Mitochondrial dysfunction, a weakest link of network of aging, relation to innate intramitochondrial immunity of DNA recognition receptors

•This article hypothesizes mitochondrial dysfunction is the weakest link of the aging network and the hub of all hallmarks of aging.•The mitochondrial dysfunction may origin from the innate intramitochondrial immunity related to the activities of pathogen DNA recognition receptors.•Pre-consumption of the intramitochondrial pathogen DNA recognition receptors by medical interventions including development of mitochondrial targeted small molecule which can neutralize these receptors may retard or even reverse the aging to significantly improve the maximum lifespan of the organisms. Aging probably is the most complexed process in biology. It is manifested by a variety of hallmarks. These hallmarks weave a network of aging; however, each hallmark is not uniformly strong for the network. It is the weakest link determining the strengthening of the network of aging, or the maximum lifespan of an organism. Therefore, only improvement of the weakest link has the chance to increase the maximum lifespan but not others. We hypothesize that mitochondrial dysfunction is the weakest link of the network of aging. It may origin from the innate intramitochondrial immunity related to the activities of pathogen DNA recognition receptors. These receptors recognize mtDNA as the PAMP or DAMP to initiate the immune or inflammatory reactions. Evidence has shown that several of these receptors including TLR9, cGAS and IFI16 can be translocated into mitochondria. The potentially intramitochondrial presented pathogen DNA recognition receptors have the capacity to attack the exposed second structures of the mtDNA during its transcriptional or especially the replicational processes, leading to the mtDNA mutation, deletion, heteroplasmy colonization, mitochondrial dysfunction, and alterations of other hallmarks, as well as aging. Pre-consumption of the intramitochondrial presented pathogen DNA recognition receptors by medical interventions including development of mitochondrial targeted small molecule which can neutralize these receptors may retard or even reverse the aging to significantly improve the maximum lifespan of the organisms.