The biguanide drugs metformin and phenformin have been used to treat type 2 diabetes since the 1950s. Metformin can also extend lifespan in worms1 and in short-lived mice2. Biguanides activate AMP-dependent kinase (AMPK), but their exact mode of action remains unclear. One possibility is that they might affect mammalian physiology via their effects on intestinal microbiota. Notably, metformin causes gastrointestinal upset. We are studying the role of E. coli, which plays a dual role as the worm's food source and microbiota3, in effects of biguanides on lifespan. Phenformin is active in humans at lower concentrations than metformin, and we find the same to be true of its effects on worm lifespan. For both drugs, the concentrations optimal for life extension on E. coli OP50 also retard bacterial growth. By contrast, E. coli HT115 are resistant to such growth inhibition, and on this strain metformin does not increase worm lifespan. Moreover, on UV-irradiated OP50 metformin does not extend lifespan either. This suggests that E. coli mediate the effects of metformin on worm lifespan. In the absence of E. coli, metformin only shortens lifespan, suggesting drug toxicity. Metformin increases lifespan in
daf-16 but not
aak-2 or
skn-1 mutants, perhaps because AMPK and SKN-1 protect against metformin toxicity. Consistent with this, larval development in
aak-2 but not
daf-16 mutants was retarded by metformin (50mM, the optimal dose for life extension). Thus, metformin seems to have a dual effect on C. elegans, extending lifespan via their effect on E. coli, and shortening lifespan via their direct effect on the worm. How do biguanides affect E. coli to increase worm lifespan? One possibility is that they reduce E. coli pathogenicity. However, metformin does not increase lifespan in the cilium structure mutants
che-3,
daf-10 and
osm-5. This could suggest that metformin increases lifespan by changing perceived food quality; moreover, metabolic defects in E. coli can increase worm lifespan. Thus, effects of biguanides on the metabolic status of the worm's E. coli microbiota may increase its lifespan. In fruitflies, metformin treatment activates AMPK and disturbs gut microbiota but does not increase lifespan. One possibility is that flies' microbiota do not influence their lifespan. Alternatively, concentrations of metformin high enough to sufficiently alter microbiota may not outweigh direct toxicity to the fly, as is the case in C. elegans cultured on E. coli HT115. 1. PLoS One 5 (2010). 2. Cell Cycle 7, 2769 (2008). 3. J. Gerontol. 63, 2422 (2008).