STAT1 Drives the Interferon-Like Response and Aging Hallmarks in Progeria

Abstract

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease caused by the mutant lamin-A protein "progerin," features robust sterile inflammation/interferon (IFN)-like response. Targeting inflammation delays cellular and organismal HGPS phenotypes. However, specific mechanisms driving the sterile inflammation/IFN-like response and how this response causes tissue degeneration/loss in HGPS are unknown. We demonstrate that signal transducer and activator of transcription 1 (STAT1) drives the IFN-like response and aging phenotypes in HGPS cellular and mouse models. Calcitriol and baricitinib strongly repress sterile inflammation/IFN-like response, improving hallmarks of progerinexpressing cells such as mitochondrial, autophagy, and proliferation defects. In vivo, calcitriol or baricitinib extend lifespan of progeria mice, and baricitinib alone or combined with a high-caloric/high-fat diet has a remarkable impact reducing skin, aortic, and adipose tissue degeneration. Critically, Stat1 haploinsufficiency reduces tissue degeneration/loss and extends lifespan of progeria mice, recapitulating baricitinib benefits. Our study unveils STAT1 as a driver of the IFN-like response and HGPS pathology and suggests that aberrant STAT1 signaling contributes to aging, providing new therapeutic possibilities for HGPS and other inflammation/IFN response-associated diseases.

Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging

“…4e). Therefore, it is plausible that IFN-I signaling perpetuates a feedforward loop for brain cell senescence, a scenario consistent with recent findings regarding accelerated aging driven by Stat1, the signaling mediator immediately downstream of IFN-I receptor, in progeria mice 38 . As IFN-I response has been pathogenically implicated in neurodegeneration 28,39,40 , this innate immune axis could be a valid target for therapeutic intervention throughout the course of disease development.…”