DO MEN HAVE BIOLOGICAL CLOCKS, TOO?
Most of us are familiar with the risks associated with advanced maternal age. Far less well known - even though scientists began identifying them 100 years ago- are the risks associated with ADVANCED PATERNAL AGE. Moreover, it turns out that in addition to a higher incidence of health issues in the children of older fathers, older men also have more difficulty conceiving and once they do, a higher rate of miscarriage. So in terms of both fertility and the health of their children, both men and women have biological clocks.
The first study showing the relationship between paternal age and genetic problems was written in German in 1912 by Wilhelm Weinberg, a scientist and obstetrician who contributed immensely to our understanding of genetics. Two decades later, Lionel Sharples Penrose published a paper showing the relationship between Down Syndrome and maternal age. Even still, Penrose, Weinberg and others continued to notice, study and show paternal age effects in several diseases.
But, only one set of data resonated with a society obsessed with all aspects of female reproductive behavior, committed to maintaining inequities in access to and compensation for similar jobs. So only data that supported that notion has infiltrated our national conversation. Afterall, if what we learn from science is ideally about making the best, most informed decisions for the health and future of our children then both sets of data would have become public knowledge with the awareness of the data on older fathers preceding that of older mothers.
Nearly 20 years ago, James F. Crow reviewed the genetic data and again raised an alarm about the effects of Advanced Paternal Age (APA). APA explains a higher incidence of congenital physical malformations (such as cleft palate, diaphragmatic hernia and pulmonary valve stenosis). For many of us, though, the most challenging issues associated with APA are those that are neurodevelopmental.
APA is associated with increased risk of schizophrenia, certain bipolar disorders (e.g. early onset and bipolar with psychosis) and other issues impacted by changes in brain development including autism. In fact, advanced paternal age is the BEST predictor of autistic spectrum disease (ASD). For some of these problems the additional risk only increases slightly with increasing age, for other conditions, the risks increase more dramatically. If the relative risk of having a child with ASD is 1/200 for dads between the ages of 25-29, the risk increases to 1/145 for Dads between the ages of 35-39 and 1 in 131 for Dads over 39. When comparing the offspring of fathers under 30 to the offspring of fathers over 40, older fathers were more 5x more likely to have children with autism (reviewed in Toriello, 2008).
What is happening in these older fathers? It turns out that the basic science explaining why there might be risk with advanced age in men makes sense. To understand this, though, let’s think about where sperm comes from. Fully mature sperm come from cells that are constantly replicating and dividing. That’s how we get the millions of sperm necessary to fertilize one egg. The cells that give rise to new sperms cells- what scientists call spermatogonia-live in Dad’s body and have been exposed to much of whatever Dad has been exposed to.
These spermatogonial cells must keep dividing to produce mature sperm. Such a high level of division can lead to mistakes. This is like the child’s game of telephone. With each new repetition- or in the case of the genes in the spermatogonia, with each new replication- the likelihood for a mistake increases. It is estimated that sperm has replicated 200 times for a young man of 20 and by age 45, the number of replications is 770 (Crow 1997).
This can lead to more mistakes (mutations) occurring in more than one gene and neuroscientists believe it is likely that many complex neurodevelopmental diseases are caused by abnormalities in more than one gene. The mutations in the genes of the sperm of older men have been found to be new ( or “de novo”) mutations (Kong, 2012). Older dads have sperm that has had a chance to accumulate new mistakes in several genes and this may be why a higher risk of several neurodevelopmental diseases is associated with advanced paternal age.
To make matters worse, the kinds of mutations that may lead to disease seem to be of a particular kind. These newly acquired mutations confer a selective growth advantage so that the mutated sperm reproduce at a higher rate than the un-mutated sperm. It’s like a survival of the fittest contest among the sperm. The spermatogonial cells that replicate better than the others become over-represented. This is called the “selfish spermatogonial selection” hypothesis (Goriely, 2012; Crow 1997). Diseases like schizophrenia and autistic spectrum disease are in fact characterized by dysregulated development of the brain and therefore scientists have suggested that the mutated genes involved in giving sperm a growth advantage are the very same mutations that are responsible for the neurological (as well as some of the other issues) associated with advanced paternal age.
