Paternal age effect

The paternal age effect is the statistical relationship between paternal age at conception and biological effects on the child. Such effects can relate to birthweight, congenital disorders, life expectancy, and psychological outcomes. A 2009 review concludes that the absolute risk for genetic anomalies in offspring is low, and states that "there is no clear association between adverse health outcome and paternal age but longitudinal studies are needed."

On the other hand, the genetic quality of sperm, as well as its volume and motility, all typically decrease with age, leading the population geneticist James F. Crow to claim that the "greatest mutational health hazard to the human genome is fertile older males".

The paternal age effect was first proposed implicitly by Weinberg in 1912, and explicitly by Penrose in 1955. Extensive research started more recently, once paternity testing became technically and economically viable on a widespread basis. Harry Fisch, a physician who has done research in this area, says that research into paternal age effect degradation of DNA is "in its infancy".

Health effects

Evidence for a paternal age effect has been proposed for a number of conditions, diseases and other effects. In many of these, the statistical evidence of association is weak, and the association may be related by confounding factors, or behavioral differences. Conditions proposed to show correlation with paternal age include the following:

Single-gene disorders

Advanced paternal age is associated with a higher risk for certain single-gene disorders caused by mutations of the FGFR2, FGFR3, and RET genes. These conditions are Apert syndrome, Crouzon syndrome, Pfeiffer syndrome, achondroplasia, thanatophoric dysplasia, multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2b. The most significant effect concerns achondroplasia (a form of dwarfism), which occurs in about 1 in 1,875 children fathered by men over 50, compared to 1 in 15,000 in the general population. However, the risk for achondroplasia is still considered clinically negligible. The FGFR genes may be particularly prone to a paternal age effect due to selfish spermatogonial selection, whereby the influence of spermatogonial mutations in older men is enhanced because cells with certain mutations have a selective advantage over other cells (see § DNA mutations).

Pregnancy effects

Several studies have reported that advanced paternal age is associated with an increased risk of miscarriage. The strength of the association differs between studies. It has been suggested that these miscarriages are caused by chromosome abnormalities in the sperm of aging men. An increased risk for stillbirth has also been observed for pregnancies fathered by men over 45.

Birth outcomes

A systematic review published in 2010 concluded the risk of low birthweight in infants with paternal age is "saucer-shaped" (U-shaped); that is, the highest risks occur at low and at high paternal ages. Compared with a paternal age of 25–28 years as a reference group, the odds ratio for low birthweight was approximately 1.1 at a paternal age of 20 and approximately 1.2 at a paternal age of 50. There was no association of paternal age with preterm births or with small for gestational age births.

Mental illness

Schizophrenia is associated with advanced paternal age with 12 out of 14 studies supporting a relationship. Paternal age older than 55 is a moderate risk factor for schizophrenia. Most studies examining autism spectrum disorder (ASD) and advanced paternal age have demonstrated an association between the two, although there also appears to be an increase with maternal age.

The risk of bipolar disorder ("manic depression") particularly for early-onset disease, is J-shaped, with the lowest risk for children of 20- to 24-year-old fathers, a twofold risk for younger fathers, and a threefold risk for fathers >50 years old. There is no similar relationship with maternal age.

Cancers

Paternal age may be associated with an increased risk of breast cancer, but the association is weak and there are confounding effects.

Diabetes mellitus

High paternal age has been suggested as a risk factor for type 1 diabetes, but research findings are inconsistent and a clear association has not been established.

Down syndrome

It appears that a paternal-age effect exists with respect to Down syndrome, but is very small in comparison to the maternal-age effect.

Intelligence

In 2005, Malaspina and colleagues detected a U-shaped relationship between paternal age and low intelligence quotients (IQs) in 44,175 people from Israel. The highest IQ was found at paternal ages of 25-44; fathers younger than 25 and older than 44 tended to have children with lower IQs. Malaspina et al. also reviewed the literature and found that "at least a half dozen other studies ... have demonstrated significant associations between paternal age and human intelligence."

A 2009 study examined children at 8 months, 4 years, and 7 years and found that paternal age was associated with poorer scores in almost all neurocognitive tests used, but that maternal age was associated with better scores on the same tests. An editorial accompanying the paper emphasized the importance of controlling for socioeconomic status in studies of paternal age and intelligence. A 2010 paper from Spain provided further evidence that average paternal age is elevated in cases of intellectual disability.

Life expectancy

A 2008 paper found a U-shaped association between paternal age and the overall mortality rate in children (i.e., mortality rate up to age 18). Although the relative mortality rates were higher, the absolute numbers were low, because of the relatively low occurrence of genetic abnormality. The study has been criticized for not adjusting for maternal health, which could have a large effect on child mortality. The researchers also found a correlation between paternal age and offspring death by injury or poisoning, indicating the need to control for social and behavioral confounding factors.

In 2012 a study showed that greater age at paternity tends to increase telomere length in offspring for up to two generations. Since telomere length has effects on health and mortality, this may have effects on health and the rate of aging in these offspring. The authors speculated that this effect may provide a mechanism by which populations have some plasticity in adapting longevity to different social and ecological contexts.

Fertility

Older men have decreased pregnancy rates, increased time to pregnancy, and increased infertility at a given point in time. Increasing paternal age may also increase the risk of reproductive failure, which has led some researchers to compare age 40 to the "Amber Light" in a man's reproductive life.

Social effects

Father's age versus risk of death in France

Age at birth	Before child's 18th birthday
25	2.2%
30	3.3%
35	5.4%
40	8.3%
45	12.1%

Later age at parenthood is associated with a more stable family environment, with older parents being less likely to divorce or change partners. Older parents also tend to occupy a higher socio-economic position and report feeling more devoted to their children and satisfied with their family. On the other hand, the risk of the father dying before the child becomes an adult increases with paternal age.

