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After combing through 40,000 genes from three different organisms, scientists have identified 30 that have a big effect on aging and lifespan. Influence only one of the 30 genes and the animals stay healthier and live longer.

Although they are found in different organisms, these so-called orthologous genes are closely related to each other—and they are all found in humans, too.

In order to detect these genes, the researchers examined around 40,000 genes in the nematode C. elegans, zebrafish, and mice. By screening them, the scientists wanted to determine which genes are regulated in an identical manner in all three organisms during each comparable aging stage: young, mature, and old.

As a measure of gene activity, the researchers measured the amount of messenger RNA (mRNA) molecules found in the cells of these animals. mRNA is the transcript of a gene and the blueprint of a protein. When there are many copies of an mRNA of a specific gene, it is very active; the gene is upregulated.

Fewer mRNA copies, to the contrary, are regarded as a sign of low activity, explains Michael Ristow, coordinating author of the study published in Nature Communications and a professor of energy metabolism at ETH Zurich.

Ristow and colleagues used statistical models to establish an intersection of genes that were regulated in the same manner in the worms, fish, and mice. They found only 30 genes in common that significantly influence the aging process.

One gene stands out

By conducting experiments in which the mRNA of the corresponding genes were selectively blocked, the researchers pinpointed their effect on the aging process in nematodes. With a dozen of these genes, blocking them extended lifespan.

One of these genes proved to be particularly influential: the bcat-1 gene. “When we blocked the effect of this gene, it significantly extended the mean lifespan of the nematode by up to 25 percent,” says Ristow.

The researchers were also able to explain how this gene works: The bcat-1 gene carries the code for the enzyme of the same name, which degrades branched-chain amino acids. Naturally occurring in food protein building blocks, these include the amino acids L-leucine, L-isoleucine, and L-valine.

When the researchers inhibited the gene activity of bcat-1, the branched-chain amino acids accumulated in the tissue, triggering a molecular signaling cascade that increased longevity in the nematodes—and extended the amount of time the worm stayed healthy.

As a measure of vitality, the researchers measured the accumulation of aging pigments, the speed at which the creatures moved, and how often the nematodes successfully reproduced. All of these parameters improved when the scientists inhibited the activity of the bcat-1 gene.

The scientists also achieved a life-extending effect when they mixed the three branched-chain amino acids into the nematodes’ food. However, the effect was generally less pronounced because the bcat-1 gene was still active, which meant that the amino acids continued to be degraded and their life-extending effects could not develop as effectively.

Ristow plans a follow-up study to determine if the same mechanism occurs in humans.

“We looked only for the genes that are conserved in evolution and therefore exist in all organisms, including humans,” he says.

Source: ETH Zurich