insight - Molecular Biology - # Age-dependent changes in sperm epigenome regulated by mTOR pathway in Sertoli cells

Mechanistic Target of Rapamycin (mTOR) Pathway in Sertoli Cells Regulates Age-Dependent Changes in Sperm DNA Methylation

Q: How do the specific molecular mechanisms by which mTOR complexes in Sertoli cells regulate the sperm epigenome evolve over the lifespan?

The mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulating the sperm epigenome through its two complexes, mTORC1 and mTORC2, in Sertoli cells. Over the lifespan, the balance between these two complexes shifts, influencing the permeability of the blood-testis barrier (BTB) and, consequently, the biochemical environment in which spermatogenesis occurs. In young individuals, mTORC2 is more active, promoting the integrity of the BTB, which creates a stable environment conducive to proper epigenetic reprogramming during spermatogenesis. This stability is essential for maintaining optimal sperm DNA methylation patterns. As males age, the activity of mTORC1 increases relative to mTORC2, leading to a deterioration of the BTB. This increased permeability allows for external factors to influence the germ cell environment, resulting in age-dependent changes in sperm DNA methylation. Specifically, the loss of BTB integrity correlates with an increase in sperm DNA methylation levels, which can adversely affect offspring health by altering the epigenetic information passed on during fertilization. The study indicates that manipulating the balance of mTOR complexes can either accelerate or decelerate epigenetic aging in sperm. For instance, suppression of mTORC2 leads to accelerated aging of the sperm epigenome, while suppression of mTORC1 can rejuvenate the sperm DNA methylome, suggesting that the molecular mechanisms governing these processes are dynamic and evolve with age.

Q: What other factors, besides age, may influence the balance of mTOR complexes in Sertoli cells and impact the sperm epigenome?

Several factors beyond age can influence the balance of mTOR complexes in Sertoli cells, thereby impacting the sperm epigenome. These include: Environmental Exposures: Exposure to environmental toxins, such as heavy metals, pesticides, and endocrine disruptors, can alter the activity of mTOR complexes. Such exposures may lead to increased mTORC1 activity, compromising BTB integrity and affecting sperm quality and epigenetic profiles. Diet and Nutrition: Nutritional status significantly impacts mTOR signaling. Diets rich in certain nutrients, such as amino acids, can activate mTORC1, while caloric restriction has been shown to enhance mTORC2 activity. This nutritional modulation can influence sperm epigenetic markers and overall reproductive health. Physical Activity: Regular physical exercise has been associated with improved metabolic health and may influence mTOR signaling pathways. Exercise can enhance mTORC2 activity, promoting better BTB integrity and potentially leading to healthier sperm epigenomes. Stress and Hormonal Changes: Psychological stress and hormonal fluctuations can also affect mTOR signaling. Increased levels of stress hormones may shift the balance towards mTORC1 activation, leading to detrimental effects on sperm quality and epigenetic stability. Metabolic Disorders: Conditions such as obesity and diabetes can dysregulate mTOR signaling pathways. These metabolic disorders are often associated with increased mTORC1 activity, which can negatively impact sperm quality and epigenetic modifications. Understanding these factors is crucial for developing strategies to mitigate the adverse effects on sperm epigenetics and improve reproductive outcomes.

Core Concepts

The balance of mTOR complexes (mTORC1 and mTORC2) in Sertoli cells regulates the rate of sperm epigenetic aging.

Abstract

The study investigated the role of the mechanistic target of rapamycin (mTOR) pathway in Sertoli cells in regulating age-dependent changes in the sperm epigenome.
Key highlights:

Age-dependent changes in sperm DNA methylation were characterized over 8 time points from 56 to 334 days post-natal. The analysis revealed linear increases and decreases in methylation with age.
Transgenic mouse models were used to manipulate the activity of mTOR complexes (mTORC1 and mTORC2) specifically in Sertoli cells.
Suppression of mTORC2 in Sertoli cells accelerated aging of the sperm DNA methylome and resulted in a reproductive phenotype concordant with older age, including decreased testes weight, sperm counts, and increased abnormal sperm morphology and mitochondrial DNA copy number.
Suppression of mTORC1 in Sertoli cells had the opposite effect, shifting the sperm DNA methylome in the direction opposite to physiological aging, indicating "rejuvenation" of the sperm epigenome.
The changes in sperm methylome induced by manipulating mTOR complexes affected developmental genes, suggesting the mTOR pathway in Sertoli cells may regulate the transfer of altered developmental epigenetic information to the next generation.
The results demonstrate that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging, providing a novel target for therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers.

Stats

Testes weight decreased in mice with inactivated mTORC2 in Sertoli cells.
Sperm counts decreased in mice with inactivated mTORC2 in Sertoli cells.
Percent of morphologically abnormal spermatozoa increased in mice with inactivated mTORC2 in Sertoli cells.
Mitochondrial DNA copy number increased in mice with inactivated mTORC2 in Sertoli cells.

Quotes

"The balance of mTOR complexes in Sertoli cells may also play a significant role in age-dependent changes in the sperm epigenome."
"The results demonstrate that the balance of mTOR complexes in Sertoli cells regulates the rate of sperm epigenetic aging, providing a novel target for therapeutic interventions to rejuvenate the sperm epigenome in advanced-age fathers."

