wishing to have children.

Prof Lewis and her colleagues in Belfast are currently conducting research into "lifestyle hazards" that affect male fertility. These include smoking, alcohol, sexually transmitted diseases, recreational drugs and substances that mimic oestrogens which are found in some products ranging from certain foods, aerosols and body creams, and plastic food coverings. Much of the research in this area was prompted by a Danish finding in 1992 that men's sperm count had declined by 50 per cent in 50 years.

Prof Lewis said a recent study in Denmark had also found that 40 per cent of young men had a low sperm count. "It appears to be a particular problem in northern Europe," she said.

The paper she presented at last week's Barcelona conference concerned the impact of cannabis use on male fertility. The study found that cannabis use decreased sperm motility - the pace at which sperm can swim. Other studies have also shown that cannabis use reduces sperm production.

She said that men who wanted to become fathers should be aware that it takes about 70 days for a sperm to be produced, so the "lifestyle hazards" such as smoking and recreational drugs should be avoided for at least three months if they want their sperm to be healthy.

She also pointed out that studies suggest that a father smoking, and the resulting damage to the sperm DNA, can lead to an increase in certain childhood illnesses, in particular some forms of cancer and more recently an association has been found with autism.

"When a mother smokes and damages the egg, the egg has the capacity to repair the damage, but the damage to the sperm becomes part of the embryo's genetic make-up," she said.

© 2008 The Irish Times



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Professor Sheena E.M. Lewis, BSc PhD

School of Medicine
Obstetrics and Gynaecology
Queen’s University Belfast
Institute of Clinical Science
Grosvenor Road
Belfast BT12 6BJ
N Ireland

e: s.e.lewis@qub.ac.uk
t: +44-28-9063-3987
f: +44-28-9032-8247


I am Professor and Director of the Reproductive Medicine research group here in Queen's having previously been Reader in Obstetrics and Gynaecology at Queen's University since October 2000. I was also appointed as an Honorary Consultant in the Royal Group of Hospitals in Belfast in 2003.

Services to the scientific community
Nationally, I am a regular reviewer for 10 specialist journals and for research charities including The Wellcome Trust, Wellbeing, and BBSRC.
I am a member of the Practice and Policy committee of the British Fertility Society and on the Research and Development Fellowship Committee and Northern Ireland Forum for Health and Social Care Research for Northern Ireland.

RESEARCH PUBLICATIONS
62 peer reviewed publications, 9 review articles, 6 invited chapters
including 23 since 2000 (First or final author on 20)

RESEARCH GRANTS AWARDED
£1,000,000 including three from The Wellcome Trust.

PROFESSIONAL SOCIETIES
• British Fertility Society
• British Andrology Society
• Society for the Study of Fertility
• International Society of Andrology
• Institute of Learning and Teaching in Higher Education
• Research and Development Fellowship Committee, N.I
• Ulster Obstetrical and Gynaecological Society
• Vice Chairperson of the Ladies Committee, Royal Maternity Hospital
• Association of University Teachers

INVITED GUEST SPEAKER AT RECENT SCIENTIFIC CONFERENCES
• First Mediterranean Congress of Reproductive Medicine, Taormina, Sicily
• Opening Doors-scientific workshop organised by British and Spanish Councils, Spain,
• GSRMC (Good Samaritan Regional Medical Centre Phoenix, Arizona, USA)
• UKEMS (The United Kingdom Environmental Mutagen Society)
• British Fertility Society
• British Andrology Society
• Biology of Spermatozoa Annual Meeting
• Senior Staff Conference, Royal College of Obstetrics and Gynaecologists
• Association of Clinical Biochemists in Ireland

INVITED SPEAKER BY MEDIA
• BBC Radios 1, 2, 4 and 5
• BBC News
• Sky news
• Ulster Television; UTV LIFE – CHAPS UK Study
• Radio Eireann – Donor Sperm
• Radio Ulster – Comment on Health Minister’s proposal and comment on BFS in Belfast.
• British Satellite News - for CNN news, Tokyo News, Mid Eastern broadcasting and others
• Ulster Television The Family Show- Infertility and Lifestyle

