Ageing Genes: The Sirtuin Story
From Papers of Interest - Jennifer Couzin-Frankel (2011) Aging Genes: The Sirtuin Story Unravels Science Vol. 334 no. 6060 pp. 1194-1198 DOI: 10.1126/science.334.6060.1194
From the perspective of a relative outsider to the sirtuin field, this News Item in a recent issue of Science is quite timely, bringing a concise overview of the state of play in the field of Sir2 and its role in the modulation of lifespan. It's an intriguing tale of scientific investigation. And from a more personal perspective, avoiding complications due to genetic background when analysing the impact of genetic interventions using transgenic Drosophila has been important in my ow research.
This article presents the story of how Sir2 was discovered in yeast, where enhancing its activity led to lifespan extension, and how it was subsequently shown to have similar effects in the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, both valuable model systems from a genetic perspective. In mice, overexpression of SIRT1 (the homologue of Sir2) was found to extend 'healthspan' rather than lifespan.
This was an attractive story reflecting homologous conserved mechanisms of monitoring the nutritional state, and led to the proposal that resveratrol could extend lifespan by acting via Sir2. (See for example Wang et al (2011) and Timmers et al (2011) - also recently featured as 'Papers of Interest' on this website).
Unfortunately for this straightforward story (or perhaps fortunately as it's become a lot more interesting!), the picture turns out to be rather more complicated than that. Matt Kaeberlein (a member of Lenny Guarente's lab who worked on the original Sir2 yeast work) revisited the story, concluding that Sir2 and calorie restriction might well not be operating through the same pathway. To add to the confusion, recently published work from Linda Partridge and David Gems on Drosophila and C. elegans suggests that where genetic background are accounted for, the effects of transgenic overexpression of Sir2 on lifespan disappear.
As a relative outsider to the Sir2 story, I can sympathise with both sides in the story. Way back when I held a couple of grants from the BBSRC's Experimental Research on Ageing programme, we were engaged in elevating levels of the antioxidant glutathione in Drosophila with a view to evaluating the impact on lifespan. Noting the published data on overexpression of human SOD1 in Drosophila motorneurons (Parkes et al (1998)), we obtained the motorneuron specific Gal4 driver stock (notably not from the lab that published the work, for technical reasons), and set up the experiment. We were greatly encouraged by the apparent lifespan extension, only to be dashed when the data from the driver-only control became available - flies heterozygous for the driver were just as long-lived as those with elevated motorneuron glutathione. The similarity between the lifespan graphs in the Partridge and Gems work and our graphs was so striking I forwarded a copy to my former student!
Having been present at a meeting in 2010 when the Partridge and Gems data were presented (quite possibly the meeting referred to in the Science news article), I'm well aware of how contentious this story is. But as with many such matters, I expect the 'truth will out', and I fully expect the story to get event more complex and interesting. Who knows - the possibility of interacting factors in different strains of our favourite model organisms might provide further illumination of what has to be a complex physiological picture.
Jennifer Couzin-Frankel (2011) Aging Genes: The Sirtuin Story Unravels Science Vol. 334 no. 6060 pp. 1194-1198 DOI: 10.1126/science.334.6060.1194