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about 38% for females and 28% for males. In an ongoing study, mice are being fed rapamycin beginning at 270 days, with a significant increase in survival also being apparent in this cohort. Rapamycin was first identified as a natural product of the bacterium Streptomyces hygroscopicus in soil samples from Easter Island — famous for its impressive rock-carved human statues (Fig. 1). The compound was selected for inclusion in the ITP on the basis of its known property as an inhibitor of the kinase enzyme, target of rapamycin (TOR). TOR signalling has previously been linked to the ageing process in invertebrates, but until now it had remained an open question as to whether TOR signalling also has a central role in mammalian ageing. The findings of Harrison et al. make TOR the first protein that has been shown to modulate lifespan in each of the four model organisms most commonly used to study ageing: yeast, worms, flies and mice. How does TOR activity influence ageing? Among other functions, TOR promotes translation of messenger RNA into protein by the ribosome, and inhibits a pathway that degrades cellular products in lysosomal vesicles (autophagy) — both of which have been implicated in ageing in invertebrate species. Regulation of mRNA translation by TOR, in particular, has emerged as a lifespan-determining pathway that is highly conserved between yeast and the nematode worm Caenorhabditis elegans. In both species, mutations in targets of TOR, such as ribosomal S6 kinase (an enzyme involved in protein translation), several translation-initiation factors and multiple ribosomal proteins, increase lifespan. In addition, TOR influences cell growth, cell-cycle progression, mitochondrial metabolism and insulin-like signalling. Untangling the relative contributions of each of these processes to the lifespan extension in mice conferred by rapamycin is likely to stimulate much interest during the next few years. TOR signalling has also received attention for its role as a possible mediator of dietary restriction. This is defined as a reduction in nutrient availability without malnutrition, and has long been known to increase lifespan in species ranging from yeast to rodents. TOR activity is reduced by dietary restriction, and genetic studies in invertebrate models have linked the inhibition of TOR to increased longevity by dietary restriction. For example, a recent study in yeast showed that TOR inhibition increases Anti-ageing drugs — compounds that slow the hands of time and allow humans to live far beyond their natural span — have long been fertile ground for science-fiction writers. More recently, however, the possibility that such compounds might exist, and might perhaps even be within reach, has gained scientific credibility. In this issue (page 392), Harrison et al. provide evidence that pharmacological intervention in the ageing process is feasible in mammals*. They report that dietary supplementation with rapamycin — a compound known to be linked to lifespan in invertebrates — significantly increases the lifespan of mice. The US National Institute on Aging’s Interventions Testing Program (ITP) was designed to test compounds of interest for effects on ageing in mice. Anyone from the scientific community can nominate a compound for consideration by the ITP, and selected compounds are tested in parallel longevity studies at laboratories at three sites, providing built-in triplicate replication and high statistical power. Several compounds have already been tested. Of these, rapamycin is the first to robustly increase lifespan across all three centres and in both male and female mice. As is often the case in science, this study benefited from a fortuitous accident. Early on, the ITP researchers realized that simply adding rapamycin to feed failed to maintain high levels of the drug, so a specially formulated feed was developed in which rapamycin is encapsulated for timed release in the intestine. It took more than a year to develop the special feed, which meant that mice in the first cohort to receive rapamycin were 600 days old when supplementation was initiated. As Harrison et al. note, this is “roughly the equivalent of a 60-yearold person”. Amazingly, both the median and maximum lifespan of these middle-aged mice were significantly increased by rapamycin supplementation. For instance, rapamycin increased maximum lifespan (defined by the 90th survival percentile) from 1,094 days to 1,245 days for female mice and from 1,078 days to 1,179 days for male mice. This translates into a striking increase in life expectancy at the time AGEING