CENTRAL UNIVERSITY ACTIVITIES
• Member of Academic Council of Queens University, Belfast
• Mentor and mentee in Gender Initiative in Queen’s University, Belfast

RESEARCH INTERESTS
Our research interest is in Andrology; the study of male reproductive function. Our twin aims are:
i) to understand the endocrine, cellular and molecular reproductive dysfunctions in infertile men compared with a fertile baseline. Within this framework, we have focused on specific lifestyle, environmental and disease factors that may exacerbate infertility
ii) to establish novel prognostic tests to enhance assisted conception


Ongoing projects:

Lifestyle hazards: recreational drugs
i) to determine the in vivo and in vitro effects of tetrahydrocannabinoid; THC the primary psychoactive cannabinoid in marijuana on human sperm function
ii)the effects of Viagra on sperm function and early embryo development using human and animal models

Environmental hazards
the effects of dietary phytoestrogens on male reproductive health

Diseases exacerbating male infertility
Endocrine, cellular and molecular effects of diabetes and impotence treatments (first generation Viagra and second generation Tadalafil) on male fertility

Development of novel male fertility tests with prognostic value in assisted conception
• assessment of sperm nuclear and mitochondrial DNA iv)investigation of the failure of post-vasectomy testicular sperm to achieve pregnancies by ICSI
• the regulation of spermatogenesis by apoptosis in fertile men and males with obstructive azoospermia- clinical implications
• Ubiquitin tagging ( internal and surface) on sperm and its implications for male fertility (in collaboration with Dr Peter Sutovsky, Columbia-Missouri )

Future Studies
• Genetic and epigenetic alterations associated with spontaneous abortion achieved by assisted conception (in collaboration with Dr Ken McIlreavey, Pasteur Institute, Paris and Dr Colum Walsh, University of Ulster )



Obstetrics and Gynaecology at Queen's.

My Paper on Paternal Age and Non familial non vaccine autism and other disorders

Fathers’ Age as Contributor to Risk for Autism
Leslie Feldman
The average age of fatherhood is increasing in the US and in Western Europe. Some research shows that offspring of older fathers are at increased risk for diseases and conditions (Bray et al., 2006). Some experts predict an upswing in cases of schizophrenia will accompany the increasing average paternal age. “The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent” (Malaspina et al., 2006). Approximately 25-33% of all cases of schizophrenia may be due to the father’s age at conception, according to Malaspina (2006). Malaspina sees a connection between advancing paternal age and neural functioning difficulties in people with autism and with schizophrenia. According to Tarin et al. (1998), there are well over 30 known conditions that the offspring of older fathers are more at risk for (see chart on paternal aging in the linked article).

The diagnosis of autism is increasing in the US and elsewhere (Centers for Disease Control, 2006). In a population study of 1990 through 1999, a total of 669,995 children, Atladóttir and colleagues (2007) reported increased diagnosese of autism, Torrette Syndrome, and hyperkinetic disorder. Is there a connection between increased cases of disorders such as autism and increased average paternal age? Psychiatrist Michael Craig Miller (2006), editor of the Harvard Mental Health Letter is convinced there is. Although a connection between the two would be corelational (not causal), the relationship encourages examination of the possibility that something related to paternal age (e.g. mutations in gametes) may contribute to the occurrence of autism. If there is a potential causal relationship, the new study by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network would provide a valuable opportunity to test the hypothesis.

Observations of a connection between advanced paternal age and difficulties for offspring go way back. Earlier research looking for a link between maternal age and autism also found the average paternal age (34) was much higher than the average age in the general population (Gillberg, 1980). Geneticist James F. Crow (1997) cites Wilhelm Weinberg (1862-1937) as noticing, during his 42 years of medical practice and helping 3,500 births, that the mutation rate might be a function of paternal age. Crow said, the evidence suggested that the greatest mutational health hazard in the population is fertile old men.

