Longevity & AgingMetformin Blocks Chromatin Escape from the Nucleus to Curb Aging Inflammation
Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation in aging by activating the cGAS–STING pathway, but how they exit the nucleus—given their size exceeds nuclear pore limits—was unknown. This study shows CCFs escape via nuclear egress, a membrane-trafficking process normally used to shuttle large complexes across the nuclear envelope. Key proteins ESCRT-III and the Torsin complex mediate this process. Blocking them traps chromatin at the nuclear membrane and suppresses inflammatory signaling. Crucially, glucose restriction or metformin activates AMPK, which phosphorylates and triggers autophagic degradation of ALIX, an ESCRT-III component, thereby reducing CCF formation. In aged mice, metformin lowered ALIX levels, CCFs, and cGAS-driven intestinal inflammation, linking metabolic state directly to inflammatory output in aging.
