This fascinating open access paper investigates a role in aging for DNA fragments that have escaped the cell nucleus, for underlying reasons probably related to stochastic nuclear DNA damage, but yet to be comprehensively explored. They may contribute to cellular senescence and the chronic inflammation generated by senescent cells, and this is accomplished by activating an innate immune sensor, cGAS-STING. This innate immune mechanism is already strongly linked to the bad behavior of senescent cells. The most interesting portion of the work here is the prospect for cleaning up extranuclear DNA fragments via some form of molecular therapy, and therefore dampening the consequence. The researchers demonstrate a proof of principle, and it would be interesting to see this explored further in naturally aging mice.
Subclinical but heightened inflammation is observed in aging tissues, and in the blood of older adults in large epidemiologic studies, with consistently higher basal levels of C-reactive protein and abundant pro-inflammatory cytokines. Such alteration is often viewed as non-cell autonomous, for example senescent cells, which increase with aging, may modulate inflammation through secretion of cytokines (i.e., senescence-associated secretory phenotype, SASP. The intrinsic processes that initiate this inflammation in aging remain largely unknown.
We previously described a cell-autonomous process in which damaged nuclear DNA is trafficked to the cytosol, transported via autophagy, and degraded by lysosomal nuclease DNASE2A. Excess DNA accumulated under conditions of increased damage, defective degradation, or autophagy blockade can activate the STING pathway leading to inflammation. DNA damage has been postulated to be a major cause of cellular aging. We hypothesize that cumulative damage may generate excess DNA leading to persistent inflammation in aging cells through a similar mechanism. Several observations in senescence seem to agree with our prediction. Unrepaired or persistent double-stranded breaks (DSBs) can be found in senescing cells, and cells are known to senesce upon DNA damage. Senescent nuclei also undergo dramatic chromatin changes with fragments budding off the nucleus.
We found that older cells harbored higher levels of extranuclear DNA compared to younger cells. Extranuclear DNA was exported by a leptomycin B-sensitive process, degraded through the autophagosome-lysosomal pathway and triggered innate immune responses through the DNA-sensing cGAS-STING pathway. Patient cells from the aging diseases ataxia and progeria also displayed extranuclear DNA accumulation. Removing extranuclear DNA in old cells using DNASE2A reduced innate immune responses and senescence-associated β-gal enzyme activity. We hypothesize a direct role for excess DNA in aging-related inflammation and in replicative senescence, and propose DNA degradation as a therapeutic approach to remove intrinsic DNA and revert inflammation associated with aging.