Whether or not this proves to be the mechanism, the data on the relationship between increasing paternal age and disease -what has come to be called Paternal Age Effects- is indisputable. Already new guidelines in Great Britain set the age limit for sperm donation at 40.
A couple of years ago, both Facebook and Apple made news when they committed to covering costs associated with the removal and storage of eggs of their young female employees. Now we have to ask should we provide young men with the opportunity to store their young sperm? Or will we finally make significant changes in society and in the workplace that allow for both successful careers and healthy children?
Related Sources:
Raebrun, The Father Factor, pgs 100-105 in HIS BRAIN, HER BRAIN, Scientific American Mind., Volume 21 (2) , 2012.
Craton, Ramos-Goyette, Darwianian Guide to Having Children. 2015
Crow JF (1997). The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci USA 94:8380-8386.
Dzurova, Dagmara and Pikhart, Hynek: Down Syndrome, paternal age and education: comparison of California and Czech Republic. BMC Health, 2005: 5 (6): 1-10.
Penrose, LS. (1955) Paternal age and mutations. Lancet, 312-3.
Penrose, LS. (1933) The relative effects of paternal and maternal age in mongolism.”
Pinon, 2002, Biology of Human Reproduction, University Science Books, Saulsilito, CA 2002
Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001 Apr;58(4):361-7
Mayo clinic: http://www.mayoclinic.org/healthy-living/getting-pregnant/expert-answers/paternal-age/faq-20057873
Penrose, LS (1955). "Parental age and mutation".Lancet 269: 312–313. doi:10.1016/s0140-6736(55)92305-9. PMID 13243724.
R. F. Green, et al., Association of Paternal Age and Risk for Major Congenital Anomalies from the National Birth Defects Prevention Study, 1997–2004 Ann Epidemiol. 2010 March ; 20(3): 241–249. doi:10.1016/j.annepidem.2009.10.009. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824069/pdf/nihms163375.pdf
Weinberg, W (1912). "Zur Vererbung des Zwergwuchses. (On the inheritance of dwarfism)".Arch Rassen-u Gesell Biol 9: 710–718.
Most of us are familiar with the risks associated with advanced maternal age. Far less well known - even though scientists began identifying them 100 years ago- are the risks associated with ADVANCED PATERNAL AGE. Moreover, it turns out that in addition to a higher incidence of health issues in the children of older fathers, older men also have more difficulty conceiving and once they do, a higher rate of miscarriage. So in terms of both fertility and the health of their children, both men and women have biological clocks.
The first study showing the relationship between paternal age and genetic problems was written in German in 1912 by Wilhelm Weinberg, a scientist and obstetrician who contributed immensely to our understanding of genetics. Two decades later, Lionel Sharples Penrose published a paper showing the relationship between Down Syndrome and maternal age. Even still, Penrose, Weinberg and others continued to notice, study and show paternal age effects in several diseases.
But, only one set of data resonated with a society obsessed with all aspects of female reproductive behavior, committed to maintaining inequities in access to and compensation for similar jobs. So only data that supported that notion has infiltrated our national conversation. Afterall, if what we learn from science is ideally about making the best, most informed decisions for the health and future of our children then both sets of data would have become public knowledge with the awareness of the data on older fathers preceding that of older mothers.
Nearly 20 years ago, James F. Crow reviewed the genetic data and again raised an alarm about the effects of Advanced Paternal Age (APA). APA explains a higher incidence of congenital physical malformations (such as cleft palate, diaphragmatic hernia and pulmonary valve stenosis). For many of us, though, the most challenging issues associated with APA are those that are neurodevelopmental.
APA is associated with increased risk of schizophrenia, certain bipolar disorders (e.g. early onset and bipolar with psychosis) and other issues impacted by changes in brain development including autism. In fact, advanced paternal age is the BEST predictor of autistic spectrum disease (ASD). For some of these problems the additional risk only increases slightly with increasing age, for other conditions, the risks increase more dramatically. If the relative risk of having a child with ASD is 1/200 for dads between the ages of 25-29, the risk increases to 1/145 for Dads between the ages of 35-39 and 1 in 131 for Dads over 39. When comparing the offspring of fathers under 30 to the offspring of fathers over 40, older fathers were more 5x more likely to have children with autism (reviewed in Toriello, 2008).
