In Caenorhabditis elegans, adding excess glucose to the growth medium shortens lifespan [1, 2, 3], while inhibiting the glycolytic enzyme hexokinase with the glucose analog 2-deoxyglucose increases lifespan [1]. We have shown that disrupting genes encoding two other glycolytic enzymes that catalyze unidirectional, irreversible reactions in glycolysis lengthens C. elegans median lifespan, induces large gains in youthful locomotory ability, and triggers a fluorescent biomarker that distinguishes a healthy metabolic state. Conversely, disrupting counterpart unidirectional gluconeogenic genes decreases nematode healthspan. In investigating potential longevity-related pathways that might impinge upon glucose metabolism, we found that disrupting glycolytic genes increases healthspan through the FOXO transcription factor DAF-16, which is also required for the increased lifespan seen with lowered levels of insulin signaling, and which is downregulated by increased glucose availability [2]. Strikingly, we also found that gluconeogenic activity is specifically required for increased healthspan under dietary restriction, and that the SKN-1 transcription factor, which is required for the beneficial effects of dietary restriction [4], is also needed for the healthspan effects seen with decreased gluconeogenesis. In addition, we found that a transcriptional reporter for gluconeogenic gene
pck-2 is induced by several dietary restriction regimens in a SKN-1-dependent manner. These results provide evidence for an intriguing new paradigm: breakdown of glucose via glycolysis negatively impacts healthy aging through insulin signaling and DAF-16, while dietary restriction engages the reciprocal gluconeogenic pathway to promote healthspan via SKN-1. Our observations support that healthspan might be optimized via dietary, pharmacological, or genetic interventions that increase gluconeogenic activity or decrease glycolysis. 1. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, et al. (2007). Cell Metab 6: 280-293. 2. Lee SJ, Murphy CT, Kenyon C (2009). Cell Metab 10: 379-391. 3. Schlotterer A, et al. (2009). Diabetes 58: 2450-2456. 4. Bishop NA, Guarente L (2007). Nature 447: 545-549.