Chronic stress induces cellular senescence: implications for aging and neurodegenerative disorders

Abstract

Chronic stress can shorten lifespan and is a risk factor for a diverse range of aging-related diseases. Despite the consistency of this relationship, it remains unclear how stress might affect aging biology. An association between stress exposure and induction of a fundamental aging process such as cellular senescence has been proposed, but experimental evidence is lacking. A complicating factor in human and rodent stress research is the variability of stressors and stress responses themselves. This dissertation presents several studies interrogating the biological processes by which chronic stress may affect aging and disease risk, and probing the relevance of stressor type to these effects. The thesis starts with a review of existing literature supporting the hypothesis that chronic psychological stress can induce cellular senescence. Chapter 2 provides the first experimental evidence causally linking chronic stress with an increase in senescent cells. Moreover, it suggests that a social stress model (chronic subordination stress; CSS), and a nonsocial psychological stress model (restraint stress) despite both most prominently affecting the brain, may be biased towards different senescence pathways (p16 or p21 respectively) and brain regions (hippocampus and cortex). Spatial transcriptomic profiling of the brains of CSS-exposed mice implicates the DNA Damage Response and elevated Ras/Raf signaling as mediators of CSS-induced senescence. CSS-induced SNCs also appears to alter the local microenvironment via pathways including interleukin signaling, and changes to the extracellular matrix. They are also associated with elevated glutamatergic neurotransmission. However, a lifelong pharmacogenetic strategy to eliminate senescent cells was detrimental to healthspan and lifespan and further exacerbates CSS-induced deficits in those measures. With the CNS emerging as a key target of stress-induced SNC, Chapter 3 reviews the association between stress and Alzheimer’s disease, with an emphasis on rodent models. Chapter 4 demonstrates differential effects of CSS and restraint stress on a mouse model of tau pathology (PS19) – one of the hallmarks of Alzheimer’s disease (AD). Although our study found only minor detrimental effects of either model, CSS appears to affect some cognitive function via a tau-independent mechanism. Lastly, Chapter 5 presents an unbiased analysis of the proteomic changes shared by mice exposed to lifelong CSS and AD patients. This work replicates the lack-of-effect of CSS on tau pathology, while demonstrating that most of the overlapping proteins were functionally associated with enhanced NMDA receptor mediated glutamatergic signaling, an excitotoxicity mechanism known to affect neurodegeneration. These findings support the association between stress and AD progression and provide valuable insight into potential early biomarkers and protein mediators of this relationship. The results of these studies provide novel insight into the mechanisms by which stress may affect aging and risk for neurodegenerative disease.