Lynne Cox, Department of Biochemistry, University of Oxford, UK 
An exciting new paper by Harrison et al. [1] describes a highly significant extension of lifespan in mice fed dietary rapamycin.

A great deal of media interest (and some rather startling headlines) have been generated by this paper, as a cursory web search for “rapamycin and lifespan” will show, so what is the real scientific significance of this new work? The study was conducted as part of the NIA Interventions Testing Program (ITP) [2], at three separate sites in the US (The Jackson Laboratory, Maine, the University of Michigan, and the University of Texas Health Science Centre) using nearly 2000 mice, giving it statistical power. Because of early technical difficulties in obtaining a form of rapamycin suitable for use in the diet, the drug was not introduced until the mice were 600 days old (equivalent to approximately 60 years of human life), but even at this late stage, lifespan extension due to dietary rapamycin was highly significant, with increases in maximal lifespan of 14% for females and 9% for males. The authors also report the effects of earlier administration of rapamycin, starting at 270 days, where they demonstrated inhibition of phosphorylation of ribosomal subunit protein S6 (rpS6) in visceral fat fads, indicative of inhibition of the mTOR pathway, together with lower mortality risk. Rapamycin (C₅₁H₇₉NO₁₃), now more correctly known as sirolimus, is a macrolide antibiotic produced by the soil bacterium Streptomyces hygroscopicus, initially found on Easter Island in the South Pacific. Perhaps this is one of the reasons why the media hype surrounding this story grew to such proportions: Easter Island is renowned for its mysterious monoliths, and it might be easy for the superstitious to find some sort of connection between this mystery and the so-called “elixir of youth”. More prosaically, the biosynthetic pathway of rapamycin, mediated by a series of bacterial Rap genes, is known [3] and the drug is manufactured commercially, disconnecting it from its ‘mysterious’ origins.  Rapamycin inhibits the highly conserved TOR (target of rapamycin; in mammals, mTOR) signaling pathway. TOR kinase is an important integrator of cellular signals including stress, energy, nutrient sensing and growth factor signaling, with pleiotropic downstream effects including biogenesis of ribosomes, increased protein synthesis, changes in metabolism, cell proliferation and motility [4]. It is important to note that TOR is made up of two multiprotein complexes, TOR1 and TOR2 that are biologically distinct. While TOR1 is predominantly involved in up-regulating protein synthesis in response to high nutrient availability, TOR2 responds to growth factor signaling (especially through the insulin and insulin-like growth factor pathways), cross-regulating TOR1 through phosphorylation of Akt kinase. That this pathway is important in “rate of living” and lifespan has already been demonstrated in the yeast Saccharomyces cerevisiae, the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster, using single gene mutants, caloric restriction or drug inhibition [5, 6, 7, 8, 9, 10]. So why is the paper by Harrison et al. hailed as such a breakthrough in ageing research? Firstly, the authors developed a method for providing rapamycin orally in food: this is an important first step in any mammalian, and particularly human, therapeutic intervention that may impact on a large percentage of the population. Secondly, the drug was found to be effective even when administered to old mice, a very important consideration when thinking in terms of human therapy. Thirdly, it emphasizes the central role of the TOR pathway in regulating longevity, and validates studies conducted in other model systems.  Are there any drawbacks? Of course: all the bases cannot be covered in any single study of this kind. At two of the study sites, male mice destined for rapamycin feeding were given different food than the controls, and even prior to the start of rapamycin feeding, showed improved longevity; however, the data from all three sites taken separately and together do still point to the effectiveness of rapamycin. Although the mice used were genetically heterogeneous to exclude the possibility that any impact was due to a genetic trait in one lab strain, the mice were in fact full siblings – not quite the situation in human populations! The greater extension in female than male lifespan is not yet explained: could it simply reflect sex differences already observed in longevity and not be related to drug treatment? Perhaps most importantly when trying to extrapolate these findings to humans, the mice were protected from infection and were kept in a pathogen-free environment: this is particularly significant given the known (and clinically useful) immunosuppressive effects of rapamycin. However, unless we are prepared to live out old age in a “bubble”, this is not a viable option for humans. Furthermore, the mice still died of diseases of old age, particularly cancer and heart problems. It is not yet clear whether the onset of these conditions was delayed, or merely their progress to a stage at which they resulted in mortality. Delaying death without delaying age-related morbidity may not be a preferred strategy for clinical intervention in human ageing.  Overall, this paper does represent a new advance in research on ageing. It does not identify an “elixir of youth” nor does it advocate using rapamycin to increase longevity in humans, since the immunosuppressive and other side effects are too risky for administration to otherwise healthy older individuals. From a researcher’s perspective, perhaps the greatest advance the paper makes is to validate all the work conducted on model lower organisms in terms of relevance to mammalian ageing. Moreover, by highlighting mTOR as a critical component in longevity, it will focus research efforts on defining more precisely how the components of this pathway integrate cellular signals to regulate lifespan. A greater understanding of this process can only be of benefit to both the research community and the wider population. For further information see: 

1.      Harrison et al. (2009) Nature advance online publication 8 July 2009, doi:10.1038/nature082212.       http://www.nia.nih.gov/ResearchInformation/ScientificResources/InterventionsTestingProgram.htm 

3.       e.g. see http://en.wikipedia.org/wiki/Sirolimus

4.       Stanfel et al. (2009) Biochimica et Biophysica Act (BBA) epub ahead for print doi:10.1016/j.bbagen.2009.06.007

5.       Kaeberlein et al. (2005) Science 310, 1193-1196

6.       Powers et al. (2006) Genes and Development 20, 174-184

7.       Vellai et al. (2003) Nature 426, 620

8.       Jia et al. (2004) Development 131, 3897-3906

9.       Kapahi et al. (2004) Current Biology 14, 885-890

10.    Pan and Shadel (2009) AGING 1,131-145 (http://www.impactaging.com)