In Tissenbaum and Guarente's research study, they concluded that increasing the dosage of a SIR2 gene is associated with extended lifespan of roundworms, Caenorhabditis elegans (Tissenbaum & Guarente 228). To easily understand their research study, let us discuss a little background abound longevity of C. elegans. In 1997, a research study headed by Kimura, Tissenbaum, Liu and Ruvkun found the gene that potentially regulates the longevity and diapause in Caenorhabditis elegans. In C. elegans, their life cycle after the initial larval stage can proceed to two different stages: either the reproductive stage, or the dauer diapause stage (Hu). In their study, Kimura et al. examined the neurosecretory signaling system that regulates this pathway to identify the genetic mediator. In fact, they determined that the gene daf-2 mediates the endocrine signaling that regulates the life cycle pathway of C. elegans (Kimura et al. 942). To be specific, decreasing DAF-2 signaling is associated with an increase in lifespan due to favoring the long-lived dauer diapause stage (Kimura et al. 942). Similarly, reducing the phosphatidylinositol-3-OH kinase signaling system regulated by the gene age-1 favors the dauer state and extends lifespan of C. elegans (Morris, Tissenbaum, & Ruvkun 384).
On a different note, the SIR2 gene is notable for determining the lifespan of mother cells in yeasts (Tissenbaum & Guarente 227). Needless to say, additional copies of SIR2 extend the lifespan of mother cells. In fact, the goal of Tissenbaum and Guarente's research study is to identify the gene that is most homologous to the SIR2 gene in yeasts, and is associated with mediating lifespan in C. elegans. Note that homologous genes from different species may have similar functions. In this case, the SIR2 gene in yeasts extends the lifespan of mother cells, which means that the gene homologous to the SIR2 gene in C. elegans may also function as a regulator of lifespan.
In their study, they found four genes in C. elegans having similarity to the SIR2 gene in yeasts. These four genes were named sir-2.1, sir-2.2, sir-2.3, and sir-2.4, with sir-2.1 having the most similarity (31%) (Tissenbaum & Guarente 228). After determining the genes related to SIR2, the authors identified whether these genes are related to the regulation of lifespan in C. elegans. However, strains containing duplications of sir-2.2, sir-2.3, and sir-2.4 does not seem to significantly affect the lifespan relative to the parental strain. Fortunately, the strain containing the chromosome IV duplication mDp4, where the sir-2.1 locus is contained, exhibited a significant extension in the lifespan. Furthermore, a different chromosome IV duplication, mDp1, without the sir-2.1 locus does not seem to significantly affect the lifespan. In other words, the potential suspects that regulate the lifespan of C. elegans are the sir-2.1 or any other genes in mDp4 (Tissenbaum & Guarente 228).
After narrowing down to the genes in mDp4, the authors tested which specific gene regulates the lifespan of C. elegans. To be specific, they tested whether sir-2.1 is the genetic mediator, or one of the genetic mediators. To be able to determine if sir-2.1 is related to the regulation of lifespan, the authors performed a test wherein they injected sir-2.1 into a parental strain. The results showed that the three identified lines containing sir-2.1 are associated with extended lifespan. A further test shows that the number of gene dosage of a SIR2 gene is positively correlated with the amount of extension to the lifespan of C. elegans (Tissenbaum & Guarente 228). At this point, the authors concluded that increasing the dosage of the SIR2 gene extends the lifespan of a C. elegans.
Based on the article, it was easy to understand how the authors came up with this conclusion, but for better understanding, let us discuss the underlying assumptions that must be true so that the conclusion would be sound and valid. After reading the article, I came up with four statements that must be met to come up with the conclusion. First, there must be a gene, or genes, in C. elegans that is/are homologous to the SIR2 gene in yeasts. Note that the hypothesis was developed on the basis that homologous genes, even if from different species, may have similar functions. In this case, the authors found that the most homologous gene in C. elegans to the SIR2 gene in yeasts can be found within the identified sir-2.1 locus. Although the similarity is only about 31% identity to the SIR2 gene, this percentage, in genetics, can be relatively significant. Moreover, the authors positively identified three more genes that have 10-20% similarity with the SIR2 gene. Therefore, it can be stated that these four gene loci are homologous to the SIR2 gene in yeasts.
As for the second parameter, one of the homologous genes must be related to lifespan extension. According to the article, the authors performed the tests to check whether any of the four identified gene is associated with the regulation of lifespan in C. elegans. In fact, only the duplication mDp4, which contains sir-2.1 was positively identified to have significantly extended the lifespan of C. elegans. The third assumption is that increasing the gene dosage of the positively identified homologous gene must be associated with longer lifespan extensions. According to the article, the authors had to test whether the dosage affects the amount of extension, which is exactly the case.
Finally, the fourth assumption is that the gene must be somehow related to the dauer state development decision, or the metabolic rate. In fact, the authors determined that the sir-2.1 gene mediates in the insulin-like signaling pathway (Tissenbaum & Guarente 229).
It is notable that all these assumptions are verified through tests. Although some experimental values might be overlooked, the experimental design was flawless. If there is another potentially homologous gene that was overlooked, it would be better to check if it is related to lifespan extension. Moreover, if lifespan extension is regulated by a combination of more than two genes, the conclusion made by Tissenbaum and Guarente would not necessarily become invalid. However, it must be verified which gene contributes as the primary factor to lifespan extension.
In summary, the article authored by Tissenbaum and Guarente aimed to determine the gene that is homologous to the SIR2 gene in yeasts, and is associated with the regulation of lifespan in C. elegans. The identified gene, sir-2.1, has a 31% similarity with the SIR2 gene in yeasts. Through tests, the gene sir-2.1 was associated with lifespan extension. In fact, increasing the gene dosage of sir-2.1 increases the lifespan extension of C. elegans.
Works Cited:
Hu, Patrick J. “Dauer.” WormBook. 21 May 2007. Web. Accessed 28 May 2016.
Kimura, K.D. et al. daf-2, an Insulin Receptor–Like Gene That Regulates Longevity and Diapause in Caenorhabditis elegans. Science 277 (1997): 942-946. Print.
Morris, J.Z., H.A. Tissenbaum & G. Ruvkun. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382 (1996): 536-539. Print.
Tissenbaum, H. A. & Guarente, L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410 (2001): 227–230. Print.
