Metformin, as the first-line oral drug for type 2 diabetes, has proven benefits against aging, cancer and cardiovascular diseases. But the influence of metformin to the immune response and its molecular mechanisms remain obscure. Metformin increases resistance to not only the Gram-negative pathogens Pseudomonas aeruginosa and Salmonella enterica but also the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Meanwhile, metformin protects the animals from the infection by enhancing the tolerance to the pathogen infection rather than by reducing the bacterial burden. Through the screening of classical immune pathways in C. elegans, we find metformin enhances innate immunity through p38 MAPK pathway. Furthermore, activated p38/PMK-1 by metformin acts on the intestine for innate immune response. In addition, metformin-treated mice have increased resistance to P. aeruginosa PA14 infection and significantly increased the levels of active PMK-1. Therefore, promoted p38/PMK-1-mediated innate immunity by metformin is conserved from worms to mammals. Our work provides a conserved mechanism by which metformin enhances immune response and boosts its therapeutic application in the treatment of pathogen infection.

Metformin, a widely prescribed first‐line drug for the treatment of type II diabetes mellitus, has been shown to extend lifespan and delay the onset of age‐related diseases. The precisely mechanisms by which these effects are realized remain elusive. We find that metformin exposure is restricted to adults, which is sufficient to extend lifespan. However, limiting metformin exposure to the larvae has no significant effect on Caenorhabditis elegans longevity. Here, we show that after metformin treatment, the level of S‐adenosylmethionine (SAM) is reduced in adults but not in the larvae. Potential mechanisms by which reduced SAM might increase lifespan include altering the histone methylation. However, the molecular connections between metformin, SAM limitation, methyltransferases, and healthspan‐associated phenotypes are unclear. Through genetic screening of C. elegans, we find that metformin promotes the healthspan through an H3K4 methyltransferase/demethylase complex to downregulate the targets, including mTOR and S6 kinase. Thus, our studies provide molecular links between meformin, SAM limitation, histone methylation, and healthspan and elucidate the mode action of metformin‐regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age‐related diseases.

The longevity of an organism is influenced by both genetic and environmental factors. With respect to genetic factors, a significant effort is being made to identify pharmacological agents that extend lifespan by targeting pathways with a defined role in the aging process. Sanguinarine (San) is a benzophenanthridine alkaloid that exerts a broad spectrum of properties. In this study, we utilized Caenorhabditis elegans to examine the mechanisms by which sanguinarine influences aging and innate immunity. We find that 0.2 μM sanguinarine extends healthspan in C. elegans. We further show that sanguinarine generates reactive oxygen species (ROS), which is followed by the activation of PMK-1/SKN-1pathway to extend healthspan. Intriguingly, sanguinarine increases resistance to pathogens by reducing the bacterial burden in the intestine. In addition, we also find that sanguinarine enhances innate immunity through PMK-1/SKN-1 pathway. Our data suggest that sanguinarine may be a viable candidate for the treatment of age-related disorders.

The p38 MAPK pathway, an evolutionarily conserved mechanism, plays a crucial role in defending hosts against bacterial infections in both mammals and nematodes. Activating p38 MAPK signaling has been identified as a promising strategy to strengthen innate immunity and enhance resistance to pathogenic infections across various organisms.Berberine hydrochloride (BH), an isoquinoline alkaloid derived from Coptis, is known for its diverse biological activities, including anticancer, antibacterial, anti-inflammatory, lipid-lowering, and hepatoprotective effects. However, its impact on innate immunity and the associated molecular mechanisms remains unclear. In this study, we discovered that 10 μM Berberine hydrochloride enhanced resistance against both Gram-negative pathogens, such as Pseudomonas aeruginosa, Salmonella enterica and Gram-positive pathogen Listeria monocytogenes. Notably, Berberine hydrochloride improved pathogen resistance by reducing bacterial load in the intestine. Screening of classical innate immune pathways in Caenorhabditis elegans revealed that Berberine hydrochloride conferred protection against infections through the p38 MAPK pathway, specifically by activating p38/PMK-1 signaling in the intestine to bolster innate immunity. Furthermore, Berberine hydrochloride also stimulated innate immunity in mice via the p38 MAPK pathway and significantly reduced bacterial load in the lungs. These findings indicate that Berberine hydrochloride may have therapeutic potential for protecting host from infectious diseases.

The Mammalian/mechanistic target of rapamycin (mTOR) played a central role in cellular survival and aging. Inhibition of mTOR had been proposed as a reasonable strategy to promote lifespan and delay age-related diseases in evolutionarily diverse organisms. The study showed that lifespan extension and age-related diseases improvement could be achieved by targeting evolutionarily conserved mTOR pathways and mechanisms using pharmacological interventions. Using this approach in Caenorhabditis elegans, We found that 2 μM Usnic Acid significantly extended the healthy lifespan in wild-type animals. Furthermore, via genetic screen, we showed that Usnic Acid acted on mTOR, which was followed by the activation of PHA-4/Foxa to extend the healthy lifespan. Intriguingly, Usnic Acid also delayed neurodegeneration diseases such as Alzheimer’s and polyglutamine disease through mTOR-dependent manner. Our work suggested that Usnic Acid might be a viable candidate for the prevention and treatment of aging and age-related diseases.