cGAS–STING drives ageing-related inflammation and neurodegeneration

Muhammet F. Gulen, Natasha Samson, Alexander Keller, Marius Schwabenland, Chong Liu, Selene Glück, Vivek V. Thacker, Lucie Favre, Bastien Mangeat, Lona J. Kroese, Paul Krimpenfort, Marco Prinz and Andrea Ablasser ()
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Muhammet F. Gulen: Swiss Federal Institute of Technology Lausanne (EPFL)
Natasha Samson: Swiss Federal Institute of Technology Lausanne (EPFL)
Alexander Keller: Swiss Federal Institute of Technology Lausanne (EPFL)
Marius Schwabenland: University of Freiburg
Chong Liu: Swiss Federal Institute of Technology Lausanne (EPFL)
Selene Glück: Swiss Federal Institute of Technology Lausanne (EPFL)
Vivek V. Thacker: Swiss Federal Institute of Technology Lausanne (EPFL)
Lucie Favre: Lausanne University Hospital
Bastien Mangeat: Swiss Federal Institute of Technology Lausanne (EPFL)
Lona J. Kroese: The Netherlands Cancer Institute
Paul Krimpenfort: The Netherlands Cancer Institute
Marco Prinz: University of Freiburg
Andrea Ablasser: Swiss Federal Institute of Technology Lausanne (EPFL)

Nature, 2023, vol. 620, issue 7973, 374-380

Abstract: Abstract Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease1. Multiple factors can contribute to ageing-associated inflammation2; 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 DNA3, 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.

Date: 2023
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DOI: 10.1038/s41586-023-06373-1

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