An analysis of the mechanism of aging: endogenous viral stimulus and the deleterious effect of chronic inflammation

Abstract

This article describes a putative mechanism of aging based on the interaction of endogenous viral particles with the receptors of the innate immune system leading to producing pro-inflammatory cytokines. The innate immune response induces a complex of signaling pathways leading to senescence or tumorigenesis. The fate of a cell is depended on the activity of the p53 tumor-suppressive signaling pathway. Chronic inflammation is characterized by upregulation of the NF-kB signaling. The NF-kB protein stimulates the expression of matrix metalloproteinases (MMPs) leading to remodeling of extracellular matrix. The extracellular matrix alterations induce the loss of stem cell environment and their depletion. The innate immune system also mediates the PI3K-Akt-mTOR signaling pathway that inhibits autophagy and transforms energy metabolism providing cell senescence, high level of blood glucose, high lipid synthesis and mitochondrial alterations. The STAT3-HIF1 signaling pathway suppresses oxidative phosphorylation increasing ROS production and promoting the MAPK pathway leading to excessive cell proliferation. The increased ROS production causes the global DNA and histone demethylation contributing to retrotransposon reactivation whose activity leads to genome instability. However, the activity of retrotransposons may be partly explained by their role in adaptation. Among retrotransposons, endogenous retroviruses may be considered as an intrinsic stimulus for the innate immune system and are also able to avoid the adaptive immune system. Therefore, I consider endogenous retroviruses as promising targets in anti-aging therapies