The genetics of aging in the Nematode C. elegans is a rapidly evolving field. Whereas, the age of a yeast cell is defined by its replicative capacity, the age of a worm refers to its post-mitotic life span. C. elegans undergoes four larval stages and an adult stage. Life span is defined as the length of time (usually reported as days) from the end of the fourth larval stage until death. Amazingly, even though yeast aging and worm aging are defiened in fundamentally different ways, the kinetics of mortality are nearly identical. This can be seen by comparing the shapes of a representative life span curve for each organism.
There are at least two well-defined genetic pathways that regulate longevity in C. elegans. One pathway involves several genes that affect an insulin/IGF-1-like signaling cascade. Many of the life span extending mutations in this class also increase the dauer response of the animals. The second pathway consists of genes that affect feeding behavior and it has been proposed that this pathway mimics caloric restriction because the animals are unable to feed as efficiently as wild type worms.
Life span regulation by Sir2.1
Recently, a striking conservation of function between yeast and worms was discovered by Heidi Tissenbaum. C. elegans has three SIR2-family members. Matt Kaeberlein and Mitch McVey had previously shown that overexpression of SIR2 in yeast extends life span. Heidi generated a strain of C. elegans that is overexpressing the most closely related homolog, sir2.1, from a multicopy array. When she measured the life span of this strain she found that overexpression of sir2.1 extends worm life span as well! These results have recently been published in Nature.
Current research in our lab is aimed at further elucidating the mechanism by which sir2.1 overexpression can increase longevity in C. elegans. Preliminary genetic analysis suggests that sir2.1 acts in the same genetic pathway as daf-2 and daf-16. We are now trying to further characterize this genetic relationship. We are also working to understand the molecular mechanism by which sir2.1 acts to regulate longevity. Of course, the next question we hope to answer is whether SIR2-overexpression can extend life span in mammals!
Caloric restriction and NAD
We are also trying to develop a system to induce a calorically restricted state in worms. We will then analyze these worms and see whether they live longer than non-restricted worms. Caloric restriction has been shown to extend life span in both yeast and mice. It is thought that caloric restriction in yeast results in an extended life span by increasing the pool of available NAD. Since Sir2p requires NAD for activity, caloric restriction might result in increased SIR2 activity. Using C. elegans as a model, we hope to determine how much of this pathway is conserved and whether NAD levels play a critical role in longevity in organisms other than yeast..
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