EXTRACELLULAR MITOCHONDRIAL DNA PLASMA LEVELS INCREASE DURING AGING AND LONGEVITY: IMPLICATIONS FOR "INFLAMMAGING"

Mitochondrial (mt) DNA or degraded mitochondrial peptides are involved in the pathogenesis of the systemic inflammatory response syndrome (SIRS), a condition that often affects patients who survive a trauma and that resembles sepsis. Indeed, SIRS is due, at least partially, to molecules called "damage-associated molecular patterns" (DAMPs), a family of conserved molecules, conceptually similar to PAMPs, that includes hyaluronan fragments, heat shock proteins, S100 proteins, beta-amyloid, uric acid, IL-1 alpha, IL-33, and the DNA-binding nuclear protein HMGB1. DAMPs can trigger an innate immune response, causing inflammation through the engagement of several TLRs. Mitochondrial DAMPs (MTDs) can be released by damaged tissues, and are highly present in plasma of patients with SIRS. MTDs are represented by formyl peptides, that bind the formyl peptide receptor-1 (FPR-1), and mtDNA, that binds TLR-9, whose activation causes a potent inflammatory reaction.In the last years, we have shown that the production of proinflammatory cytokines is highly increased during the aging process, which is characterized by the accumulation of cellular and molecular defects, and involutive phenomena occurring concomitantly to a hyperstimulation of both innate and adaptive immunity (accumulation of expanded clones of memory and effector T cells, shrinkage of the TCR repertoire, progressive activation of macrophages). These phenomena result in a low-grade, chronic state of inflammation defined as “inflammaging”.To investigate the possible role of extracellular mtDNA during inflammaging, by an original real time PCR assay we have measured plasma levels of mtDNA in individuals who have been followed for 5 years: 429 siblings >90 years old (including 20 ultracentenarians) and 231 controls (50-75 y.o.). Moreover, we have studied 50 young donors (<30 years). A highly significant age-related increase of mtDNA plasma levels was observed. In donors >90 years, mtDNA plasma levels were significantly similar within families, suggesting the existence of a possible genetic component that controls this parameter. mtDNA was not correlated to classical inflammatory markers (CRP, VES), nor to main hematochemical conventional risk factors (among which ALT, albumin, cholesterol and glycemia). Finally, individuals who died within one year from the plasma collection had a lower level of mtDNA, while those who survived >5 years had much higher mtDNA plasma content.We can hypothesize that the age-related increase in plasma mtDNA could be either a marker of an optimal elimination of potentially dangerous cells, or the result of a complex remodeling of the entire organism, that makes use of potentially proinflammatory molecules like MTDs.