Team Prolongs 'Young Adult' State in Worms

By Madeline McCurry-Schmidt

A new study led by scientists at The Scripps Research Institute (TSRI) shows that an antidepressant drug, called mianserin, can extend the “young adult” state in roundworms, a common model of aging.

While it is too soon to know whether the treatment has any effect in humans, the study reveals a new metric to track aging—one that can reveal troubling age-associated changes relatively early in life.

“We think it is exciting to see that extending lifespan by extending young adulthood can be done at all,” said biologist Michael Petrascheck of TSRI.

In the study, published today in the journal eLife, the researchers administered mianserin to Caenorhabditis elegans, a type of roundworm with a typical lifespan of 21 days. The research built on the 2007 discovery that mianserin increases the lifespan of roundworms up to 40 percent.

“We wanted to follow-up and study how this drug extends lifespan,” said Petrascheck.

The researchers treated thousands of worms with either water or mianserin and looked at the activity of genes as the worms aged. The team observed surprising changes in gene expression. Groups of genes with similar functions were found to change expression in opposing directions. In metabolism, for example, some gene expression increased while other genes slowed down.

Interestingly, these shifts could be tracked reliably as the worms aged, giving researchers a new way to predict the lifespan of a worm, even if the worm was still an adolescent.

The researchers called this phenomenon “transcriptional drift.” By examining data from mice and from 32 humans, aged 26 to 106 years, they confirmed that the phenomenon also occurs in mammals.

“We now have a reliable measuring tape in our tool box to study aging,” said study first author Sunitha Rangaraju, a senior research associate at TSRI.

Instead of tracking aging by waiting to see when an organism dies, researchers could track transcriptional drift to see when age-related changes occur in an organism’s lifespan. “Having a new tool to study aging could help us make new discoveries, for example, to understand genetic predispositions where aging starts earlier, such as Hutchinson-Gilford progeria syndrome,” said Rangaraju.

This new metric revealed that treatment with mianserin can suppress transcriptional drift, but only when administered early on. By intervening with mianserin on their first day of life, the researchers could prolong a worm’s lifespan by 7 to 8 days. By tracking transcriptional drift, they found that they were specifically extending the duration of the worms’ young adulthood. In fact, mianserin-treated ten-day-old worms had the transcriptional drift of three-day-old worms, thus prolonging the period of young adulthood by more than 3 fold.

Subsequent studies showed that the treatment could only pause aging, not reverse it. Treating the worms at day three showed only a small extension of lifespan, and treatment on day five showed no effect.

“If you add the drug early, you preserve a youthful gene expression pattern,” said Petrascheck. “But if you add it too late, the damage is already done.”

The findings suggest that mianserin blocks signals related to the regulation of serotonin, and this delays physiological changes associated with age—including transcriptional drift and degenerative processes that lead to death.

A next step for the team will be to test the effect in mice and to investigate whether there are any side effects to the mianserin treatment.

“We don’t want people to get the impression they can take the drug we used in our study to extend their own teens or early twenties,” added Petrascheck. “We may have done this in worms, but there are millions of years of evolution between worms and humans.”

In addition to Petrascheck and Rangaraju, authors of the study, “Suppression of Transcriptional Drift Extends C. elegans Lifespan by Postponing the Onset of Mortality,” were Gregory M. Solis, Ryan C. Thompson, Rafael L. Gomez-Amaro, Sandra E. Encalada and Daniel R. Salomon of TSRI; Leo Kurian of the University of Cologne; and Alexander B. Niculescu of the Indiana University School of Medicine, formerly of TSRI. See http://dx.doi.org/10.7554/eLife.08833

The study was supported by the National Institutes of Health (grant DP2 OD008398), The Ellison Medical foundation (grants AG-NS-0928-12 and AG-NS-0950-1), an MDA Development Grant, a National Science Foundation GRFP Fellowship and a Baxter Foundation Young Faculty Award. Some resources were provided by Shigen-Japan or the CGC, which is funded by National Institutes of Health Office of Research Infrastructure Programs (grant P40 OD010440).

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