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CSHL 2008, Session I: Genetics of simple organisms

Posted Sep 26 2008 2:49pm

This first session focused on the smaller model organisms that led the first wave of modern biogerontology: yeast, worm, and fly. The talks covered a wide range of systems and techniques, but they held together nicely because they (mostly) converged on common themes: control of calorie-restriction-mediated lifespan extension, and the genetics of the insulin-like growth factor pathway that governs lifespan in many organisms.

  • In the worm, the daf-2 insulin/IGF-I-like pathway regulates lifespan: loss of function in the pathway kinases results in extended longevity, while mutations in the pathway’s lone kinase ( daf-18 ) result in decreased longevity. Heidi Tissenbaum expanded on this pattern, reporting on work from her lab that revealed a new phosphatase in this pathway that is also required for daf-2 lifespan extension.

  • Over the course of worm aging, a significant fraction of the genome is differentially regulated. Yelena Budovskaya (from Stuart Kim’s lab) described the computational identification of a cis -acting motif that occurs frequently in the promoters of aging-regulated genes, and the GATA transcription factors that bind this motif.

  • What actually causes the chronological aging of yeast? Chris Burtner (from Brian Kennedy ’s lab) argued that time-dependent reduction in cell viability is due to accumulation of a specific organic acid in the growth media. This acid doesn’t build up when cells are cultured in low glucose — particularly interesting given recent suggestions that aerobic respiration is required for yeast longevity. Long-lived mutants such as ∆sch9 are resistant to the accumulated acid.

  • Malene Hansen (a friend from my UCSF days, who this morning arranged for the entire Campisi lab to ride from the airport in a black stretch limo) shared her data demonstrating that induction of autophagy — already known to be required for life extension by daf-2 mutations — is also essential for longevity enhancement by calorie restriction (CR). Her overall conclusions, however, are more complex: autophagy appears to be important for some longevity pathways but not others.

  • Steve Helfand told us about the long-lived fly mutant Indy, focusing on the decrease in mitochondrial ROS and oxidative damage observed in this mutant. He made the intriguing suggestion that the ATP:ROS ratio may be a significant factor in determining longevity — implying, among other things, that the age-related decrease in mitochondrial electron transport may be compensatory/protective, not passive/degenerative (see our earlier discussion of this perennial conundrum in interpreting age-related change, in another context).

  • Scott Pletcher talked about neuro-sensory circuits that modulate lifespan in Drosophila, which I stupidly missed most of because I was typing this post.

  • Su-Ju Lin recapitulated the findings of her lab’s recent paper about the malate-aspartate shuttle in yeast CR (briefly, the shuttle communicates the CR-induced increase mitochondrial NAD+/NADH ratio to the cytosol), and further proposed a role for nitric oxide in CR-mediated lifespan extension.

  • Zhuoyu Ni described two novel negative regulators of DAF-16, mutation in either of which extends lifespan. These genes are both downstream targets of the DAF-16 transcription factor, so they are likely involved in negative feedback.

At this point, only seven talks into the session (!), I got too tired to follow carefully. (We flew out on a red-eye last night, and I haven’t slept). I’m going to turn in now and hope for a good night’s sleep. More tomorrow — though judging from the attention-deficit problems I suffered when blogging this session, as well as the not-very-readable sea of text that resulted, I won’t be trying to cover every talk in every series. Instead, I’ll try to extract general themes, using specific examples where they are useful.

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