Manganese overload as a previously underappreciated trigger of cellular senescence: unraveling mechanisms and therapeutic rescue by the senolytic quercetin.

Manganese (Mn) is an essential trace element, but excessive Mn exposure is associated with neurotoxicity and aging-related dysfunction. Whether Mn overload promotes cellular senescence and the mechanisms involved remain insufficiently defined. Here, we investigated Mn-induced senescence-associated injury using Caenorhabditis elegans and neuron-like PC12 cells. Mn exposure shortened lifespan, impaired locomotor behavior, altered dopaminergic neuronal signals, and increased senescence-associated β-galactosidase activity in C. elegans. In PC12 cells, Mn induced senescence-associated phenotypes, including reduced viability, β-galactosidase positivity, telomere attrition, p53/p21 activation, oxidative stress, mitochondrial dysfunction, DNA damage-related alterations, inflammatory responses, and stimulator of interferon genes (STING)-related signaling. Quercetin attenuated Mn-induced oxidative, mitochondrial, inflammatory, and senescence-associated changes, while STING inhibition partially alleviated cell injury and β-galactosidase positivity. These findings suggest the involvement of STING-related signaling in Mn-induced neurotoxic injury accompanied by senescence-associated changes and suggest that this process may be pharmacologically attenuated.