What's the deal with Sirtuins?

Why and how we age is a question that affects all of us. As we get older, the frailty of life becomes all the more poignant. While the concept of aging can seem ephemeral, it also has a very practical side. In fact, researchers all across the world are studying the mechanism of aging and not just how we age but how we can stay young. Humans live a long time and are impractical for the study of the why and the how of aging. For this reason aging researchers use model organisms. C. elegans, for example, is a nematode found in a rotting apple in your back yard. Conveniently, the "worm" lives on average three weeks and has a great number of genes in common with higher organisms. So it is possible to probe conserved signaling pathways in this short lived creature to generate hypotheses that may apply to humans.

Recently, two groups published articles in the journal Nature that concerned the aging process; one story identified a novel way by which the "worm" can live longer, and another suggested an accepted mechanism of longevity was erroneous. Bad news first, always, so here it goes.

Sirtuins are a class of enzymes that are known to be NAD+ dependent deacetylases as well as ribosyl transferases. Originally identified in yeast, sirtuins have been implicated in healthy living in a plethora of model organisms including mice. Resveratrol, a popularized small molecule that might lead to longer life, achieves its beneficial affects in a sirtuin dependent manner. Humans have seven types of sirtuins and understanding the role of these enzymes is of great interest to the medical community.

A few years back one of the four sirtuins in C. elegans was over-expressed, which in turn led to a higher level of the protein SIR-2.1 and a 30% longer lifespan in the "worm". A similar extension in humans would mean a 70 year old man would live to be 91. Unfortunately, the recently published work dampened the enthusiasm for sirtuins as lifespan modulators. It turns out that the way in which the sirtuin enzyme was originally over-expressed brought along another mutated gene that also extends lifespan. The original research team crossed the mutant strain with a non mutated wild type strain 6 times to remove any additional mutations. However, that was not enough. "Back crossing", as this genetic cleaning method is called, has to be done 10 times for an organisms that has 100 million base pairs in its genome. A dye filling mutation (dyf) was very close to the sir-2.1 gene on the C. elegans chromosome and just kept sticking around from generation to generation. All hope is not lost though. When the additional mutation was removed, the over-expressing sirtuins still lived almost 10% longer. That same 70 year old man now lives to be 77, still not too bad. Ultimately, more research is necessary to explore how we can optimize sirtuin activity for healthy living and get some good news out of this.

A joke for every end:

What do you get when you cross a snowman and a vampire?
Frost bite!