Excess manganese (Mn) — encountered occupationally in welding, mining, and battery manufacturing — drives cellular senescence in both C. elegans and PC12 neuron-like cells through a previously uncharacterized mechanism involving STING (stimulator of interferon genes) signaling. In worms, Mn exposure shortened lifespan, impaired locomotion, and disrupted dopaminergic signaling. In PC12 cells, Mn triggered the full senescence phenotype: β-galactosidase positivity, telomere attrition, p53/p21 pathway activation, mitochondrial dysfunction, oxidative stress, DNA damage, and sterile inflammation. Crucially, pharmacological STING inhibition partially reversed senescence markers, and quercetin — a flavonoid already recognized as a senolytic — attenuated the oxidative, mitochondrial, inflammatory, and senescence-associated damage.
This finding matters because it repositions Mn neurotoxicity within the cellular senescence framework, a conceptual shift with therapeutic implications. STING is best known in innate immunity and viral defense, but its emerging role in senescence-associated secretory phenotype (SASP) amplification is gaining traction. Linking environmental Mn exposure to STING-driven neuronal senescence is mechanistically novel and potentially explains the accelerated neurodegeneration seen in manganism.
Limitations are significant: both models are preclinical, with no human or mammalian in vivo data. PC12 cells are a rat adrenal tumor line — imperfect proxies for primary neurons. Quercetin's bioavailability and CNS penetration in humans remain pharmacological hurdles. Still, this is incrementally paradigm-shifting for environmental neurotoxicology: it frames heavy-metal overload as a senescence trigger amenable to senolytic intervention.