Senescent Subtypes Transition Model

Abstract

Senescence has both beneficial and detrimental roles across the tissues over time. This dual nature is mediated by the senescence-associated secretory phenotype (SASP). Still, transient and persistent SASP secretion is poorly understood. There are some unknown mechanisms through which phenotypic transition takes place from beneficial helper (H) senescent cells to deleterious (D) senescent cell states. NOTCH1 is suggested to mediate switching between the different SASP secretomes. NOTCH1 also suppresses a transcription factor C/EBP{beta} during the SASP secretion. Therefore, a hypothesis is proposed about the existence of negative feedback from C/EBP{beta} to NOTCH1 together forming a senescence-switching circuit that might be mediating this phenotypic transition at the molecular level. Using a population dynamics model with competitive interaction to decipher the underlying transition mechanism between the senescent cell subtypes and a mechanistic model to explain the underlying molecular mechanisms of NOTCH1 signaling in modulating the two waves of SASP secretion. By designing effective senescence therapies with selective removal of deleterious senescent cells and maintaining sufficient helper senescent cells can enhance health span and reduce age-related effects.