PROGRAM & ABSTRACTS - Wisconsin Union - University of ...

Aging, Metabolism, Stress, Pathogenesis, and Small RNAs in C. elegans Topic Meeting 2012
Metformin increases C. elegans lifespan by altering E. coli folate
metabolism
Filipe Cabreiro 1 , Catherine Au 1 , Kit-Yi Leung 2 , Nick Greene 2 , David Gems 1
1 Institute of Healthy Ageing, University College London, London, UK, 2 Institute of
Child Health, University College London, London, UK
Metformin is the most widely prescribed drug for type II diabetes, and also increases
lifespan in C. elegans and rodents, possibly by inducing a dietary restriction-like state. Worms
are co-cultured with E. coli, which exerts complex nutritional and pathogenic effects on their
host/predator affecting lifespan. In mammals, intestinal microbiota mediates effects of nutrition
on host metabolic status, and risk of metabolic disease. We are investigating how metformin
acts to increase worm lifespan and, perhaps, ameliorate metabolic disease. In the absence
of E. coli, or on UV-irradiated or metformin-resistant E. coli, this drug only shortens lifespan.
Moreover, using a range of E. coli strains, effects of metformin on worm lifespan correlate
positively with its inhibitory effect on bacterial growth. This implies that E. coli mediates effects
of metformin on worm lifespan. Metformin inhibits E. coli growth by impairing folate metabolism
via a so-called “methyl trap” involving methionine synthase inhibition. Metformin effects on worm
lifespan are phenocopied by the dihydrofolate reductase inhibitor trimethoprim (an antibiotic),
but are independent of effects on bacterial proliferation. Thus, metformin has two effects on
adult worms: a direct, life-shortening one (probably reflecting drug toxicity), and an indirect,
life-extending effect promoted by bacterial metabolic alteration. The latter is mediated in the
worm by a metabolic sensing pathway controlling the S-adenosyl-methionine/S-adenosylhomocysteine
ratio. Life-extending effects of metformin involve sams-1 (S-adenosyl methionine
synthetase), metr-1 (methionine synthase) and aak-2 (AMP-activated protein kinase). skn-1
(homologous to mammalian Nrf2) and aak-2 also mediate the life-extending effects of metformin
by protecting against drug toxicity. Consistent with this, the latter two mutants are hypersensitive
to developmental retardation by metformin. Finally, elevated glucose, a risk factor for metabolic
disease, abolishes life extension by metformin. In humans, side effects of metformin include
gastrointestinal upset and folate deficiency. This, with our findings, suggests evolutionarily
conserved bacterial mediation of metformin effects on host metabolism, and the therapeutic
power of manipulating intestinal microbiota to assure metabolic health.
Contact: F.cabreiro@ucl.ac.uk
Lab: Gems
2
Session 1