Scientists Find the Hidden Link Between Metabolism and Aging—And It Involves a Diabetes Drug

Scientists have discovered a crucial mechanism connecting metabolism to aging inflammation, revealing why the diabetes drug metformin might help slow the aging process. The breakthrough research shows that fragments of DNA escaping from cell nuclei trigger chronic inflammation that accelerates aging, but metabolic interventions can block this harmful pathway.

The study, published in Nature Aging, identifies how cytoplasmic chromatin fragments (CCFs)—pieces of DNA that leak from the cell's nucleus—drive the persistent, low-grade inflammation associated with aging. These DNA fragments are too large to pass through normal nuclear pores, so researchers investigated how they actually escape to cause trouble in the cytoplasm.

How Do DNA Fragments Escape the Nucleus to Cause Aging?

The research team discovered that chromatin fragments exit the nucleus through a process called nuclear egress, which normally helps shuttle large molecular complexes across the nuclear envelope. This process involves two key protein systems: the ESCRT-III complex and the Torsin complex, which work together to transport materials out of the nucleus.

When researchers blocked these nuclear egress proteins in laboratory studies, they successfully trapped the DNA fragments at the nuclear membrane. This prevented the activation of the cGAS-STING pathway, a cellular alarm system that triggers inflammation when it detects foreign DNA in the cytoplasm.

What Role Does Metformin Play in Healthy Aging?

The most exciting discovery involves how metabolic interventions can interrupt this aging pathway. The researchers found that glucose limitation or treatment with metformin—a common diabetes medication—significantly reduces the formation of these harmful DNA fragments.

Metformin works by activating AMPK (AMP-activated protein kinase), often called the body's "metabolic master switch." When activated, AMPK triggers a process that degrades ALIX, a component of the ESCRT-III system responsible for nuclear egress. Without functional ALIX, fewer DNA fragments can escape the nucleus to trigger inflammation.

In studies with aged mice, metformin treatment reduced several key markers of aging inflammation in the intestine:

• ALIX Levels: Significant reduction in the protein that helps DNA fragments escape the nucleus
• DNA Fragment Formation: Fewer cytoplasmic chromatin fragments were detected in treated animals
• Inflammatory Signaling: Decreased activation of the cGAS-mediated inflammation pathway that contributes to aging

The research provides a molecular explanation for why metformin, beyond its diabetes benefits, has shown promise in longevity studies. By targeting the nuclear egress of DNA fragments, the drug may help suppress age-associated inflammation at its source rather than just treating the symptoms.

This discovery opens new possibilities for anti-aging interventions. Rather than broadly suppressing inflammation, future treatments could specifically target the nuclear egress machinery to prevent inflammatory DNA fragments from escaping in the first place. The researchers suggest this approach could be more effective than current strategies for managing age-related inflammation and its associated diseases.