Companies working on novel therapeutics targeting senescent cells, to selectively destroy these errant cells or alter their metabolism to reduce harmful inflammatory signaling, are largely steering clear of neurodegenerative conditions, at least for now. Any successful systemic treatment that destroys senescent cells or suppresses the inflammatory signaling of senescent cells throughout the body will likely see off-label use for many age-related conditions, of course, but not all such treatments will affect the burden of senescent cells in the brain. The present consensus in the research community is that cellular senescence in the various populations of supporting cells in the brain appears to be important in the onset and development of neurodegenerative conditions, and therefore more attention should be given to the application of senotherapeutics to the aging of the brain.
Cellular senescence is a state of stable cell cycle arrest, initially identified in proliferative cells, accompanied by persistent metabolic activity and the secretion of a pro-inflammatory cocktail of molecules known as the senescence-associated secretory phenotype (SASP). Initially, it acts as a beneficial mechanism by halting the proliferation of damaged cells, thus suppressing tumor development, and facilitating wound repair through the coordinated release of specific factors. The pathology arises from the chronic accumulation of these senescent cells. Their persistent SASP creates a toxic tissue environment. In the brain, the accumulation of senescent microglia and astrocytes is a major driver of neuroinflammation. Recent studies directly link this process to cognitive decline and neurodegenerative pathologies, making the clearance of senescent cells (senolysis) a promising strategy to combat brain aging.
The identification of senescence as a modifiable factor in brain aging has led to the emergence of senotherapeutics, a new class of pharmacological interventions aimed at either eliminating senescent cells (senolytics) or modulating their harmful secretory profile (senomorphics). Senolytics, such as dasatinib and quercetin, selectively induce apoptosis in senescent cells by targeting pro-survival pathways unique to the senescent state.
Senotherapeutics offer a promising and innovative approach to managing brain aging and its associated cognitive decline. By targeting the fundamental process of cellular senescence, either through selective elimination of senescent cells or modulation of their harmful secretions, these interventions have demonstrated the ability to reduce neuroinflammation, improve synaptic function, and enhance cognitive performance in preclinical models. Although clinical translation is still in early stages, ongoing trials and emerging delivery technologies provide a pathway toward safe and effective use in humans. Challenges such as blood-brain barrier permeability, senescence biomarker development, and long-term safety must be addressed through continued research and technological advancement.
Link: https://doi.org/10.3390/neurolint17120204
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