cGAS-STING pathway
An innate immune sensing pathway triggered by cytosolic DNA; drives inflammatory senescence signaling. In aging mouse macrophages it is held in check by the Ragulator subunit Lamtor5, which binds cGAS directly and routes it for ESCRT-mediated degradation; whether mTORC1 or mTORC2 signalling contributes to this step is untested, because the one study behind it measured neither.
An immune alarm system that goes off when it detects DNA where it shouldn't be – floating loose in the cell, not tucked inside the nucleus. An immune alarm system that detects DNA where it shouldn't be (in the cell's main fluid, not the nucleus). It drives inflammatory 'senescence' signaling. In old mice, a protein called Lamtor5 normally grabs the alarm sensor and sends it to be destroyed; as Lamtor5 declines with age, the sensor survives and the alarm stays on. Lamtor5 is part of a complex that also activates mTOR, but nobody has yet measured whether mTOR itself is involved in this particular step.
cGAS binds cytosolic double-stranded DNA and synthesises cGAMP, which activates STING to drive type-I-interferon and NF-κB-dependent inflammatory gene expression. In aged mouse macrophages the Ragulator subunit Lamtor5 binds cGAS directly and routes it for ESCRT-mediated degradation; its age-related decline leaves cGAS stabilised, which is sufficient to trigger cGAS-mediated paracrine inflammatory senescence, and restoring Lamtor5 reverses the phenotype (LV2026). Lamtor5 sits in the complex that recruits mTORC1 to the lysosome, but LV2026 measured no mTORC1 or mTORC2 readout for the cGAS step, so whether mTOR signalling contributes at all is untested rather than established. Single mouse study – human relevance of the Lamtor5–cGAS/STING link is untested.
TL;DR. cGAS-STING pathway appears in 1 curated study in Oliver's mTOR Atlas: 1 in animal models. No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| cGAS-STING pathway activates Cellular senescence mechanism: functional-consequence · this link in full · on the map table | In aged immune cells called macrophages, cGAS-STING switches on an inflammatory programme that spreads to neighbouring cells, so the ageing effect does not stay in the cell where it started. This comes from a single mouse study, and whether the same spread happens in human tissue has not been tested. cGAS-STING activation in aged macrophages drives a paracrine inflammatory senescence programme that spreads the phenotype to neighbouring cells, contributing to systemic ageing. cGAS-STING activation in aged macrophages drives a paracrine inflammatory senescence programme that spreads the phenotype to neighbouring cells, contributing to systemic ageing. Holds under: Single mouse study; the human magnitude of this effect, and whether the same paracrine spread occurs in human tissue, are untested. not tested in people · emerging, few independent studies | A | LV2026 |
| Ragulator inhibits cGAS-STING pathway mechanism: degradation · this link in full · on the map table | Lamtor5 belongs to Ragulator, the lysosome complex that switches mTORC1 on, but this link does not run through mTORC1 as far as the source shows. Lamtor5 grabs the inflammation sensor cGAS and sends it for disposal. When Lamtor5 falls with age in immune cells called macrophages, cGAS builds up and drives inflammation that spreads to neighbouring cells; in mice, moving such macrophages into young animals sped up their ageing. This is one mouse study, so it is not known whether the same happens in people, or whether mTORC1 plays any part. Lamtor5 binds cGAS directly and routes it for degradation through the ESCRT machinery, so the Ragulator subunit acts as a physical brake on the sensor itself. Age-related decline of Lamtor5 in macrophages leaves cGAS stabilised, and that is sufficient to unleash cGAS-mediated paracrine inflammatory signalling: transferring Lamtor5-deficient macrophages accelerates ageing in young mice, while restoring young macrophages, clearing senescent cells, or applying a small peptide that blocks the Lamtor5/cGAS interface alleviates the phenotype in aged mice. Lamtor5 binds cGAS directly and routes it for degradation through the ESCRT machinery, so the Ragulator subunit acts as a physical brake on the sensor itself. Age-related decline of Lamtor5 in macrophages leaves cGAS stabilised, and that is sufficient to unleash cGAS-mediated paracrine inflammatory signalling: transferring Lamtor5-deficient macrophages accelerates ageing in young mice, while restoring young macrophages, clearing senescent cells, or applying a small peptide that blocks the Lamtor5/cGAS interface alleviates the phenotype in aged mice. Holds under: One mouse study (LV2026), A - animal, and no human data for this link. The abstract reports no mTORC1 or mTORC2 measurement for the cGAS step, so whether mTORC1 signalling contributes at all is untested here rather than established. Macrophage-specific: the conditional knockout is myeloid, and the ageing phenotypes are read out at the organismal level, which is a long inferential chain from one protein interaction. not tested in people · emerging, few independent studies | A | LV2026 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| A | Animal model | 1 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2026 | A | Age-associated decline of Lamtor5 drives immunosenescence and systemic aging via cGAS-mediated paracrine inflammation. LV2026 Age-driven loss of Lamtor5, a key lysosomal mTOR activation complex subunit, drives macrophage immunosenescence and systemic aging phenotypes in mice by unleashing cGAS-STING paracrine inflammation; restoring Lamtor5 in aged mice rescued immunosenescence and attenuated systemic ageing phenotypes. |
Related entities
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