Cytosolic Self-DNA-A Potential Source of Chronic Inflammation in Aging

Abstract

Aging is the consequence of a lifelong accumulation of stochastic damage to tissues and cellular components. Advancing age closely associates with elevated markers of innate immunity and low-grade chronic inflammation, probably reflecting steady increasing incidents of cellular and tissue damage over the life course. The DNA sensing cGAS-STING signaling pathway is activated by misplaced cytosolic self-DNA, which then initiates the innate immune responses. Here, we hypothesize that the stochastic release of various forms of DNA from the nucleus and mitochondria, e.g., because of DNA damage, altered nucleus integrity, and mitochondrial damage, can result in chronic activation of inflammatory responses that characterize the aging process. This cytosolic self-DNA-innate immunity axis may perturb tissue homeostasis and function that characterizes human aging and age-associated pathology. Proper techniques and experimental models are available to investigate this axis to develop therapeutic interventions.

Keywords: DNA repair; aging; cGAS-STING; cytosolic self-DNA; inflammation; mitochondria.

Figure 1

Activation and propagation of the cGAS-STING signaling by cytosolic self-DNA. Release of DNA from the nucleus and mitochondria as well as release of retroelement RNA molecules (Retro RNA) into cytoplasm in cells undergoing stress (1) can exceed the capacity of TREX 1 to clear cytosolic DNA (2). This will activate cGAS and the synthesis of the secondary messenger cyclic dinucleotide cGAMP (3) that binds to STING and results in its transport from the ER to the Golgi (4) subsequently leading to the production of Type I interferons (IFNI) (5). cGAMP can move into the neighboring cells through GAP junctions and specific cGAMP translocators and activate IFNI genes there (6). IFNIs subsequently activate the expression of interferon stimulated genes (ISGs) via paracrine and endocrine activation of specific IFNI membrane receptors (IFNAR) on the infected (7) as well as uninfected nearby and distant cells (8) that collectively promote the innate and adaptive defense responses. Red filled circles, IFNI. The Figure was created in BioRender.

Figure 2

The intricate network of genome instability and inflammation in cellular senescence. Senescent cells typify the connection between genome instability and inflammation. cGAS-STING activation is key in the expression of senescence-associated secreted phenotype, SASP, that defines cellular senescence. Black filled circles, SASP; Retro RNA, Retroelement RNA. The Figure was created in BioRender.