Intestinal permeability (zonulin, leaky gut)

Intestinal permeability is the regulated passage of molecules between the cells lining your gut. It is controlled by 'tight junction' complexes (claudins, occludin, ZO-1, and junctional adhesion molecules) that seal the gaps between gut cells. When permeability rises too much ('leaky gut'), bacterial endotoxin (LPS) can slip into your bloodstream. That triggers a TLR4-driven 'endotoxemia' and a release of cytokines (IL-1β, IL-6, TNF-α) linked to inflammaging. Zonulin (identified as prehaptoglobin-2) is the only known natural tight-junction opener. Signals like gluten's gliadin, or bacteria, set off a cascade. It runs through CXCR3, EGFR (via PAR2), and PKCα. The result loosens ZO-1 and rearranges the cell's scaffolding. In healthy aging, one study is telling (Qi et al., 2017, 37 people). It found serum zonulin about 22% higher in older versus younger adults, correlated with TNF-α and IL-6. That fits barrier decline as part of the inflammaging loop. The functional gold-standard test is the urinary lactulose-mannitol ratio. It compares lactulose (which should be blocked) against mannitol (freely absorbed), over a 2.5-to-4-hour collection. But beware a big caveat about commercial zonulin blood tests. Two studies (Scheffler et al., 2018; Ajamian et al., 2019) showed a problem. The widely used kits actually detect other proteins (complement C3 and properdin), not prehaptoglobin-2. And intervention data for barrier-targeted strategies (prebiotics, short-chain fatty acids, dietary exclusion) are limited to small trials. No agent is approved for longevity as of 2026.

Last reviewed: June 22, 2026

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