A study by Reichenberg et al. (2006) found a strong connection between cases of autism and advancing paternal age. Reichenberg and colleagues, who found more autism as paternal age increased, also found that the ratio of girls to boys in this cohort was 1:1, suggesting that this was a special subset of autism, maybe de novo rather than familial autism.

What might be the mechanism that produces higher rates of disorders among children of older fathers? The DNA in a 20 year-old male has been copied approximately100 times but in a 50 year-old father it has been copied over 800 times. Singh and colleagues (2003) studied differences in the sperm of older and younger men. Men over age 35 have sperm with lower motility and more highly damaged DNA in the form of double-strand breaks. The older group also had fewer apoptotic cells, an important discovery. (Apoptosis is form of cell death that protects the parent organism from problems or that permits differentiation, as in resorption of a tadpole’s tail.) A really key factor that differentiates sperm from other cells in the body is that they do not repair their DNA damage, as most other cells do. As a result, the only way to avoid passing DNA damage to a child is for the damaged cells to undergo apoptosis, a process that the study indicates declines with age. Singh is quoted in Science Blog (Sullivan, 2002) as explaining that, “In older men, the sperm are accumulating more damage, and those severely damaged sperm are not being eliminated.”

Sources

The following list of sources is for works cited in this document or for other studies finding a connection between age of fathers at conception and various disorders. Access to some of the Web-based resources may be limited because of the policies of the publishers.

Atladóttir, H. O., Parner, E. T., Schendel, D., Dalsgaard, S., Thomsen, P. H., & Thorsen, P. (2007). Time trends in reported diagnoses of childhood neuropsychiatric disorders. Arch Pediatr Adolesc Med., 161, 193-198. Link

Brown et al. (2002): Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry, 159, 1528-1533. Link

Bray, I., Gunnell, D., & Smith, G. D. (2006). Advanced paternal age: How old is too old? Journal of Epidemiology and Community Health, 60, 851-853. Link

Burd et al., (1999). Prenatal and perinatal risk factors for autism. J. Perinatal. Med., 27, 441-450. Link

Byrne, M., Agerbo, E., Ewald, H., Easton, W. W., & Mortensen, P. D. (2003). Parental age and risk of schizophrenia, A case control study. Arch Gen Psychiatry, 60, 673-678. Link

Centers for Disease Control, (2006). How common are Autism Spectrum Disorders (ASD)? Link

Centers for Disease Control. (2002). Prevalence of the Autism Spectrum Disorders (ASDs) in multiple areas of the United States, 2000 and 2002. Atlanta, GA: Author. Link

Crow, J. F. (1997). The high spontaneous mutation rate: Is it a health risk? Proc. Natl. Acad. Sci. USA, 94, 8380-8386. Link

Dalman, C., & Allebeck, D. (2002). Paternal age and schizophrenia: Further support for an association. Am J Psychiatry, 159, 1591-1592. Link

Gillberg, C. (1980). Maternal age and infantile autism. J. Autism and Developmental Disorders, 10, 293-297. Link

Lauritsen M. B., Pedersen, C. B., & Mortensen, P. B. (2005) Effect of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. J. Child Psychology and Psychiatry, 46, 963-971. Link

Miller, M. C. (2006) A new key to Autism. Aetna IntelliHealth, September 25. Link

Malaspina, D., et al. (2001): Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry, 58, 361-367. Link

Malaspina, D. (2006). In session with Dolores Malaspina, MD, MSPH: Impact of childhood trauma on psychiatric illness (interview by N. Sussman). Primary Psychiatry, 13(7), 33-36. Link

Malaspina, D. (2006). Schizophrenia risk and the paternal germ line. Schizophrenia Research Forum. Link

Rasmussen, F. (2006) Paternal age, size at birth, size in young adulthood&mdashrisk factors for schizophrenia. Eur Journal of Endocrinology, 155 Suppl 1:S65-69. Link

Reichenburg, A., Gross, R., Weiser, M. Bresnahan, M., Silverman, J. Harlap, S., et al. (2006). Advancing paternal age and autism. Arch Gen Psychiatry, 63, 1026-1032. Link

