Both stochastic DNA damage and chronic inflammation are characteristic of aging. DNA damage can contribute to inflammatory signaling via a range of mechanisms, but, as noted here, it is challenging in a system as complex as our cellular biochemistry to pick apart the relative importance of these mechanisms. It is nonetheless reasonable to think that some fraction of the unresolved inflammation of aging, disruptive to tissue function throughout the body, results from the increased amount of DNA damage in later life.
Persistent DNA lesions build up with aging triggering inflammation, the body's first line of immune defense strategy against foreign pathogens and irritants. Once established, DNA damage-driven inflammation takes on a momentum of its own, due to the amplification and feedback loops of the immune system leading to cellular malfunction, tissue degenerative changes, and metabolic complications.
There is much work to be done before we will be able to dissect the functional links between persistent DNA damage and inflammation in vivo. The use of progeroid murine models with tissue-specific defects in genome maintenance will allow us to further delineate the causal contribution of specific cell types to systemic inflammation with old age. In parallel, animal models with tagged DNA repair factors coupled to functional genomics and proteomics strategies may prove valuable for identifying new gene targets or protein partners that could link genome maintenance with innate immune signaling. It will also be essential to identify how an active DNA damage response originating from any alterations in the physicochemical structure of the DNA activates cytoplasmic stress responses and the release of proinflammatory factors in the tissue microenvironment.
Likewise, it will be vital to dissect the functional links between DNA damage-driven chronic inflammation and metabolic rewiring with old age. Finally, the recent development of novel therapeutic strategies indicates that, in the long run, it may be more valuable to invest in approaches targeting the DNA damage itself rather than suppressing downstream proinflammatory signals. Such strategies could open new, meaningful avenues towards the development of new rationalized therapeutic interventions against a wide range of adverse pathological outcomes during aging
Link: https://doi.org/10.3...agi.2022.973781
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