The hypoxic response (the way in which cells respond to low oxygen levels) can be beneficially manipulated to produce a number of positive results, such as triggering cells to work harder to remove a buildup of damaging biochemicals. Now it seems that this signaling system is also involved in calorie restriction, and may be the cause of some fraction of the resulting health and longevity benefits: "HIF-1 (hypoxia-inducible factor 1) [helps] cells survive by 'turning on' when oxygen levels are low. ... [scientists] have shown that HIF-1 is also a key player in dietary restriction. HIF-1 is involved in a molecular pathway known to regulate cell growth and metabolism in response to nutrients and growth factors. ... the molecular mechanisms involved in how dietary restriction slows cancer and extends lifespan have been largely unknown. ... This study gets us closer to understanding that process and gives us better targets for both designing and testing drugs which could mimic the effects of dietary restriction in humans ... The research involved nematode worms that were genetically altered to both under and over-express HIF-1. The animals, which are the most-often used model to study aging, were fed different diets. Animals that were designed to over-express HIF-1 did not get the benefit of lifespan extension even though their diets were restricted. Animals that under-expressed HIF-1 lived longer, even when they had a nutrient-rich diet."