Linking defects in DNA repair to activation of the inflammatory response via cGAS-STING and defects in mitophagy in mononuclear cells from humans with cognitive decline

Abstract

Aging is commonly defined as an overall progressive functional decline in organisms over time with an increasing risk of disease and death. At the molecular level, aging is attributed to the accumulation of stochastic damage to tissues and cellular components. The free radical theory of aging, proposed by Harman, postulated that both aging and degenerative disease are caused by the accumulation of cellular damage triggered by reactive oxygen species (ROS) from mitochondria. In this context, researchers have invested in the mitochondria as a potential target for understanding aging mechanism and the etiology of age-associated diseases. It is well described in the literature that aging is directly related to a decrease in DNA repair capacity in cells, and consequently to a significant accumulation in DNA damage. In a recently published study using a transgenic mouse model of Alzheimer's disease, a link between the accumulation of DNA damage and defective mitophagy in the progression of Alzheimer's disease was demonstrated. Notably, both processes, accumulation of DNA damage and defective mitophagy, were associated with the presence of cytosolic DNA and activation of the cGAS-STING pathway in triggering the inflammatory response. A recently published study evaluated mitochondrial bioenergetics, mitochondrial DNA copy number and DNA repair capacity in peripheral blood mononuclear cells from humans centenarians. The researchers observed that centenarians with the most severe cognitive impairment displayed the lowest activity of the central DNA repair enzyme, APE1. Our unpublished findings in monocytes isolated from the peripheral blood of elderly with cognitive decline demonstrated that the maximal oxygen consumption rate (OCR) inhibition correlates with increased plasma IL-6, supporting the hypothesis that low chronic inflammation represents a common mechanism underlying age-related functional decline. Data regarding the measurement of relative DNA amplification rate showed a significant decrease in monocytes isolated from these individuals compared to healthy individuals at the same age. The decrease in this rate is directly related to the increase in mitochondrial DNA damage. Taken together, our findings point to mitochondrial dysfunction, DNA damage and inflammation as mechanisms related to cognitive decline in elderly individuals. In this context, the aim of the present project is to advance the understanding of mechanistic associations of the presence of cytosolic DNA, activation of the cGAS-STING pathway and alterations in the level of mitophagy as a potential source of chronic inflammation in the onset and/or progression of cognitive decline throughout aging. (AU)