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.