Targeting the microbiota-mitochondria crosstalk in neurodegeneration with senotherapeutics.

Neurodegenerative diseases are a group of age-related disorders characterized by a chronic and progressive loss of function and/or structure of synapses, neurons, and glial cells. The etiopathogenesis of neurodegenerative diseases is characterized by a complex network of intricately intertwined pathophysiological processes that are still not fully understood. Safe and effective disease-modifying treatments are urgently needed, but still not available. Accumulating evidence suggests that gastrointestinal dyshomeostasis and microbial dysbiosis might play an important role in neurodegeneration by acting as either primary or secondary pathophysiological factors. The research on the role of microbiota in neurodegeneration is in its early phase; however, accumulating evidence suggests that dysbiosis might promote neurodegenerative diseases by disrupting mitochondrial function and inducing mitochondrial dysfunction-associated senescence (MiDAS), possibly due to bidirectional crosstalk based on the common evolutionary origin of mitochondria and bacteria. Cellular senescence is an onco-supressive homeostatic mechanism that results in an irreversible cell cycle arrest upon exposure to noxious stimuli. Senescent cells resist apoptosis via senescent cell anti-apoptotic pathways (SCAPs) and transition into a state known as senescence-associated secretory phenotype (SASP) that generates a cytotoxic proinflammatory microenvironment. Cellular senescence results in the adoption of a detrimental vicious cycle driven by dysbiosis, mitochondrial dysfunction, inflammation, and oxidative stress - a pathophysiological positive feedback loop that results in neuroinflammation and neurodegeneration. Detrimental effects of MiDAS might be prevented and abolished by mitochondria-targeted senotherapeutics, a group of drugs specifically designed to alleviate senescence by inhibiting SCAPs (senolytics), or inhibiting SASP (senomorphics).