Singh, N. P., Muller, C. H., & Burger, R. E. (2003). Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertility and Sterility, 80, 1420-1430. Link

Sipos, A., Rasmussen, R., Harrison, G., Tynelius, P., Lews, G., Leon, D. A., et al. (2004). Paternal age and schizophrenia: A population based cohort study. BMJ, 329, 1070. Link

Sullivan, B. J. (2002). Research reveals a cellular basis for a male biological clock. Science Blog, 2002-11-25 22:31. Link

Tarin, J. J., Brines, J., & Cano, A. (1998). Long-term effects of delayed parenthood. Human Reproduction, 13, 2371-2376. Link

Tsuchiya, K. J., Takagai, S., Kawai, M., Matsumoto, H., Nakamura, K., Minabe, Y., et al. (2005). Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophrenia Research, 76, 337-342. Link

Wohl, M. & Gorwood, P. (2006). Paternal ages below or above 35 are associated with a different risk for schizophrenia in offspring. Eur. Psychiatry, Dec 1 [Epub ahead of print]. Link

Zammit, S., Allebeck, P., Dalman, C., Lundgerg, I., Hemming, T., Owen, M. J., et al. (2003). Paternal age and risk for schizophrenia. Br. J. Psychiatry, 183, 405-408. Link

Associate Professor Les Sheffield is a clinical geneticist with the Victorian Clinical Genetics Services

Genetic clock ticks for men: 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

Many Men Do Not Know That they Have A Genetic Biological Clock

Alarm rings for Peter PanBy Sarah Wilson

July 12, 2008 12:00am

IHAVE a friend who recently told his 38-year-old fiancee that he didn't want to have kids for, oh, you know, another 10 years or so.

There were so many other things he still wanted to do, he said. Like buy a dirt bike!

Did someone say "spanner in works''?

My friend - no longer with said fiance - is part of a growing phenomenon of so-called Peter Pans.
This city is apparently full of them.

The Sunday Telegraph picked up on the trend a few weeks back and the recent book The Lost Boys describes a generation of 30-something blokes living in Bondi who behave like they're 17 again and put off relationships and kids because they're having too much fun surfing and pulling bongs with the boys.

And because they can.

But Peter Pan had a wake-up call this week. According to new research from France, men, not just women, have ticking biological clocks.

After the age of 35, sperm deteriorates, resulting in higher rates of miscarriage and defects. One in three partners of men over 40 will lose a baby.

I tell you, the implications of this news are bigger than you might think.

In the sex wars, sperm has always got around in a bulletproof vest.

Declining fertility rates have been blamed on the short shelf life of female eggs; sperm has dodged the bullets.

And so men have not really joined the frontline of the issue like women have.

This has caused a huge disconnect between the sexes, particularly in the dating game.

We're all partnering and having kids much later, right.

But as women in their 30s reach the stage where they're ready to settle down with the bloke and kids, they're aware they must move fast to catch the fertility boat. (Buzz term: accelerated settling.)

But many arrive at this risky juncture only to be met with men who, fair enough, aren't ready to be rushed.

Or who've perhaps already moved on to a younger model to maybe procreate with a bit later.

Because they can. Or could.

I reckon it's an interesting time for this male biological clock issue to rear its cautionary head.

Despite all the harsh Peter Pan talk, I've noticed a pendulum swing, with men wanting to be far more involved in this modern parenthood/partnering debate.

Another mate (37, Bondi, professional bachelor) told me he doesn't want to date women half his age any more.

"I want to partner with my peers, who have the same cultural cues,'' he said.

"I guess I'm going to get my skates on.'' I mentioned previously in this column the Rad Dad phenomenon of men embracing dadhood by giving it a fashionable spin (akin to what the Yummy Mummy did to motherhood).

And a University of Queensland study this week reveals men are doing more housework than ever before.

Granted, these are random and essentialist examples, but are part of a picture commentators worldwide are picking up on.

