Science of Aging  

Matt Kaeberlein et al. propose that the TOR and Sch9 kinases regulate longevity in yeast

Who:Matt Kaeberlein, R. Wilson Powers III, Kristan K. Steffen, Eric A. Westman, Di Hu, Nick Dang, Emily O. Kerr, Kathryn T. Kirkland, Stanley Fields, Brian K. Kennedy
When:November 18, 2005
Methods: Large-scale analysis of 564 gene deletions which yielded 6 genes corresponding to the TOR and Sch9 pathways
Funding: National Institutes of Health

In 2005 Kaeberlein et al. published a paper suggesting that the mechanism for calorie restriction is via the TOR1 Sch9 pathways, independent of the Sir2 pathway.

Kaeberlein et al. reached their conclusion via analysis 564 gene deletion strains of yeast. The strains were then classified as follows:

  1. Mean life span less than 20 generations are short lived (SL)
  2. Mean life span less than 26 generations are not long lived (NLL)
  3. Mean life span more than 36 generations are long lived (LL)
Out of the 564 gene deleted strains 44 were initially classified as long lived (LL), and out of the 44, 13 were classified as statistically significant in extending lifespan. Further, of the 13 genes classified as significant all showed reduced expression of FOB1, a known pathway of increasing longevity, which helped to confirm the assay.

The resultant deletion strains showed that decreased expression of TOR1, protein kinase A (PKA), and Sch9 all increased replicative life-span. TOR1 is thought to run upstream and parallel to PKA and Sch9. All three mechanisms regulate common downstream targets such as ribosomal proteins Rp131a and Rp16b.

Since it has been shown that orthologs of TOR1 and Sch9 in Caenorhabditis elegans and Drosophila melanogaster regulate lifespan, the authors conclude that the reduced activity of TOR1 and Sch9 presents "a model whereby CR increases life span through a highly conserved, Sir2-independent signaling network from nutrients to ribosomes."

References

  1. Kaeberlein, M., Powers, R. W., 3rd, Steffen, K. K., Westman, E. A., Hu, D., Dang, N., Kerr, E. O., Kirkland, K. T., Fields, S., and Kennedy, B. K. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193-1196.

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