A chronic state of cellular strain within the central nervous system characterized by accumulated molecular damage and compromised homeostatic mechanisms, primarily driven by the biological aging process. This physiological stress involves heightened oxidative burden, mitochondrial dysfunction, and the accumulation of misfolded proteins, which collectively impair neuronal function and communication. It represents the measurable deterioration of the neuronal microenvironment that precedes overt neurodegenerative pathology.
Origin
The concept stems from cellular biology and neurogeroscience, where the inevitable decline in cellular maintenance and repair capacity over time is recognized as a fundamental driver of age-related diseases. The stress is induced by the long-term cumulative effects of intrinsic cellular processes and extrinsic factors, such as systemic inflammation and hormonal senescence. It highlights the vulnerability of post-mitotic neurons to persistent sub-lethal insults throughout the lifespan.
Mechanism
The core mechanism involves a dysregulation of cellular energy metabolism, leading to a diminished capacity to manage reactive oxygen species (ROS) and maintain adenosine triphosphate (ATP) production. This metabolic shift is often exacerbated by declining neurotrophic support and hormonal signaling, such as reduced Brain-Derived Neurotrophic Factor (BDNF) and neurosteroid synthesis. Ultimately, this stress activates pro-apoptotic pathways and contributes to synaptic retraction and eventual neuronal loss.
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