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

Sperm epigenome undergoes age-dependent changes increasing risks of adverse conditions in offspring conceived by fathers of advanced age. The mechanism(s) linking paternal age with epigenetic changes in sperm remains 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. One-Sentence Summary The balance between mTOR complexes in Sertoli cells regulates sperm methylome aging. ### Competing Interest Statement Alexander Suvorov is a CEO of ReGENE LLC. All other authors declare that they have no competing interests.