What is happening in these older fathers? It turns out that the basic science explaining why there might be risk with advanced age in men makes sense. To understand this, though, let’s think about where sperm comes from. Fully mature sperm come from cells that are constantly replicating and dividing. That’s how we get the millions of sperm necessary to fertilize one egg. The cells that give rise to new sperms cells- what scientists call spermatogonia-live in Dad’s body and have been exposed to much of whatever Dad has been exposed to.
These spermatogonial cells must keep dividing to produce mature sperm. Such a high level of division can lead to mistakes. This is like the child’s game of telephone. With each new repetition- or in the case of the genes in the spermatogonia, with each new replication- the likelihood for a mistake increases. It is estimated that sperm has replicated 200 times for a young man of 20 and by age 45, the number of replications is 770 (Crow 1997).
This can lead to more mistakes (mutations) occurring in more than one gene and neuroscientists believe it is likely that many complex neurodevelopmental diseases are caused by abnormalities in more than one gene. The mutations in the genes of the sperm of older men have been found to be new ( or “de novo”) mutations (Kong, 2012). Older dads have sperm that has had a chance to accumulate new mistakes in several genes and this may be why a higher risk of several neurodevelopmental diseases is associated with advanced paternal age.
To make matters worse, the kinds of mutations that may lead to disease seem to be of a particular kind. These newly acquired mutations confer a selective growth advantage so that the mutated sperm reproduce at a higher rate than the un-mutated sperm. It’s like a survival of the fittest contest among the sperm. The spermatogonial cells that replicate better than the others become over-represented. This is called the “selfish spermatogonial selection” hypothesis (Goriely, 2012; Crow 1997). Diseases like schizophrenia and autistic spectrum disease are in fact characterized by dysregulated development of the brain and therefore scientists have suggested that the mutated genes involved in giving sperm a growth advantage are the very same mutations that are responsible for the neurological (as well as some of the other issues) associated with advanced paternal age.
Whether or not this proves to be the mechanism, the data on the relationship between increasing paternal age and disease -what has come to be called Paternal Age Effects- is indisputable. Already new guidelines in Great Britain set the age limit for sperm donation at 40.
A couple of years ago, both Facebook and Apple made news when they committed to covering costs associated with the removal and storage of eggs of their young female employees. Now we have to ask should we provide young men with the opportunity to store their young sperm? Or will we finally make significant changes in society and in the workplace that allow for both successful careers and healthy children?
Related Sources:
Raebrun, The Father Factor, pgs 100-105 in HIS BRAIN, HER BRAIN, Scientific American Mind., Volume 21 (2) , 2012.
Craton, Ramos-Goyette, Darwianian Guide to Having Children. 2015
Crow JF (1997). The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci USA 94:8380-8386.
Dzurova, Dagmara and Pikhart, Hynek: Down Syndrome, paternal age and education: comparison of California and Czech Republic. BMC Health, 2005: 5 (6): 1-10.
Penrose, LS. (1955) Paternal age and mutations. Lancet, 312-3.
Penrose, LS. (1933) The relative effects of paternal and maternal age in mongolism.”
Pinon, 2002, Biology of Human Reproduction, University Science Books, Saulsilito, CA 2002
Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001 Apr;58(4):361-7
Mayo clinic: http://www.mayoclinic.org/healthy-living/getting-pregnant/expert-answers/paternal-age/faq-20057873
Penrose, LS (1955). "Parental age and mutation".Lancet 269: 312–313. doi:10.1016/s0140-6736(55)92305-9. PMID 13243724.
R. F. Green, et al., Association of Paternal Age and Risk for Major Congenital Anomalies from the National Birth Defects Prevention Study, 1997–2004 Ann Epidemiol. 2010 March ; 20(3): 241–249. doi:10.1016/j.annepidem.2009.10.009. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824069/pdf/nihms163375.pdf
Weinberg, W (1912). "Zur Vererbung des Zwergwuchses. (On the inheritance of dwarfism)".Arch Rassen-u Gesell Biol 9: 710–718.