Summary: Researchers have identified the cGAS–STING signaling pathway as a central driver of chronic inflammation and functional decline in aging. Experimental blockade of STING reduced inflammatory signals in aged cells and tissues and improved cognitive and physical outcomes in mice, revealing a promising target for counteracting age-related neuroinflammation and degeneration.
This work clarifies how innate immune sensing of cellular DNA can fuel low-grade, persistent inflammation during aging and points to therapeutic strategies for slowing cognitive decline in age-related neurodegenerative conditions.
Key Facts:
- The cGAS–STING pathway, which senses cytosolic DNA and initiates immune responses, contributes directly to chronic inflammation and functional deterioration with age.
- Pharmacological or genetic inhibition of STING suppresses inflammatory phenotypes in senescent human cells and in aged mouse tissues, including the brain.
- Blocking STING in aged animals improved memory, muscle strength and endurance, highlighting potential avenues to reduce neuroinflammation and preserve tissue function in old age.
Source: EPFL
Overview
Aging is commonly accompanied by a persistent, low-level inflammatory state that accelerates tissue decline and increases vulnerability to disease. While many contributors to this “inflammaging” state have been proposed, the precise molecular drivers and their impact on natural aging remained incompletely understood. New research led by Andrea Ablasser at EPFL demonstrates that the DNA-sensing cGAS–STING pathway is a major conduit linking cellular damage to chronic inflammation and functional loss during aging.
The study, published in Nature, builds on earlier findings linking cGAS–STING to cellular senescence and other age-associated processes. cGAS (cyclic GMP–AMP synthase) detects DNA in the cytoplasm and activates STING (Stimulator of Interferon Genes), initiating an innate immune response normally used to fight infections. In aging, however, intracellular DNA can accumulate for non-infectious reasons and aberrantly trigger this pathway.
In aged microglia—the brain’s resident immune cells—researchers observed distinctive gene-expression programs induced by STING activation. Those reactive microglial transcriptional states strongly resembled profiles previously associated with neurodegenerative diseases and with aging itself. Crucially, inhibition of STING in aged mice reduced these inflammatory signatures both in peripheral organs and in the brain.
Mechanistically, the team identified mitochondrial DNA as a likely trigger for cGAS activation in old microglia. Mitochondria, which often become dysfunctional with age, can release DNA fragments into the cytosol; in microglia from older mice, mitochondrial DNA was detected in the cytoplasm where it can stimulate cGAS and activate STING-driven inflammation.
The functional consequences of blocking STING were notable. Aged animals treated with STING inhibitors showed reduced markers of inflammation and meaningful improvements in cognition: both spatial and associative memory improved. Physical measures also improved, with enhanced muscle strength and endurance reported in treated animals. These outcomes indicate that restraining cGAS–STING signaling can restore aspects of tissue function compromised by age-associated inflammation.
To probe causality, the researchers used a cGAS gain-of-function mouse model and single-nucleus RNA sequencing of microglia and hippocampal tissue. They found that activating cGAS in microglia was sufficient to drive aging-like transcriptional states, bystander cell inflammation, neurotoxic changes and impaired memory—strengthening the link between microglial DNA sensing and neurodegeneration.
Together, these findings position the cGAS–STING pathway as a central mediator of aging-related inflammation across multiple organs, and they suggest that targeted blockade of this pathway could be a viable strategy to slow neurodegenerative processes and preserve function during aging. The study provides a mechanistic bridge between mitochondrial dysfunction, innate immune activation, and age-associated tissue decline, and it highlights microglia as a key cellular locus of neuroimmune crosstalk driving cognitive deterioration.
About this neuroinflammation and aging research news
Author: Andrea Ablasser
Source: EPFL
Contact: Andrea Ablasser – EPFL
Image: The image is credited to Neuroscience News
Original Research: Open access. “cGAS–STING drives ageing-related inflammation and neurodegeneration” by Andrea Ablasser. Nature
Abstract (summary)
Low-grade, chronic inflammation is a defining feature of aging and a major contributor to age-related impairment and disease. Although multiple factors feed inflammation during aging, the molecular routes that translate cellular damage into persistent inflammatory signaling have been unclear. This study shows that the cGAS–STING DNA-sensing pathway drives chronic, aging-associated inflammation and functional decline. Blocking STING reduces inflammatory phenotypes in senescent human cells and attenuates age-related inflammation in multiple peripheral organs and the brain of mice, improving tissue function. In the aging brain, STING activation induces reactive microglial transcriptional states, neurodegeneration and cognitive decline; mitochondrial DNA released into the cytosol of old microglia activates cGAS, linking mitochondrial dysfunction to neuroinflammation. Single-nucleus RNA sequencing of a cGAS gain-of-function model indicates that microglial cGAS engagement alone is sufficient to elicit aging-like microglial states, bystander inflammation, neurotoxicity and memory impairment. These results establish cGAS–STING as a central driver of inflammation in aging and nominate pathway blockade as a potential approach to limit neurodegenerative processes in old age.