Worm Study May Resolve Discrepancies in Research About Aging

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 Brown University-led 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 in Mechanics of Ageing and Development, neuroscience Professor Anne Hart, lead author Edward Anderson and colleagues 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,” Hart said.

Reviewing dozens of studies with discordant findings across many genetic models of worm longevity, Anderson found that a consistent difference-maker was using FUdR.

“There were very different effects in published papers that had different doses of FUdR in them,” said Anderson, formerly a technician in Hart’s lab and now a biology graduate student at Brown. “Sometimes it’s a very profound disagreement.”

Moreover, some other studies may involve FUdR-related discrepancies but insufficient documentation of the methods prevented Anderson from being sure.

An instructive mistake

One of the first studies Anderson examined was a mysterious one from within the Hart lab that had employed FUdR in the conventional way for an aging study, leading to results they couldn’t reconcile with published results.

“We didn’t expect to have this happen,” Hart said. “We decided to figure out what was going on.”

They started to suspect FuDR might be the difference. Studies were beginning to enter the scientific literature – and rumors were welling up at conferences – suggesting it might affect more than just reproduction in worms.

To truly prove it or rule it out, they began a series of experiments testing FUdR’s effects in the worms and found that rather than simplifying their experiments on worm longevity, the drug was indeed dramatically changing their results.

Image shows a C. elegans.
The C. elegans worm serves as a useful model in aging studies, including a new one that reveals the unintended role of a drug. Credit: Anne Hart/Brown University.

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.

Time to retire FUdR?

While many scientists in the biology of aging field may now find it helpful to reconcile disparate results of the past, Hart said, the new findings should also give them pause about continuing to use FUdR in the future.

It’s now clear that the drug has high potential to confound aging studies, the authors wrote. If it’s to be used at all, then it’s important for scientists in their published research to be very clear about if it was used and to state the genetic lines of worms and experimental conditions of the research.

But, it may be best not to use it at all, they wrote.

About this genetics and aging research

In addition to Anderson and Hart, the paper’s other authors are Mark Corkins, Jia-Cheng Li, Komudi Singh, Sade Parsons, Tim Tucey, Altar Sorkac, Huiyan Huang, Maria Dimitriadi, and David Sinclair.

Funding: The Ellison Medical Foundation and the National Institutes of Health funded the study (R01GM78171, R01NS055813, P01NS66888).

Source: David Orenstein – Brown University
Image Source: The image is credited to Anne Hart/Brown University.
Original Research: Abstract for “C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins” by Edward N. Anderson, Mark E. Corkins, Jia-Cheng Li, Komudi Singh, Sadé Parsons, Tim M. Tucey, Altar Sorkaç, Huiyan Huang, Maria Dimitriadi, David A. Sinclair, and Anne C. Hart in Mechanisms of Ageing and Development. Published online February 2016 doi:10.1016/j.mad.2016.01.004


Abstract

C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins

Moderate stress can increase lifespan by hormesis, a beneficial low-level induction of stress response pathways. 5′-fluorodeoxyuridine (FUdR) is commonly used to sterilize Caenorhabditis elegans in aging experiments. However, FUdR alters lifespan in some genotypes and induces resistance to thermal and proteotoxic stress. We report that hypertonic stress in combination with FUdR treatment or inhibition of the FUdR target thymidylate synthase, TYMS-1, extends C. elegans lifespan by up to 30%. By contrast, in the absence of FUdR, hypertonic stress decreases lifespan. Adaptation to hypertonic stress requires diminished Notch signaling and loss of Notch co-ligands leads to lifespan extension only in combination with FUdR. Either FUdR treatment or TYMS-1 loss induced resistance to acute hypertonic stress, anoxia, and thermal stress. FUdR treatment increased expression of DAF-16 FOXO and the osmolyte biosynthesis enzyme GPDH-1. FUdR-induced hypertonic stress resistance was partially dependent on sirtuins and base excision repair (BER) pathways, while FUdR-induced lifespan extension under hypertonic stress conditions requires DAF-16, BER, and sirtuin function. Combined, these results demonstrate that FUdR, through inhibition of TYMS-1, activates stress response pathways in somatic tissues to confer hormetic resistance to acute and chronic stress. C. elegans lifespan studies using FUdR may need re-interpretation in light of this work.

C. elegans lifespan extension by osmotic stress requires FUdR, base excision repair, FOXO, and sirtuins” by Edward N. Anderson, Mark E. Corkins, Jia-Cheng Li, Komudi Singh, Sadé Parsons, Tim M. Tucey, Altar Sorkaç, Huiyan Huang, Maria Dimitriadi, David A. Sinclair, and Anne C. Hart in Mechanisms of Ageing and Development. Published online February 2016 doi:10.1016/j.mad.2016.01.004

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