Exercise training mitigates age-related cognitive decline by attenuating TMAO-induced inflammation

Area of Science:

• Neuroscience
• Gastroenterology
• Metabolomics

Background:

• Gut microbiota metabolites influence the gut-brain axis and contribute to age-related cognitive decline.
• Trimethylamine N-oxide (TMAO) is a key metabolite that can trigger central nervous system inflammation and cognitive impairment.
• The precise mechanisms by which exercise training mitigates cognitive decline, particularly its effects on TMAO and neuroinflammation, require further elucidation.

Purpose of the Study:

• To investigate the neuroprotective effects of exercise training on D-galactose-induced cognitive decline in aging rats.
• To determine if exercise training modulates trimethylamine N-oxide (TMAO) levels and inhibits the TXNIP-NLRP3 inflammasome pathway.
• To elucidate the cellular mechanisms underlying TMAO's role in senescence and inflammation.

Main Methods:

• An aging rat model was induced using D-galactose, followed by exercise training and TMAO interventions.
• Cognitive function was assessed using behavioral tests: NOR, MWM, and RAM.
• TMAO levels and NLRP3 inflammasome-related proteins were quantified using ELISA and Western blotting; cellular senescence was analyzed in HT22 cells.

Main Results:

• Exercise training significantly improved cognitive function in aging rats, enhancing performance in NOR, MWM, and RAM tests.
• Plasma TMAO levels were reduced by 40.3% in exercise-trained rats, correlating with neuroprotection.
• Cellular studies confirmed TMAO's role in promoting senescence and inflammation via the TXNIP-NLRP3 pathway, with TMAO enhancing disulfide bond formation between TXNIP and Trx1.

Conclusions:

• Exercise training effectively delays age-related cognitive dysfunction by reducing TMAO and suppressing the TXNIP-NLRP3-Caspase-1-GSDMD inflammatory cascade.
• TMAO acts as a critical mediator in the gut-brain axis, promoting neuroinflammation and cognitive decline.
• Targeting TMAO and the TXNIP-NLRP3 pathway presents a potential therapeutic strategy for mitigating age-related cognitive impairment.