The host-microbe-metformin interplay in the aged gut

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ABSTRACT The three main aims expected from the anti-aging drugs are-“healthspan,” “rejuvenation,” and “longevity.” Metformin is one such drug, tested in clinical trials and are propagated to fulfill one or even all of the promises of anti-aging drugs. Metformin is not only the best drug in lowering the blood glucose level in the treatment of type 2 diabetes, but it can modulate age-related changes in innate immunity, chronic diseases including cancers and infections. Metformin can alter the gut microbiota that leads to the improvement of metabolic parameters, including obesity and insulin resistance. During the aging process, changes in gut microbiota composition occur, such as decreased diversity, a decrease in health-promoting bacteria and an increase in potential pathobionts. This disturbed balance in microbiota composition increases the risk of impaired intestinal barrier function and inflammation linked to age-associated chronic diseases. Gut-barrier dysfunction may be a pivotal driver of an unhealthy aging-low level of inflammation and inflammaging. However, knowledge of mechanism(s) that might reinforce the inflammaging is incomplete; the physical and immunological properties of the human microbiome and gut barrier during aging are largely unknown. Although an array of the potential role of metformin’s beneficial action has been proposed, the underlying mechanisms to use metformin as an anti-aging drug is still less clear. We have recently identified that metformin activates the specialized stress- polarity signaling (SPS) pathway with the AMPK-GIV axis, which fortifies epithelial tight junctions [TJs] against stress-induced collapse. The phosphorylation of GIV by AMP-activated kinase [AMPK] could act as a biomarker for chronic diseases and appears to be necessary and sufficient for the barrier-protective functions of the SPS-pathway. Using the colonic organoid-based model, we have identified that metformin activates the SPS-pathway in the colon epithelium in an AMPK-dependent manner and reinforces the gut barrier following an attack with microbial stressors. In the aged gut, the barrier is ‘broken,’ the SPS-pathway is suppressed; and metformin can restore the TJ integrity. Based on the preliminary studies, we have hypothesized that the SPS- pathway can be targeted by metformin to restore the compromised epithelial barrier in the aging gut, to reduce inflammation and to restore the levels of the aging-related proteins sirtuins (SIRTs). Using monolayers generated from murine and human gut-derived enteroids from the young and old, we will assess, the effect of age-related microbes and metformin on intestinal epithelial cell junction and inflammation (Aim1); determine the impact of metformin on cellular senescence and oxidative stress in the aged gut (Aim2); determine the protective effect of metformin on chronic inflammation using gut-in-a-dish model with microbe-epithelial and immune cells (Aim3). The insights gained are expected to develop an entirely new strategy to tackle aging by targeting the gut through activation of a specialized pathway by metformin in conjunction with probiotics, prebiotics or dietary components, with an ultimate intent to promote healthy aging.