It's a snappy use of metaphor to say that faced with a ticking biological clock, men will merely roll over, hit the snooze button and sleep through it.

And many in the media are saying it this week. But I think the alarm has already sounded.

They Never Talk About the High Risk of ICSI to the Health of Offspring

Science News Share Blog Cite Print Email BookmarkNormal-looking Sperm May Have Serious Damage; Scientists Urge More Care In Selection
ScienceDaily (July 8, 2008) — Intracytoplasmic sperm injection (ICSI), where a single sperm is injected into an egg to fertilise it, is increasingly used to help infertile men father children. Although the sperm chosen for the procedure may appear quite normal, researchers in the US have found that many of them in fact have DNA damage, which can decrease the chances of pregnancy.

Biological Clocks Tick for Men, Too

"As men get older, there is an increase in the risk of having that fragmented DNA," Schlegel explained. Dah!


But the study also found that if the father was in his late 30s, the chances of a successful pregnancy went down. Ten percent of treatments led to pregnancy in fathers over 40.


The father's age also affected rates of miscarriage. If a father was over 34, the miscarriage rate was 16.7 percent. Between the ages of 35 and 39, it went up to 19.5 percent. And if the father was older than 44, it jumped to 32.4 percent -- which means nearly one-third of the pregnancies ended in miscarriages.

Researchers said the problems were likely the result of DNA damage and fragmentation in sperm, which can lead to pregnancy failure and miscarriage.

Dr. Peter Schlegel, chairman of urology at the Weill Cornell Medical Center in New York, works at the Male Center for Reproductive Medicine. He told ABC News it is possible that there is a link between DNA damage and age.

"As men get older, there is an increase in the risk of having that fragmented DNA," Schlegel explained.

doctors warn today, after research found that male fertility begins to decline when they reach their mid-30s

Deteriorating sperm is key factor from mid-30s on
· Delaying fatherhood linked to miscarriages



Ian Sample in Barcelona The Guardian, Monday July 7, 2008 Article historyThe biological clock ticks for men as well as women, doctors warn today, after research found that male fertility begins to decline when they reach their mid-30s.

Doctors said men who wait until their 40s before starting a family face a greater chance of their partner having a miscarriage, because of the poorer quality of their sperm.

Researchers examined patient records of more than 12,000 couples treated at a fertility clinic in Paris, and separated out the influence of male and female ages on the couples' chances of having a baby.

They found that women whose partners were 35 or older had more miscarriages than those who were with younger men, regardless of their own age. The men's ages also affected pregnancy rates, which were lower in the over-40s.

Doctors have long known that a woman's fertility drops sharply in her mid to late 30s, but the effect of age on male fertility is less well understood. Among women, miscarriage rates typically double to 40% between the ages of 20 and 40.

The findings are a concern, researchers say, because of the trend for men to delay fatherhood. The latest figures from the Office for National Statistics show the typical age of married fathers rose from 29.1 in 1971 to 34.1 in 2003. The age of men having children outside marriage has remained stable at about 30. And, for the first time, more women in Britain are giving birth in their early 30s than in their late 20s.

Yves Ménézo, an embryologist at the Eylau Centre for Assisted Reproduction, said older men become less fertile because genetic defects build up in their sperm. In younger men, the damage is minor and can be repaired inside the fertilised egg. But in older men the amount of DNA damage can overwhelm the body's natural repair mechanisms. "We think there's a critical threshold of DNA damage and above that, the damage can no longer be repaired. When that happens, genetic mistakes get through to the embryo and you get an increase in miscarriages," Ménézo said.

The findings should cause fertility clinics to reconsider how they treat couples, Ménézo added. Those who fail to conceive after mild forms of fertility treatment, such as intrauterine insemination (IUI), in which sperm is washed and transferred directly into the uterus, should move quickly to more advanced treatments, such as ICSI, where the best quality sperm are picked out and injected directly into the woman's egg.

