Inhibition of bcat-1 Extends Life in Nematodes

Another day, another method of slowing aging in a laboratory species. The diversity of techniques is increasing every year, and many slip by without comment, as there are simply too many now to remark on every one of them. This particular method has the look of working via hormesis - allowing an accumulation of molecules that cells react to as damage, and thus increase repair and maintenance activities, but which is not harmful enough in and of itself to outweigh the benefits of that increased cellular housekeeping.

One of the reasons for such a wealth of ways to slow aging in short-lived species is that there are countless possible methods by which researchers can provoke a hormetic response, and the same is true for the other underlying mechanisms that might work to modestly slow aging if manipulated. Everything in cellular biochemistry is connected, so a core mechanism of interest might be tweaked by altering any one of dozens of genes or levels of circulating proteins. Indeed, part of the challenge inherent in this situation is that it is very hard to determine the identity of the core mechanism when there are so many actions that produce benefits, and every change cascades throughout cellular biochemistry. Another thing to bear in mind while reading these sorts of research results is that all of the methods of slowing aging in short-lived animals for which we also have data in humans show that in our species the result on life span is small at best, even when the result on health is worth chasing, as is the case for calorie restriction and exercise:

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 ageing process. By conducting experiments in which the mRNA of the corresponding genes were selectively blocked, the researchers pinpointed their effect on the ageing process in nematodes. 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."

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 so-called 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 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 ageing 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.