cGAS–STING drives ageing-related inflammation and neurodegeneration

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

Standort
Deutsche Nationalbibliothek Frankfurt am Main
Umfang
Online-Ressource
Sprache
Englisch
Anmerkungen
Nature. - 620, 7973 (2023) , 374-380, ISSN: 1476-4687

Ereignis
Veröffentlichung
(wo)
Freiburg
(wer)
Universität
(wann)
2023
Urheber
Gulen, Muhammet F.
Samson, Natasha
Keller, Alexander
Schwabenland, Marius
Liu, Chong
Glück, Sélène
Thacker, Vivek V.
Favre, Lucie
Mangeat, Bastien
Kroese, Lona J.
Krimpenfort, Paul
Prinz, Marco
Ablasser, Andrea

DOI
10.1038/s41586-023-06373-1
URN
urn:nbn:de:bsz:25-freidok-2383196
Rechteinformation
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
Letzte Aktualisierung
25.03.2025, 13:45 MEZ

Datenpartner

Dieses Objekt wird bereitgestellt von:
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.

Beteiligte

Entstanden

  • 2023

Ähnliche Objekte (12)