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Muhammet Fatih Gulen, Natasha Samson, Alexander Keller, Marius Schwabenland, Chong Liu, Selene Glück, Vivek V. Thacker, Lucie Favre, Bastien Mangeat, Lona John Kroese and 3 more
Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease 1 . Multiple factors can contribute to ageing-associated inflammation 2 ; however, the molecular pathways that transduce aberrant inflammatory signalling and their impact in natural ageing remain unclear. Here we show that the cGAS–STING signalling pathway, which mediates immune sensing of DNA 3 , is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglial transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia, defining a mechanism by which cGAS–STING signalling is engaged in the ageing brain. Single-nucleus RNA-sequencing analysis of microglia and hippocampi of a cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglial states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS–STING pathway as a driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS–STING signalling as a potential strategy to halt neurodegenerative processes during old age.
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Gulen, M. F., Samson, N., Keller, A., Schwabenland, M., Liu, C., Glück, S., Thacker, V. V., Favre, L., Mangeat, B., Kroese, L. J., Krimpenfort, P., Prinz, M., & Ablasser, A. (2023). cGAS–STING drives ageing-related inflammation and neurodegeneration. Nature, 620(7973), 374–380. https://doi.org/10.1038/s41586-023-06373-1
Gulen, Muhammet Fatih, et al. "cGAS–STING drives ageing-related inflammation and neurodegeneration." Nature, vol. 620, no. 7973, 2023, pp. 374–380, https://doi.org/10.1038/s41586-023-06373-1.
Gulen, Muhammet Fatih, Natasha Samson, Alexander Keller, Marius Schwabenland, Chong Liu, Selene Glück, Vivek V. Thacker, et al. "cGAS–STING drives ageing-related inflammation and neurodegeneration." Nature 620, no. 7973 (2023): 374–380. https://doi.org/10.1038/s41586-023-06373-1.
Gulen M. F., Samson N., Keller A. [и др.] cGAS–STING drives ageing-related inflammation and neurodegeneration // Nature. — 2023. — Vol. 620, № 7973. — P. 374–380. — URL: https://doi.org/10.1038/s41586-023-06373-1
@article{gulen2023cgassting,
title = {{cGAS–STING drives ageing-related inflammation and neurodegeneration}},
author = {Muhammet Fatih Gulen and Natasha Samson and Alexander Keller and Marius Schwabenland and Chong Liu and Selene Glück and Vivek V. Thacker and Lucie Favre and Bastien Mangeat and Lona John Kroese and Paul Krimpenfort and Marco Prinz and Andrea Ablasser},
journal = {Nature},
year = {2023},
volume = {620},
number = {7973},
pages = {374--380},
doi = {10.1038/s41586-023-06373-1},
url = {https://doi.org/10.1038/s41586-023-06373-1}
}TY - JOUR AU - Gulen, Muhammet Fatih AU - Samson, Natasha AU - Keller, Alexander AU - Schwabenland, Marius AU - Liu, Chong AU - Glück, Selene AU - Thacker, Vivek V. AU - Favre, Lucie AU - Mangeat, Bastien AU - Kroese, Lona John AU - Krimpenfort, Paul AU - Prinz, Marco AU - Ablasser, Andrea TI - cGAS–STING drives ageing-related inflammation and neurodegeneration JO - Nature VL - 620 IS - 7973 SP - 374 EP - 380 PY - 2023 DA - 2023/08/02 DO - 10.1038/s41586-023-06373-1 UR - https://doi.org/10.1038/s41586-023-06373-1 ER -
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