Exercise has been identified as a powerful maintenance promoter, with anti-cancer, anti-diabetes, anti-sarcopenia, anti-cognitive decline, and possibly pro-immune consequences in humans. Nonetheless, the molecular, cellular, and systems-wide changes by which exercise extends healthspan remain poorly understood, limiting exploitation of molecular exercise pathways for therapeutic application. We have developed a swim training regimen for the nematode Caenorhabditis elegans. Adult and juvenile worms "exercised" by swimming in M9 on successive days exhibit an exercise benefit, as measured by CELEST swimming analysis software developed by Dr. C. Restif together with the Driscoll lab. We show that like in mammals, exercise can increase physical performance after repeat training, exercise benefits diminish if training is stopped, and too much exercise is deleterious. Importantly, two independent mutants for
aak-2, a conserved subunit of an AMP kinase homologue that acts upstream of the transcriptional activator PGC-1a to increase mitochondrial density in response to physical activity in higher organisms, do not gain a training benefit, even though they swim train like wild type worms. We have also found that increased mitochondrial biogenesis is associated with improved swimming prowess. Our data suggest that molecular mechanisms by which C. elegans gain an exercise benefit may be conserved from nematodes to humans. Interestingly, animals that exercise exhibit some systemic health benefits such as extended period of pharyngeal pumping and longer median lifespans. In sum, our results suggest that C. elegans can be used as a model system for elucidating the molecular, cellular, and systems-wide benefits that occur as a consequence of exercise.