Role of self-DNA and sterile inflammation driving age/progeria-related metabolic defects

摘要

Abstract The goal of this project is to unravel mechanisms of metabolic dysfunction and tissue degeneration during aging through the Hutchinson Gilford Progeria Syndrome (HGPS) model. This devastating accelerated aging disease is caused by the production of a truncated lamin A protein “ progerin” that compromises nuclear architecture, genome function and stability, and mitochondrial function, eliciting cellular toxicity and early senescence. HGPS holds many similarities with normal aging, including alopecia, bone and joint defects, severe metabolic problems, and cardiovascular disease (CVD), which ultimately causes patients’ death in the second decade. Interestingly, progerin is also produced in advanced age individuals and in patients with cardiomyopathies. Understanding the molecular mechanisms driving metabolic dysfunction in HGPS will likely unravel some of the mysteries behind metabolic problems in normal aging. We recently reported that mice with the human HGPS mutation (LmnaG609G/G609G) succumb to metabolic dysfunction. Feeding a high-fat diet to these mice extends healthspan and lifespan, unleashing patient-like severe tissue degenerative phenotypes. In addition, cells from HGPS patients and mice, and from progerin- inducible cultured cells, exhibit traits of metabolic alterations typical of senescent cells, including mitochondrial dysfunction, AMPK activation, and increased glycolysis and autophagy. These metabolic changes are accompanied by nuclear and mitochondrial damage, accumulation of self-DNA in the cytoplasm (cytDNA), and activation of sterile inflammation pathways such as the DNA-sensing cGAS-STING pathway and the downstream STAT1-ISG (interferon stimulated gene) response. Importantly, our preliminary data show that reducing the activity of STING and STAT1 improves the metabolic phenotypes and the fitness of progerin-expressing cells. Given the emerging evidence linking sterile inflammation with metabolic dysfunction and CVD, our working model is that the metabolic phenotype of HGPS is the result of a maladaptive response to nuclear and mitochondrial DNA damage/leakage, which triggers a sustained and unresolved sterile inflammation/ISG response that impacts key metabolic pathways. We will test the hypotheses that cytDNA triggers metabolic alterations in progeria through the cGAS-STING pathway (Aim 1) and the STAT1:ISG15 response (Aim 2), promoting cell/tissue degeneration and organismal aging, and that targeting cytDNA sensing/signaling pathways has therapeutic benefits for HGPS (Aim 3). The danger of accumulating self-DNA in the cytoplasm during aging is not understood and this issue is becoming increasingly relevant to human health. We have gathered a team with complementary expertise that via advanced biochemical, physiological, and -omics methods, will test transformative ideas and define novel mechanisms linking sterile inflammation and metabolic defects in progeria/aging.