Key Insights Distilled From

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

by Amir,S., Aro... at www.biorxiv.org 05-23-2023

https://www.biorxiv.org/content/10.1101/2023.05.23.541978v3

Deeper Inquiries

How do the specific molecular mechanisms by which mTOR complexes in Sertoli cells regulate the sperm epigenome evolve over the lifespan?

The mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulating the sperm epigenome through its two complexes, mTORC1 and mTORC2, in Sertoli cells. Over the lifespan, the balance between these two complexes shifts, influencing the permeability of the blood-testis barrier (BTB) and, consequently, the biochemical environment in which spermatogenesis occurs.
In young individuals, mTORC2 is more active, promoting the integrity of the BTB, which creates a stable environment conducive to proper epigenetic reprogramming during spermatogenesis. This stability is essential for maintaining optimal sperm DNA methylation patterns. As males age, the activity of mTORC1 increases relative to mTORC2, leading to a deterioration of the BTB. This increased permeability allows for external factors to influence the germ cell environment, resulting in age-dependent changes in sperm DNA methylation. Specifically, the loss of BTB integrity correlates with an increase in sperm DNA methylation levels, which can adversely affect offspring health by altering the epigenetic information passed on during fertilization.
The study indicates that manipulating the balance of mTOR complexes can either accelerate or decelerate epigenetic aging in sperm. For instance, suppression of mTORC2 leads to accelerated aging of the sperm epigenome, while suppression of mTORC1 can rejuvenate the sperm DNA methylome, suggesting that the molecular mechanisms governing these processes are dynamic and evolve with age.

What other factors, besides age, may influence the balance of mTOR complexes in Sertoli cells and impact the sperm epigenome?

Several factors beyond age can influence the balance of mTOR complexes in Sertoli cells, thereby impacting the sperm epigenome. These include:

Environmental Exposures: Exposure to environmental toxins, such as heavy metals, pesticides, and endocrine disruptors, can alter the activity of mTOR complexes. Such exposures may lead to increased mTORC1 activity, compromising BTB integrity and affecting sperm quality and epigenetic profiles.

Diet and Nutrition: Nutritional status significantly impacts mTOR signaling. Diets rich in certain nutrients, such as amino acids, can activate mTORC1, while caloric restriction has been shown to enhance mTORC2 activity. This nutritional modulation can influence sperm epigenetic markers and overall reproductive health.

Physical Activity: Regular physical exercise has been associated with improved metabolic health and may influence mTOR signaling pathways. Exercise can enhance mTORC2 activity, promoting better BTB integrity and potentially leading to healthier sperm epigenomes.

Stress and Hormonal Changes: Psychological stress and hormonal fluctuations can also affect mTOR signaling. Increased levels of stress hormones may shift the balance towards mTORC1 activation, leading to detrimental effects on sperm quality and epigenetic stability.

Metabolic Disorders: Conditions such as obesity and diabetes can dysregulate mTOR signaling pathways. These metabolic disorders are often associated with increased mTORC1 activity, which can negatively impact sperm quality and epigenetic modifications.

Understanding these factors is crucial for developing strategies to mitigate the adverse effects on sperm epigenetics and improve reproductive outcomes.

What are the potential implications of manipulating the mTOR pathway in Sertoli cells for transgenerational inheritance of traits?

Manipulating the mTOR pathway in Sertoli cells has significant implications for transgenerational inheritance of traits. The mTOR pathway's role in regulating sperm epigenetics means that alterations in this pathway can lead to changes in the epigenetic information passed on to offspring.

Rejuvenation of Sperm Epigenome: By suppressing mTORC1, it may be possible to rejuvenate the sperm epigenome, potentially reversing age-related epigenetic changes. This rejuvenation could lead to healthier sperm with more favorable epigenetic profiles, thereby improving reproductive outcomes and offspring health.

Altered Offspring Phenotypes: Changes in sperm DNA methylation patterns due to mTOR manipulation can result in altered phenotypes in offspring. For instance, if the sperm epigenome is rejuvenated, offspring may exhibit improved health outcomes, reduced susceptibility to diseases, and enhanced developmental potential.

Transgenerational Effects: The epigenetic changes induced by manipulating the mTOR pathway may not only affect the immediate offspring but could also have transgenerational effects. If these epigenetic modifications are stable and heritable, they could influence the health and development of subsequent generations, potentially leading to a new understanding of how paternal factors contribute to offspring phenotypes.

Therapeutic Interventions: Targeting the mTOR pathway in Sertoli cells could serve as a novel therapeutic strategy for advanced-age fathers seeking to improve sperm quality and reduce the risk of transmitting age-related epigenetic changes to their children. This approach could be particularly beneficial in addressing the increasing prevalence of reproductive challenges associated with advanced paternal age.

In summary, the manipulation of the mTOR pathway in Sertoli cells presents a promising avenue for enhancing sperm quality and influencing the epigenetic landscape of future generations, with far-reaching implications for reproductive health and offspring development.

Mechanistic Target of Rapamycin (mTOR) Pathway in Sertoli Cells Regulates Age-Dependent Changes in Sperm DNA Methylation