Losing a DNA sensor accelerates cell inflammation

The protein cGAS normally acts as a cellular guard. It detects DNA that ends up in the wrong place and triggers an immune response. Researchers tested what happened when they completely disabled cGAS in mice. They expected less inflammation. The opposite turned out to be true, as reported in a study published in Nature Aging. The researchers found that mice without cGAS had a shorter median lifespan than normal mice.

Repetitive DNA becomes active and disrupts chromatin

Without cGAS, so-called LINE1 elements became more active. LINE1 elements are stretches of repetitive DNA (repeating sequences in the genome that are normally kept silent). At the same time, the organisation of a specific chromatin modification, H3K9me3, became disrupted. Chromatin is the structure in which DNA is packaged inside the cell nucleus; H3K9me3 is a chemical mark that keeps certain parts of the DNA silenced. When that organisation breaks down, genes that are normally suppressed become active, leading to a state of chronic low-grade inflammation that researchers call inflammaging.

This finding upends a common assumption. It has long been proposed that inhibiting the cGAS-STING pathway (the signalling route of which cGAS is a part) could reduce age-related inflammation. This study suggests it is not that simple: cGAS also has protective functions that are lost when it is disabled.

What this means for therapy

This is a relevant caution for the development of inhibitors of this immune pathway as a treatment for inflammaging. Complete elimination of cGAS appears to be too blunt an approach. Researchers argue for a more nuanced strategy that preserves balance within the pathway. The fact that it plays a dual role (both pro-inflammatory and protective) makes therapeutic development more complex.

The study was conducted in mice. Extrapolation to humans requires caution and further research.

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