Long-life roundworms help identify new anti-aging compounds among FDA-approved drugs

Researchers from Gero, the Institute of Science and Technology Skolkovo (Skoltech), the Institute of Physics and Technology of Moscow (MIPT) and the University of 39, Arkansas for Medical Sciences (UAMS) collaborated to obtain a transcriptomic signature of aging, which they confirmed by extensive transcriptomic analysis. data base. They discovered that nematode aging is partially programmed and that it can be therapeutically reversed by a number of FDA-approved drugs. The study is published in Scientific reports.

C.elegans, a non-parasitic roundworm, is one of the most studied animals on the planet. His genome was the first to be sequenced among multicellular organisms; each of its nearly one thousand cells has been characterized by biologists. These nematodes normally have a short life span of 15 to 25 days, making them a convenient model organism for aging studies. However, their lifespan can be almost multiplied by ten by introducing a mutation into a single gene. The details remained unanswered, as to how such a dramatic intervention affects gene expression and aging to achieve this extension, and whether it can be imitated therapeutically, ideally with drugs already approved for human use.

To answer this question, an international team of researchers led by Peter Fedichev, founder of start-up Gero, a biotechnology company for longevity, has requested data on the activity of nematode genes having a wide variety lifetimes, at different ages. UAMS researchers created the necessary strains (mutant worms in a constant and normal context) as well as wild-type normal worms after deletion of the selected target genes and evaluated their expression profile at different ages. .

Gero / Skoltech / MIPT scientists then used machine learning techniques to analyze these experimental results and compare them with previous data available on the public fund. The cost of the resulting dataset, called MetaWorm, is close to $ 10 million and is a perfect example of scientific "data recycling". Through analysis of the unique MetaWorm dataset, they have confirmed and extended the structure of transcriptomic changes that accompany nematode aging.

"Our main concern was that aging in an extremely live worm could be totally different from that of normal wild type nematodes, in which case the drastic lengthening of the lifespan would require complex interventions and studies on animals with dramatically slower aging would not help us in our quest for a truly effective anti-aging treatment, "says Peter Fedichev, lead investigator of the Gero / Skoltech / MIPT group.

It has been shown that at the molecular level, the aging process in nematodes is always the same and that all differences in life expectancy appear to reflect changes in the aging rate. The researchers proposed that similar effects are achievable without genetic intervention. To test this hypothesis, researchers used the connectivity map (CMAP) created by scientists from the Broad Institute of MIT and Harvard. The CMAP contains information on the effect of almost all FDA-approved drugs on the activity of genes in human cells. The researchers searched for drugs that modify the expression of human genes to counter the age-related changes observed for the corresponding nematode genes.

Of the 1309 drugs in the CMAP database, the researchers chose 10 candidates that appear to act on the genes in the desired direction. Six of these drugs had been previously documented for anti-aging potential, while four of the preselected drugs had never been studied before in this context. Experience has shown that all these drugs slow the aging of nematodes, to varying degrees however. The most effective compound prolonged the life of nematodes by 30%.

"This study has had several practical implications for aging research and the growing longevity sector.First, we have demonstrated that nematode aging is partially programmed and can be therapeutically modified. Other multicellular organisms, including humans, have proposed a new method of looking for life-prolonging compounds The usual procedure involves the laborious screening of large potential drug banks Unfortunately, even positive results are sometimes overlooked by chance or due to a suboptimal dosage.Our method allows targeted research of compounds with required activity, including FDA approved drugs.These have the advantage that 39, they have already passed all necessary clinical trials and that they can be used as medicine It's anti-aging, "said Andrei Tarkhov, researcher at Gero. and a Ph.D. candidate at the Skolkovo Institute of Science and Technology.

Robert Shmookler Reis, head of the UAMS team, pointed out how amazing these results were. "Previous studies on pharmacologically active compounds had revealed that less than one in 20 drugs was able to prolong the life span of C. elegans, which contrasts sharply with our observation on the lengthening of the duration of 4 out of 4 drugs for which no prior aging data existed, this is conclusive proof that the aging expression profile must be preserved from nematodes to humans and that it's probably fundamental for all animals. "