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!

Aging

My favorite magazine Proto (free subscription - check it out) had an article in the spring issue about aging. The whole concept of getting older is a tricky one. How can you evaluate life span and tease out the factors that modulate the aging process? Is aging a process at all or just a collection of random degeneration? Is our lifespan dictated by oxidative damage that leads to radicals or something more structured?

These questions were first addressed by a nutritionist at Cornell University, Clive McCay. In the 1930s he put rats on a calorie-restricted diet and saw that they lived 40% longer than other, normally fed, rats. Aging research is perhaps the product of the times and started toward the end of the great depression, as concern about food deprivation and its effect on lifespan was at a high. Surprisingly, in response to dietary limitation life was prolonged.

Since the 1930's the research community has come quite a long way. Last year, the University of Wisconsin published a study that observed rhesus monkeys on a calorie-restricted diet. The dieting monkeys lived 20% longer. Considering rhesus monkeys live on average 27 years, this was an extensive examination and suggests the possibility that caloric restriction might be relevant for primates. Check out these monkeys, can you guess which one is on a diet? (it's the one on the left, both are pretty cute) These results need further validation and leave certain issues unanswered. The calorie-restricted monkeys had more deaths that were considered age unrelated and were excluded from the final statistical analysis. Additionally, the article did not seem to clarify whether the monkeys were kept in isolation or not. A second study is currently in progress sponsored by the National Institutes of Health.

Other researchers utilize model organisms to study the process of aging a little faster. The model organisms C. elegans has a much shorter life expectancy (~30 days), a short generation time (~ 3 days) and a well developed system to study various signalingg pathways. And these nematodes are very cute too (well maybe you have to be there). Nevertheless, it has been shown that even in a simple organism such as C. elegans restricting diet can increase life span through different pathways. Cynthia Kenyon has summarized these observations nicely in a recent review. The timing of the diet has a role in the pathway that leads to life span increase. To clarify, a pathway for life elongation is identified in C. elegans by putting the worm on a diet and then knocking out genes for certain elements of known pathways (i.e. daf-2 is the gene responsible for the insulin/IGF-1 receptor ortholog in the worm). If lifespan elongation is no longer achieved, it is suggested that the mechanism of increase occurs through the role of the gene product. As shown nicely in the chart above the pathways are dramatically different. Mild chronic food limitation acts through sir-2.1, a NAD-dependent histone deacetylase and the putative target of resveratrol, the well known small molecule that is found in red wine (structure on the left). Every other day feeding, however, elongates life through the insulin signaling pathway.

The aging picture is very complex, and the research (as well as more aging themed blog posts) are coming. It is striking that temporal variation in a diet can contribute to the same outcome in such different ways. Imagine varying the type of diet as well. The pathways that are considered in the worms are similar to those found in more complicated organisms such as humans, suggesting that there might be elements in many fundamental pathways, such as insulin signaling or control of gene expression that module life span.

If the science community can properly understand this signaling networks - perhaps humans can live longer healthier lives. It is important to note that health is part of the life elongation process. Interestingly enough, even in the little C. elegans (1mm long) it is possible to differentiate between sickly looking long lived worms and happier long lived worms. The C. elegans community is starting to identify these differences and highlight the pathways that lead to longer lived healthier worms and maybe one day people.

A joke at every end:

Three sisters, a 92, a 94 and a 96 year old, all live together. One day the 96 year old is taking a shower. Suddenly she yells out "hey sisters, can one of you help me? I am in the shower and I don't know whether I am getting in or getting out." So the 94 year old sister starts walking up the stairs to help and suddenly she turns around and yells "hey sisters, can one of you help me? I am walking up the stairs and I don't know if I am going up or coming down?"

The 92 year old sister is sitting at the kitchen table. She mumbles to herself "I hope I never get to be like those two" and knocks on wood for superstition's sake. She yells back "Hold on, I'll be right there as soon as I see who is at the door!"