Chronic inflammation promotes aging and age-related diseases. Although metabolic interventions are capable of regulating inflammatory responses, the precise mechanistic link between metabolism and inflammation remains poorly understood.
During cellular senescence and organismal aging, cytoplasmic chromatin fragments (CCFs) drive the onset of chronic inflammation via the cGAS-STING signaling pathway. Nevertheless, CCFs exceed the size limit of nuclear pores, and the exact mechanism mediating their translocation from the nucleus to the cytoplasm has not been elucidated.
On January 16, 2026, the team led by Zhixun Dou from Harvard Medical School and Massachusetts General Hospital published a paper in Nature Aging (a Nature journal) entitled: Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
This study reveals for the first time that metformin suppresses the release of chromatin fragments from the nucleus to the cytoplasm during aging, thereby proposing a novel therapeutic strategy targeting the nuclear egress of chromatin fragments to curb age-associated inflammation.
In this latest work, the research team uncovered that chromatin fragments exit the nucleus through a process termed "nuclear egress".
Nuclear egress represents a specialized membrane trafficking mechanism: the inner nuclear membrane buds inward to form vesicles enclosing large cargoes, which subsequently fuse with the outer nuclear membrane to release cargo into the cytoplasm. This pathway specializes in transporting cargo too large in size or structure to pass through the nuclear pore complex.
The team demonstrated that inactivation of key nuclear egress proteins (the ESCRT-III complex or Torsin complex) traps chromatin fragments at the nuclear envelope, suppressing activation of the cGAS-STING pathway as well as senescence-associated inflammation. Glucose restriction or metformin treatment inhibits the ESCRT-III component ALIX via AMPK-dependent phosphorylation and autophagic degradation pathways, consequently blocking CCF formation.
The researchers further validated these findings in aged mouse models. The results show that metformin treatment markedly reduces ALIX expression in intestinal tissues, lowers CCF levels, and alleviates cGAS-mediated inflammatory responses.
Collectively, this study identifies a novel molecular mechanism bridging metabolism and inflammation, and puts forward a therapeutic strategy targeting nuclear egress of chromatin fragments to inhibit age-related inflammation.
