| Description |
The effects of advanced paternal age have received little attention in the past. However, recent data from multiple groups suggesting an association between advanced paternal age and various disorders in the offspring have sparked a great deal of interest. Specifically, offspring of older fathers have an increased risk of autism, bipolar disorder, and schizophrenia among other issues. Further fueling this interest is the striking trend of delayed parenthood in developed countries, likely a result of socioeconomic pressures and increasing divorce rates with subsequent remarriage. Increased interest in the "paternal age effect" has driven some private tissue banks to promote cryopreservation of sperm at a young age to avoid the detrimental impacts of aging. Taken together, there is a great need for further investigation into this phenomenon. Although there is solid epidemiological evidence to substantiate the impacts of advanced paternal age on the offspring, the etiological mechanisms that drive this process remain poorly defined. Among the most plausible contributing factors to the increased incidence of various diseases in the offspring of older fathers are age-associated alterations to the sperm epigenome. Specifically, sperm DNA methylation perturbations may have the capacity to affect offspring phenotype through transcription inhibition/activation but have yet to be explored in the context of advancing age. To investigate age-associated sperm DNA methylation alterations, we have analyzed sperm from 17 donors who collected samples between 9 and 19 years apart. DNA methylation was analyzed in all samples at both the global and cytosine phosphate guanine (CpG) level. The results indicate that global sperm DNA methylation increases with age while regional alterations are strongly biased toward hypomethylation, a finding in stark contrast to somatic cell age-associated methylation alterations. Intriguingly, many of the genes affected by regional methylation alteration have been previously suggested to be associated with many types of neuropsychiatric disorders, including schizophrenia, bipolar disorder, developmental delay, personality disorders, and autism. These data provide the first direct evidence that age-associated epigenetic alterations to the sperm represent a plausible mechanism for the increased incidence of various abnormalities in offspring of older fathers. |
