Metformin, a biguanide drug commonly used to treat type-2 diabetes, has been noted to extend healthspan of non-diabetic mice, but this outcome, and the molecular mechanisms that underlie it, have received relatively little experimental attention. To develop a genetic model for study of biguanide effects on healthspan, we investigated metformin impact on aging C. elegans. We find that metformin increases nematode healthspan, slowing lipofuscin accumulation and extending median lifespan and youthful locomotory ability in a dose-dependent manner. Genetic data suggest that metformin acts through a mechanism similar to that operative in eating-impaired dietary restriction mutants, but independent of the insulin signaling pathway. Energy sensor AMPK and AMPK-activating kinase LKB1, which are activated in mammals by metformin treatment, are essential for health benefits in C. elegans, suggesting that metformin engages a metabolic loop conserved across phyla. We also show that the conserved oxidative stress-responsive transcription factor SKN-1/Nrf2 is essential for metformin healthspan benefits, a mechanistic requirement not previously described in mammals. skn-1, which functions in nematode sensory neurons to promote DR longevity benefits and in intestine for oxidative stress resistance lifespan benefit, must be present in both neurons and intestine for metformin-promoted healthspan extension, indicating that metformin improves healthy middle-aging by activating both DR and anti-oxidant defense longevity pathways. In addition to defining molecular players operative in metformin healthspan benefits, our data support that metformin may be a plausible pharmacological intervention to promote healthy human aging. Metformin has been proposed to promote DR metabolism by controlling flux through the glycolytic pathway. In keeping with this, we find a striking concentration of candidate DR inductions consequent to manipulations of the glycolytic/gluconeogenic components of metabolism. We show that disruption of glycolytic and gluconeogenic genes impacts lipofuscin accumulation, and our results suggest differential regulation of healthspan/lifespan by glycolytic and gluconeogenic pathway components. Overall, our findings identify new potential points for pharmacological induction of DR via these two metabolic processes.