Supplementation with brush border enzyme alkaline phosphatase slows aging.

Diminished integrity of the intestinal epithelial barrier with advanced age is believed to contribute to aging-associated dysfunction and pathologies in animals. In mammals, diminished gut integrity contributes to inflammaging, the increase in inflammatory processes observed in old age. Recent work suggests that expression of intestinal alkaline phosphatase (IAP) plays a key role in maintaining gut integrity. IAP expression decreases with increasing age in mice and humans. Absence of IAP leads to liver inflammation and shortened lifespans in mice lacking the IAP gene. In normal mice, exogenous supplemental IAP reverses age-induced barrier dysfunction, improves aging-associated metabolic dysfunction, prevents microbiome dysbiosis (imbalance), and extends lifespan. Consistent with a IAP playing a conserved role in maintaining gut integrity, increased dietary IAP increases aging-diminished physical performance in flies. IAP helps maintain gut integrity in part by supporting the expression of tight junction proteins that maintain the intestinal epithelial barrier and by inactivating bacterial pro-inflammatory factors such as lipopolysaccharides (LPS) by dephosphorylation. Recombinant IAP is in late clinical trials for sepsis-associated acute kidney injury suggesting it may soon become available as a therapeutic. Taken together these reports support the idea that directly increasing IAP levels by supplemental recombinant IAP or by indirectly increasing IAP levels using dietary means to induce endogenous IAP may slow the development of aging-associated pathologies.