Dynamic modelling of pathways to cellular senescence reveals strategies for targeted interventions

Area of Science:

• Cellular and Molecular Biology
• Systems Biology
• Aging Research

Background:

• Cellular senescence is a state of irreversible cell cycle arrest with dual roles in cancer protection and aging.
• Senescence involves complex, interconnected signaling and feedback pathways that are difficult to predict.
• Understanding these networks is crucial for developing interventions against aging and age-related diseases.

Purpose of the Study:

• To apply a systems biology approach to understand the complex signaling networks governing cellular senescence.
• To investigate the roles of DNA damage, insulin-TOR, FoxO3a, oxidative stress, and mitochondrial regulation in senescence.
• To identify potential therapeutic targets for delaying or reversing cellular senescence.

Main Methods:

• In silico computational modeling and in vitro experimental validation.
• Analysis of signaling pathways including DNA damage response, insulin-TOR (mTOR), FoxO3a transcription factors, oxidative stress, and mitochondrial dynamics (mitophagy, fission).
• Dynamic sensitivity analysis of the senescence network model.

Main Results:

• Inhibition of reactive oxygen species (ROS) prevented mitochondrial membrane potential loss; mTOR inhibition partially rescued mitochondrial mass changes.
• Dual inhibition of ROS and mTOR reduced senescence-induced mitochondrial dysfunction and DNA double-strand breaks, confirming model predictions.
• Decreased mitochondrial fission, preventing mitophagy, was identified as a key driver of increased mitochondrial mass.
• Late-stage senescence networks showed poor sensitivity, high noise, low energy, and high inflammation, indicating limited therapeutic potential.

Conclusions:

• Targeted interventions, such as dual ROS and mTOR inhibition, can delay the onset of cellular senescence by modulating mitochondrial dysfunction and DNA damage.
• Complete abrogation of senescence-induced mitochondrial dysfunction is not achieved with these interventions.
• Late-stage senescence is characterized by network stabilization with unfavorable cellular conditions, suggesting interventions are most effective at earlier stages.
• Combinatorial therapies show potential for intervening in senescence pathways, but primarily delay, rather than reverse, the process.