Mechanistic target of rapamycin (mTOR) pathway in Sertoli cells regulates age-dependent changes in sperm DNA methylation

Over the past several decades, a trend toward delayed childbirth has led to increases in parental age at the time of conception. Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. Animal experiments also demonstrate that epigenetic transfer of maladaptive information of advanced age fathers is associated with reduced offspring health including reduced life span. The mechanism(s) linking paternal age with epigenetic changes in sperm remain unknown. The sperm epigenome is shaped in a compartment protected by the blood-testes barrier (BTB) known to deteriorate with age. Permeability of the BTB is regulated by the balance of two mTOR complexes in Sertoli cells. We hypothesized that this balance is also responsible for age-dependent changes in the sperm epigenome. Experiments with transgenic mice demonstrate that the shift of the balance in favor of mTOR complex two rejuvenates sperm DNA-methylome while the shift in favor of mTOR complex one accelerates aging of the sperm DNA-methylome and results in a reproductive phenotype concordant with older age. These results demonstrate for the first time that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging. Thus, mTOR pathway in Sertoli cells may be used as novel target of therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.