New Problems in Nematode Life Span Studies
Researchers have uncovered a new way in which many past studies of extended life span in nematode worms have been distorted by a part of the experimental process. This isn't the first time this has happened in recent years. The metabolic processes and life spans of short-lived species are very plastic in response to all sorts of circumstances, and thus smaller effects are easier to produce, intentionally and otherwise. As a general rule these effects are irrelevant to longer-lived species, where life span is much less plastic. Even large extension of life in short-lived species via methods of metabolic alteration that have also been tried in humans, such as calorie restriction or growth hormone receptor loss of function, have no such matching effect in humans.
In matters of the fundamental molecular biology of aging, we mammals are not so different from tiny C. elegans worms. Some of the biggest differences only serve to make them convenient research models. But one distinction - their ability to asexually reproduce exact copies of themselves - may have led to many research discrepancies. The reason, according to a new study, is that the drug scientists use prevent such confusing reproduction turns out to help aging worms rebound from stress, thereby significantly lengthening their lifespan in some cases. In the study researchers identify the human chemotherapy drug FUdR as the culprit. Their detailed experiments show that the drug goes well beyond squelching worm reproduction. It also triggers stress response and turns on DNA repair pathways (that are also found in mammals) that allow the worms to better endure adverse conditions such as saltiness, heat, or low oxygen."We can explain a lot of the disagreement in the C. elegans aging field by realizing that FuDR can dramatically change the answer. There were very different effects in published papers that had different doses of FUdR in them. Sometimes it's a very profound disagreement." Moreover, some other studies may involve FUdR-related discrepancies but insufficient documentation of the methods prevented researchers from being sure.
In the absence of any stress, FUdR makes no difference to lifespan in normal worms, they confirmed. But when worms were exposed to a modest concentration of salt, animals who were not exposed to FUdR had only half the lifespan of those who were exposed to the drug. Meanwhile, adding even more FUdR caused even longer lifespan under salt stress. A tenfold increase in FUdR concentration extended lifespan by a factor of three. Other experiments suggested that FUdR causes better stress resistance in hot or low-oxygen conditions. Further research revealed details of how FUdR protects the worms from stress. They found evidence that the drug turns on the gene that produces the protein FOXO, a master regulator of stress resistance in many organisms that is often central in longevity studies. They also found that exposure to FUdR forced DNA mutations that then activated a DNA-repair process. That process, once activated, also fixes a lot of DNA damage caused by environmental stresses, including dreaded double-strand breaks, a clean severing of the DNA molecule.