8th December 2015

Genes for longer and healthier life identified

From a 'haystack' of 40,000 genes in three different organisms, scientists have found genes that are involved in physical aging. If you influence only one of these genes, the healthy lifespan of laboratory animals is extended – and possibly that of humans, too.

Driven by the quest for eternal youth, humankind has spent centuries obsessed with the question of how exactly it is that we age. With advancements in molecular genetics in recent decades, the search for genes involved in the aging process has greatly accelerated. Until now, this was mostly limited to genes of individual model organisms such as the C. elegans nematode, which revealed that around 1% of its genes could influence life expectancy. However, researchers have long assumed that such genes arose during the course of evolution and in all living beings whose cells preserved a nucleus – from yeast to humans.

Researchers at ETH Zurich and the JenAge consortium in Germany have now systematically gone through the genomes of three different organisms in search of the genes associated with the aging process that are present in all three species – and thus, derived from a common ancestor. 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.

To detect them, researchers examined around 40,000 genes in the nematode C. elegans, zebra fish and mice. By screening them, the scientists wanted to determine which genes are regulated in an identical manner in all three organisms in each comparable aging stage: young, mature and old. As a measure of gene activity, they recorded 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 said to be "upregulated". Fewer mRNA copies, to the contrary, are regarded as a sign of low activity.

From this information, the researchers 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 three organisms have only 30 genes in common that significantly influence the aging process.



From left to right: C. elegans nematode, zebra fish and mouse. Credit: Bob Goldstein [CC BY-SA 3.0]

By conducting experiments in which the mRNA of the corresponding genes were selectively blocked, the researchers pinpointed their effect on the aging process in nematode worms. With a dozen of these genes, blocking them extended the lifespan by at least five percent.

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 Professor Michael Ristow, coordinating author of the recently published study and Professor of Energy Metabolism at ETH.

When the gene activity of bcat-1 was inhibited, branched-chain amino acids accumulated in the tissue, triggering a molecular signalling cascade that increased longevity. Moreover, the timespan during which the worms remained healthy was extended. As a measure of vitality, the researchers observed the accumulation of aging pigments, the speed at which the creatures moved, and how often the nematodes successfully reproduced. All of these parameters improved markedly.

Professor 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. A follow-up study is already planned. "However, we can't measure the life expectancy of humans for obvious reasons," he adds. Instead, they plan to incorporate various health parameters, such as cholesterol or blood sugar levels in their study to obtain indicators on the health status of their subjects.

Multiple branched-chain amino acids are already being used to treat liver damage and also feature in sports nutrition products. This follow-up study will deliver new and important indicators on how the aging process could be influenced and how age-related diseases might be prevented.

"However, the point is not for people to grow even older – but rather, to stay healthy for longer," the researchers argue. Given the unfavourable demographics and steadily increasing life expectancy, it is important to extend the healthy life phase – or "healthspan" – and not to simply reach an even higher age that is characterised by chronic diseases. With such preventive measures, elderly people could greatly improve their quality of life, while at the same time cutting their healthcare costs by more than half.

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