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December 1, 2015

Suppressing Aging Genes Extends Lifespans

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    A recurring theme in art, the three ages, features in a new study of age-related changes in gene expression. The study identified a set of highly conserved genes that could, when suppressed, improve health and extend lifespans. [The Three Ages of Man, by Giorgione, is a work in the public domain that appears in the Web Gallery of Art and Wikipedia]

    Youth. Maturity. Old age. Each stage in physiological aging is characterized by different patterns of gene expression, which complicates the search for “aging genes.” To deal with this complication, scientists centered at ETH Zurich compared aging-related patterns in gene expression in young, mature, and old model organisms—nematodes, zebrafish, and mice. By studying gene expression patterns in three different organisms, the scientists hoped to highlight genes that have been conserved through evolution, and are thus likely to be found in humans, too.

    After measuring the production of messenger RNA (mRNA)—a proxy for gene activity—for each of 40,000 genes and for each of the aging stages, the scientists were able to identify genes that were regulated similarly in each of the model organisms. They found that the three organisms have only 30 genes in common that significantly influence the aging process.

    What’s more, the scientists conducted experiments in which the mRNAs of the corresponding genes were selectively blocked. These experiments allowed the scientists to determine the effect of these genes on the aging process in nematodes. By blocking a dozen of these genes, the scientists were able to extend the lifespan of the nematodes 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%," said Michael Ristow, M.D., professor of energy metabolism at ETH Zurich.

    Dr. Ristow is the coordinating author of a study that appeared December 1 in the journal Nature Communications. The study—“Branched-chain amino acid catabolism is a conserved regulator of physiological ageing”—not only explains what bcat-1 does, it explains how the gene works.

    The bcat-1 gene carries the code for the enzyme of the same name, which degrades so-called branched-chain amino acids (BCAAs). Naturally occurring in food protein building blocks, these include the amino acids L-leucine, L-isoleucine, and L-valine.

    “BCAAs reduce a LET-363/mTOR-dependent neuro-endocrine signal, which we identify as DAF-7/TGFβ, and that impacts lifespan depending on its related receptors, DAF-1 and DAF-4, as well as ultimately on DAF-16/FoxO and HSF-1 in a cell-non-autonomous manner,” wrote the authors of the Nature Communications article. “The transcription factor HLH-15 controls and epistatically synergizes with BCAT-1 to modulate physiological ageing.”

    When the researchers inhibited the gene activity of bcat-1, BCAAs accumulated, triggering a molecular signaling 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.

    The scientists also achieved a life-extending effect when they mixed the three BCAAs 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.

    In the present study, the investigators purposefully opted not to study the impact on humans. But a follow-up study is already being planned. "We cannot measure the life expectancy of humans for obvious reasons," explained Dr. Ristow. Instead, 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 their subjects.

    Dr. Ristow added that the multiple BCAAs 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," he asserted.

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