Transcriptional control of bcat-1-mediated regulation of lifespan.
Out of a ‘haystack’ of 40,000 genes from 3 different organisms, scientists have found genes involved in physical aging. If you influence only 1 of these genes, the healthy lifespan of lab animals is extended – and possibly that of humans, too.
Until now, this was mostly limited to genes of individual model organisms such as the C. elegans nematode, which revealed that ~1% of its genes could influence life expectancy. However, researchers have long assumed that such genes arose in the course of evolution and in all living beings whose cells have a preserved a nucleus – from yeast to humans.
Researchers at ETH Zurich and JenAge consortium from Jena have now systematically gone through genomes of 3 different organisms in search of the genes associated with the aging process that are present in all 3 species – and thus derived from the genes of a common ancestor. Although they are found in different organisms, 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 40,000 genes in the nematode C. elegans, zebra fish and mice. By screening them, they wanted to determine which genes are regulated in an identical manner in all 3 organisms in each comparable aging stage – young, mature and old; i.e. either are they upregulated or downregulated during aging.
As a measure of gene activity, the researchers measured the amount of messenger RNA (mRNA) molecules found in the cells of these animals. 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. They then used statistical models to establish an intersection of genes that were regulated in the same manner in the worms, fish and mice. This showed that the organisms have only 30 genes in common that significantly influence the aging process.
By conducting experiments in which mRNA of the corresponding genes were selectively blocked, they pinpointed their effect on the aging process in nematodes. With a dozen of these genes, blocking them extended the lifespan by at least 5%. 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%,” says Ristow.
MOA: bcat-1 gene carries the code for the enzyme of the same name, which degrades branched-chain amino acids. including L-leucine, L-isoleucine and L-valine. When they inhibited the gene activity of bcat-1, the branched-chain amino acids accumulated in the tissue, triggering a molecular signalling cascade that increased longevity in the nematodes. Moreover, the timespan during which the worms remained healthy was extended. 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 3 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 has no doubt that 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.
The researchers plan to incorporate various health parameters such as cholesterol or blood sugar levels in their study to obtain indicators on the health status of humans.
Ristow says that the multiple branched-chain amino acids are already being used to treat liver damage and are also added to sport nutrition products. “However, the point is not for people to grow even older, but rather to stay healthy for longer,” says the internist. With such preventive measures, an elderly person could greatly improve their quality of life while at the same time cutting their healthcare costs by more than half.
https://www.ethz.ch/en/news-and-events/eth-news/news/2015/12/genes-for-longer-healthier-life-found.html
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