The role of extracellular DNA in COVID-19: Clues from inflamm-aging

•The concept of inflamm-aging can help to better understand the potent inflammatory response produced by COVID-19.•The age associated imbalance between misplaced and extracellular inflammatory DNA sequences (e.g. mtDNA) and anti-inflammatory DNA (e.g. telomere) leads to inflamm-aging derangement.•Extracellular mtDNA levels increase and correlate with the extent of damage, clinical evolution and the onset of multi-organ failure in patients affected by multiple systemic damage or sepsis. Epidemiological data convey severe prognosis and high mortality rate for COVID-19 in elderly men affected by age-related diseases. These subjects develop local and systemic hyper-inflammation, which are associated with thrombotic complications and multi-organ failure. Therefore, understanding SARS-CoV-2 induced hyper-inflammation in elderly men is a pressing need. Here we focus on the role of extracellular DNA, mainly mitochondrial DNA (mtDNA) and telomeric DNA (telDNA) in the modulation of systemic inflammation in these subjects. In particular, extracellular mtDNA is regarded as a powerful trigger of the inflammatory response. On the contrary, extracellular telDNA pool is estimated to be capable of inhibiting a variety of inflammatory pathways. In turn, we underpin that telDNA reservoir is progressively depleted during aging, and that it is scarcer in men than in women. We propose that an increase in extracellular mtDNA, concomitant with the reduction of the anti-inflammatory telDNA reservoir may explain hyper-inflammation in elderly male affected by COVID-19. This scenario is reminiscent of inflamm-aging, the portmanteau word that depicts how aging and aging related diseases are intimately linked to inflammation.