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Despite being principally prescribed to treat type 2 diabetes, biguanides, especially metformin and phenformin, have been shown to extend lifespan and healthspan in preclinical models. Although there have been conflicting results in studies involving rodents and humans, consistent evidence indicates metformin and phenformin's ability to significantly extend lifespan in . We find that variation in agar from lot-to-lot or from different manufacturers influences metformin's ability to extend lifespan in diverse species. Using unbiased metabolomics and genetics, we traced the ability of certain agars to interfere with metformin-prompted lifespan extension to differences in glucose, dipeptide, and trace element levels. These compounds act directly in the worm, independently of the bacterial food source, preventing longevity through action downstream of longevity effectors and AMPK. In contrast, phenformin prompts robust lifespan extension in the face of environmental changes and exhibits broad positive effects in aging across genetically diverse species.