Neuronal aging is associated with declined autophagy caused by reduced functionality of cGAS-STING signaling

ABSTRACT The lifelong maintenance of cognitive abilities in an increasingly aging human society is one of the major challenges of future research and medical services. For this, a better understanding of the cellular aging processes in the mammalian brain is a fundamental requirement. In particular, the functioning of postmitotic neurons, which require special strategies for lifelong functionality, is still elusive in many details. Among many other hallmarks of neuronal aging, the impairment of autophagy as an essential element of cellular homeostasis is of particular importance. However, the mechanisms for regulating these processes have not yet been fully elucidated. Establishing an in vitro model from primary cortical cells of the mouse brain, which shows the characteristic features of cellular senescence that are also observed in the total brain, we found the accumulation of dsDNA in the cytosol of neurons. Since dsDNA is a trigger for the activation of the cGAS-STING signaling and its primordial function is a non-canonical activation of autophagy, we analyzed its impact on aging neurons. We were able to demonstrate that the age-dependent downregulation of cGAS- STING signaling in neurons leads to an inhibition of autophagy at different levels. In contrast, activation of STING led to a complete rescue of autophagy in old neurons. Additionally, we found no evidence for age dependent cGAS-STING mediated IFN-I production. Hence, we propose that the primary function of cGAS-STING signaling in neurons is to maintain autophagy rather than contribute to age-related inflammation, and thus represents a target for therapeutic intervention.