The study looked at pregnancies and miscarriages recorded for couples having IUI treatment at the clinic between 2002 and 2006. It found the risk of miscarriage was on average 16.7% when men were aged 30-34. That rate rose to 19.5% when men were 35-39 and 33% in men aged 40 or over.

Stéphanie Belloc, lead author of the study, which is due to be published in the journal RBM Online, said: "Until now, gynaecologists only focus on maternal age, and the message was to get pregnant before the age of 35 or 38 because afterwards it would be difficult. But now the gynaecologists must also focus on paternal age and give this information to the couple." She is to discuss her findings at the annual European Society of Human Reproduction and Embryology meeting in Barcelona today.

Jacques de Mouzon, a co-author at the French National Institute for Medical Research, said: "People say men are fertile into old age, 90 even. That may be true sometimes, but the product is different and there are more semen abnormalities as age advances. There is a decrease [in male fertility] and an increase in the spontaneous abortion rate after the age of 40 and especially after 45. It is necessary for men to try to have children before the ages of 40 to 45."

Previous research has pointed to a slight increase in birth defects in babies born to older men. A 2005 study of 70,000 couples by epidemiologist Jorn Olsen at the University of California, Los Angeles, found a fourfold rise in Down's syndrome among babies born to men aged 50 and older. They were also more likely to have limb deformities.

The chances of having a baby with Down's syndrome increase rapidly with a woman's age. About one in 1,000 babies born to mothers under 30 have it, a figure that rises to one in 400 by the age of 35 and one in 105 by the age of 40.

"There is growing evidence from a number of studies to show that men are not totally immune from reproductive ageing," said Allan Pacey, an expert in male fertility at Sheffield University. "Previous studies of couples trying to conceive naturally or undergoing IVF have shown that men over the age of about 40 are less fertile than younger men."

Age and fertility also an issue for men

Age and fertility also an issue for men
Kate Benson
July 7, 2008
IT HAS long been known that a woman's chance of reproducing declines after she turns 35, but now scientists have found that it is the same for men who have some forms of fertility treatment in their 30s.

A study by the Eylau Centre for Assisted Reproduction in Paris followed more than 21,000 men who had intrauterine inseminations at fertility clinics and found that the process, where semen is washed to extract the sperm, resulted in fewer pregnancies and more miscarriages. All the men in the study were older than 35.

"We already believed that couples where the man was older took longer to conceive," the study's author, Dr Stephanie Belloc said.

"But how DNA damage in older men translates into clinical practice has not been shown up to now. Our research shows for the first time that there is a strong paternal age-related effect on (intrauterine insemination) outcomes and this information should be considered by both doctors and patients in assisted reproduction."

She said sperm with DNA damage, common in older men, was still able to enter the egg during intrauterine insemination, which could result in failure to conceive or miscarriage.

But in the case of in vitro fertilisation, the outer membrane of the egg stopped sperm with DNA damage penetrating.

Dr Belloc followed 21,239 patients, and examined the sperm of each partner for count, motility and morphology. Pregnancy rates, miscarriage and delivery rates were also recorded.

"Some recent studies have established a relationship between the results of (intrauterine insemination) and DNA damage, which also correlated to a man's age, suggesting it might be an important factor, but until now there was no clinical proof. We have now found that the age of the father was important in pregnancy — men over 35 had a negative effect."

Oral clefts: A significant association with maternal and paternal age, abortion rate, and parity was found

1: J Oral Sci. 2008 Jun;50(2):123-9.
Oral clefts: a retrospective study of prevalence and predisposal factors in the State of Mexico.González BS, López ML, Rico MA, Garduño F.
Laboratory of Oral Pathology, Research Center, Autonomous University of the State of Mexico.

The purpose of this study was to up-date the records concerning oral clefts (OCs) encountered at the Child Hospital of the Maternal Infantile Institute of the State of México, and to examine the association of predisposing factors. A retrospective study of the medical records of patients generated over a 5-year period was carried out. A total of 835 files were reviewed, representing 504 boys and 331 girls. The studied variables were the type of oral clefts and predisposing factors. Kendal correlations at P