Sterile inflammation arises without external cause, such as infection or injury, and chronic sterile inflammation is a characteristic of aging. Inflammatory signaling becomes constant and pronounced in tissues, and the immune system is constantly roused to action. Processes, such as regeneration from injury, that depend upon a clear cycle of inflammation that starts, progresses, and resolves are significantly disrupted. It is no exaggeration to say that the downstream consequences of chronic inflammation accelerate the progression of all of the common age-related conditions. It is of great importance in atherosclerosis and neurodegenerative conditions, for example. Like raised blood pressure, chronic inflammation is one of the more important mechanisms acting to convert the low-level molecular damage at the root of aging into the various proximate causes of age-related disease and mortality.

Thus the research community is greatly interested in understanding how and why sterile inflammation arises in later life. Cellular senescence is one sizable area of investigation, as senescent cells accumulate with age, and secrete inflammatory signals. Additionally, visceral fat tissue acts to increase the pace at which senescent cells arise, but also contributes to inflammation via other mechanisms. In the short open access commentary here, the authors discuss a potential mechanism whereby cells in aged tissues start to eject DNA fragments from the cell nucleus, and this can cause reactions that lead to inflammatory signaling. This is probably important in cellular senescence, but may also operate in other cells.

Damaged DNA marching out of aging nucleus

Subclinical but heightened inflammation in the absence of infection is a key feature of aging, and includes senescent cells that secrete cytokines. Yet, what are the intrinsic processes that initiate 'inflammaging', and possibly other forms of sterile inflammation, like autoimmunity? Self-DNA has long been suspected as trigger and target of autoimmunity, as anti-nuclear antibodies, anti-dsDNA (double-stranded DNA) antibodies and plasma DNA are observed in autoimmune patients of lupus and rheumatoid arthritis.

In studying the initiating events leading to autoimmune arthritis in mice deficient for the lysosomal nuclease DNASE2A, we revealed an unexpected 'hidden' source of this inflammatory DNA - the cell's own nucleus. In healthy cells, damaged and irreparable nuclear DNA fragments are trafficked to the cytosol, enclosed by autophagosomes, and delivered to the lysosomes for degradation by DNASE2A. Lacking DNASE2A, extranuclear DNA accumulates in cells and induces inflammation via innate DNA sensing. Cytosolic DNA sensing is activated when dsDNA binds the DNA sensor enzyme cGAS (cyclic GMP-AMP synthase), converting GTP and ATP into the endogenous second messenger cGAMP, which in turns activates the adaptor protein STING (stimulator of interferon genes) and induces innate immune responses and inflammation. Nuclear DNA as a trigger of immunity could help explain a range of inflammatory conditions.

As cells age, damaged DNA accumulates over time. As an interesting aside, anti-dsDNA antibodies are also found at higher levels in older adults. Could damaged DNA march out of the nucleus of an old cell to set off inflammaging? Indeed, in replicative and oncogene-induced senescent cells, damaged nuclear DNA is exported. Clearing DNA is perhaps the most effective way to eliminate its inflammatory danger. As the only known acidic DNA endonuclease, DNASE2A preferentially degrades dsDNA. It resides with the lysosome, where intracellular and extracellular DNA cargoes converge for degradative digestion. In mice, Dnase2a-deficient cells exhibits the typical senescent phenotype of enlarged cells, slow cell growth, and increased expression of aging markers (senescence-associated β-gal activity, p16 and HP1β expression). Indeed, ectopic expression of DNASE2A substantially reduces cytosolic DNA abundance, innate immune activation and cellular aging phenotype in old cells, thus confirming the protective role of enzymatic DNA degradation in limiting inflammation.

Growing evidence now supports a unifying theory that damaged or irreparable DNA leaves the nucleus to drive aging-related inflammation via innate DNA sensing. Where DNA damage is increased (aging), DNA repair inhibited (ataxia), or nuclear barrier compromised (progeria), DNA load may be not reduced promptly or sufficiently, leading to inflammation. So how far can this DNA theory help to understand the cellular immune mechanisms underlying aging? Each nucleus holds a massive reservoir of endogenous DNA that can trigger local and systemic immunity if there are internal abnormalities such as DNA damage. How nuclear DNA export, trafficking, sensing, and degradation is coordinated to maintain cellular homeostasis is largely unknown. DNA danger coming from within generates exciting questions that probe into the basic life cycle of broken DNA fragments, and suggest ways of treating self-DNA-mediated sterile inflammation (autoimmunity, cancer, neurodegeneration, and chemotherapy) by regulating the abundance of mis-localized DNA.