Impact of Advanced Paternal Age on Fertility and Risks of Genetic Disorders in Offspring

Abstract

The average age of fathers at first pregnancy has risen significantly over the last decade owing to various variables, including a longer life expectancy, more access to contraception, later marriage, and other factors. As has been proven in several studies, women over 35 years of age have an increased risk of infertility, pregnancy problems, spontaneous abortion, congenital malformations, and postnatal issues. There are varying opinions on whether a father’s age affects the quality of his sperm or his ability to father a child. First, there is no single accepted definition of old age in a father. Second, much research has reported contradictory findings in the literature, particularly concerning the most frequently examined criteria. Increasing evidence suggests that the father’s age contributes to his offspring’s higher vulnerability to inheritable diseases. Our comprehensive literature evaluation shows a direct correlation between paternal age and decreased sperm quality and testicular function. Genetic abnormalities, such as DNA mutations and chromosomal aneuploidies, and epigenetic modifications, such as the silencing of essential genes, have all been linked to the father’s advancing years. Paternal age has been shown to affect reproductive and fertility outcomes, such as the success rate of in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), and premature birth rate. Several diseases, including autism, schizophrenia, bipolar disorders, and paediatric leukaemia, have been linked to the father’s advanced years. Therefore, informing infertile couples of the alarming correlations between older fathers and a rise in their offspring’s diseases is crucial, so that they can be effectively guided through their reproductive years.

Relationship between degree of methylation of sperm long interspersed nuclear element-1 (LINE-1) gene and alteration of sperm parameters and age: a meta-regression analysis

“…This is because some evidence suggests an association between paternal age and sperm quality, ART success rate, RPL, and offspring health. Specifically, advanced paternal age has been associated with DNA mutations, chromosomal aneuploidies, and epigenetic changes that can be transmitted to offspring resulting in health impairments [ 42 ]. Additionally, several diseases, including autism, schizophrenia, bipolar disorders, and pediatric leukemia, have been linked to the father’s advanced age [ 42 ].…”

“…Specifically, advanced paternal age has been associated with DNA mutations, chromosomal aneuploidies, and epigenetic changes that can be transmitted to offspring resulting in health impairments [ 42 ]. Additionally, several diseases, including autism, schizophrenia, bipolar disorders, and pediatric leukemia, have been linked to the father’s advanced age [ 42 ]. We hypothesized that the alteration of LINE1 methylation status is a possible explanation of the above-mentioned association.…”

“…LINE1 hypermethylation has also been associated with neurodevelopmental disorders [ 28 ], and as previously mentioned, paternal age is associated with a higher prevalence of these disorders in offspring [ 42 ]. A study analyzing LINE1 methylation in blood and brain tissue of mice to evaluate the dynamics of the LINE1 gene during mammalian brain development observed methylation waves of the LINE1 promoter in both the blood and brain during development.…”

Dietary nutrients that potentially mitigate autism spectrum disorder and dietary recommendations for children and pregnant women

“…Although maternal risk factors play a crucial role in the elevated risk of offspring developing ASD during pregnancy, the influence of fathers is also noteworthy. Current research indicates a clear correlation between advanced paternal age and an increased risk of offspring developing ASD, primarily mediated through reproductive influences leading to adverse birth outcomes (Kaltsas et al., 2023). Animal studies suggest that aging induces alterations in the microRNA profile of sperm, which is associated with neurodevelopmental disorders and may mean an increased incidence of ASD (Miyahara et al., 2023).…”

The “Bad Father”: Paternal Role in Biology of Pregnancy and in Birth Outcome

“…Even in the absence of an accepted definition of advanced paternal age (APA) in the current literature, the father’s aging leads to several modifications of sperm cells: decreased sperm quality [ 51 ], increased DNA damage [ 52 , 53 ], telomere elongation [ 54 , 55 , 56 ], centrosome aberrations [ 57 ], de novo DNA mutations [ 58 ], aneuploidies [ 59 ], and epigenetics alterations [ 51 ]. These sperm modifications harm fertility, decrease pregnancy rates in assisted reproductive technology, and increase the risk of miscarriage [ 51 ], aneuploidies [ 59 ], congenital anomalies (cleft palate, limb defects, musculoskeletal anomalies, patent ductus arteriosus) and rare syndromes related to fibroblast growth factor receptor (FGFR) mutations (achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, Apert syndrome, Pfeiffer syndrome, Crouzon syndrome).…”