Mechanisms

Several hypothesized chains of causality exist whereby increased paternal age may lead to health effects.

DNA mutations

In contrast to oogenesis, the production of sperm cells is a lifelong process. Each year after puberty, spermatogonia (precursors of the spermatozoa) divide meiotically about 23 times. By the age of 40, the spermatogonia will have undergone about 660 such divisions, compared to 200 at age 20. Copying errors sometimes happen during the DNA replication preceding these cell divisions, which can lead to new (de novo) mutations in the sperm DNA. A study of 78 Icelandic families found that each additional year in the age of the father causes about two new mutations in the child. Regarding the increased risk at very young paternal ages, an international study indicates that the DNA mutation rate in very young fathers may also be elevated.

The selfish spermatogonial selection hypothesis proposes that the influence of spermatogonial mutations in older men is further enhanced because cells with certain mutations have a selective advantage over other cells. Such an advantage would allow the mutated cells to increase in number through clonal expansion. In particular, mutations that affect the RAS pathway, which regulates spermatogonial proliferation, appear to offer a competitive advantage to spermatogonial cells, while also leading to diseases associated with paternal age.

Epigenetic changes

DNA methylation

The production of sperm cells involves DNA methylation, an epigenetic process that regulates the expression of genes. Improper genomic imprinting and other errors sometimes occur during this process, which can affect the expression of genes related to certain disorders, increasing the offspring's susceptibility. The frequency of these errors appears to increase with age. This could explain the association between paternal age and schizophrenia.

Telomere length

Telomeres are genetic sequences that protect the structures of chromosomes. As men age, most telomeres shorten, but sperm telomeres increase in length. The offspring of older fathers have longer telomeres in both their sperm and white blood cells. Because people with longer telomeres are at decreased risk for age-related diseases, higher paternal age may also be associated with certain health benefits. This mechanism may have evolved because the environment of children born to older fathers is likely to have a higher expected age of reproduction.

Semen

A 2001 review on variation in semen quality and fertility by male age concluded that older men had lower semen volume, lower sperm motility, and a decreased percent of normal sperm. One common factor is the abnormal regulation of sperm once a mutation arises. It has been seen that once taking place, the mutation will almost always be positively selected for and over time will lead to the mutant sperm replacing all non-mutant sperm. In younger males, this process is corrected and regulated by the growth factor receptor-RAS signal transduction pathway.

A 2014 review indicated that increasing male age is associated with declines in many semen traits, including semen volume and percentage motility. However, this review also found that sperm concentration did not decline as male age increased.

X-linked effects

Some classify the paternal age effect as one of two different types. One effect is directly related to advanced paternal age and autosomal mutations in the offspring. The other effect is an indirect effect in relation to mutations on the X chromosome which are passed to daughters who are then at risk for having sons with X-linked diseases.

History

In 1912, Wilhelm Weinberg, a German physician, was the first person to hypothesize that non-inherited cases of achondroplasia could be more common in last-born children than in children born earlier to the same set of parents. Weinberg "made no distinction between paternal age, maternal age and birth order" in his hypothesis. In 1953, Krooth used the term "paternal age effect" in the context of achondroplasia, but mistakenly thought the condition represented a maternal age effect. The paternal age effect for achondroplasia was described by Lionel Penrose in 1955.

Scientific interest in paternal age effects increased in the late 20th and early 21st centuries because the average paternal age increased in countries such as the United Kingdom, Australia, and Germany, and because birth rates for fathers aged 30–54 years have risen between 1980 and 2006 in the United States. Possible reasons for the increases in average paternal age include increasing life expectancy and increasing rates of divorce and remarriage. Despite recent increases in average paternal age, however, the oldest father documented in the medical literature was born in 1840: George Isaac Hughes was 94 years old at the time of the birth of his son by his second wife, a 1935 article in the Journal of the American Medical Association stated that his fertility "has been definitely and affirmatively checked up medically," and he fathered a daughter in 1936 at age 96. In 2012, two 96-year-old men, Nanu Ram Jogi and Ramjit Raghav, both from India, claimed to have fathered children that year.,

Medical assessment

The American College of Medical Genetics recommends obstetric ultrasonography at 18–20 weeks gestation in cases of advanced paternal age to evaluate fetal development, but it notes that this procedure "is unlikely to detect many of the conditions of interest." They also note that there is no standard definition of advanced paternal age; it is commonly defined as age 40 or above, but the effect increases linearly with paternal age, rather than appearing at any particular age. According to a 2006 review, any adverse effects of advanced paternal age "should be weighed up against potential social advantages for children born to older fathers who are more likely to have progressed in their career and to have achieved financial security."

Geneticist James F. Crow described mutations that have a direct visible effect on the child's health and also mutations that can be latent or have minor visible effects on the child's health; many such minor or latent mutations allow the child to reproduce, but cause more serious problems for grandchildren, great-grandchildren and later generations.

See also

• Maternal age effect
• Pregnancy over age 50

Further reading

• Gavrilov, L.A., Gavrilova, N.S. Human longevity and parental age at conception. In: J.-M.Robine, T.B.L. Kirkwood, M. Allard (eds.) Sex and Longevity: Sexuality, Gender, Reproduction, Parenthood, Berlin, Heidelberg: Springer-Verlag, 2000, 7-31.
• Gavrilov, L.A., Gavrilova, N.S. Parental age at conception and offspring longevity. Reviews in Clinical Gerontology, 1997, 7: 5-12.
• Gavrilov, L.A., Gavrilova, N.S. When Fatherhood Should Stop? Letter. Science, 1997, 277(5322): 17-18.