Intermittent Fasting Extends Life of Liver Cells
Primary human liver cells (PHHs) are crucial for testing harmful drug reactions in human patients. Normally, these cells lose their functions quickly in simple cultures, but when grown with other supportive cells, they last 2-4 weeks. However, since liver cells in the body function for much longer (200-400 days), we want to extend their functional life in the lab to study long-term drug effects and diseases.
Fasting has been shown to improve the health & longevity of tissues like the liver. We thought that mimicking fasting in cell cultures might activate beneficial pathways and extend the life of PHHs. To do this, we periodically removed serum and hormones from a 'micropatterned coculture' of liver cells, which is a special arrangement of liver cells surrounded by connective tissue cells (fibroblasts) for support. A weekly 2-day starvation period extended the life of PHHs to over 6 weeks, compared to just 3 weeks without fasting. This fasting also improved the function of simpler 'monoculture' liver cells for 2 weeks.
In the 'micropatterned cocultures', fasting activated a key energy-regulating protein called AMPK and prevented the supportive fibroblast cells from overgrowing, helping maintain liver cell structure (polarity). Similar benefits were seen when we activated AMPK with a drug called metformin or stopped the growth of supportive cells with another drug, mitomycin-C.
Finally, liver cells in the fasting cultures were better at predicting drug toxicity and had higher drug-processing activities even after 5 weeks. In summary, intermittent fasting in cell cultures extends the functional life of liver cells, making them more useful for drug testing.
Publication >> Intermittent Starvation Extends the Functional Lifetime of Primary Human Hepatocyte Cultures
