The protein called silent information regulator 2 (Sir2) was first discovered in budding yeast, Saccharomyces cerevisiae. It belongs to a highly conserved family of proteins christened sirtuins, which are found in almost all organisms and are involved in responses to stressors, such as heat and starvation. In 1999, Sir2 was reported to increase lifespan in yeast cells (Genes Dev. 13, 12570–2580). Then in 2001, scientists reported a link between overexpression of the gene sir-2 and longevity in the nematode Caenorhabditis elegans (Nature 410, 227–230). A few years later, a second group of researchers noted a similar association of Sir2 with longevity in Drosophila melanogaster fruit flies (Proc. Natl. Acad. Sci. USA 101, 15998–16003; 2004). Furthermore, it was suggested that activation of Sir2 could be the mechanism underlying the lifespan-lengthening effects of calorie restriction, a well-documented phenomenon in many organisms, including mammals.

The gathering body of work focused a great deal of attention on sirtuins as the fabled 'fountain of youth.' Research groups began looking for evidence that sirtuins' longevity effects extended to mammals, such as mice, and began looking for ways to activate sirtuins and, they hoped, extend lifespan.

But trouble was brewing in sirtuin research, as contradictory and inconclusive results began to accumulate, and questions began to surface about the genetic background of the experimental animals and the controls used in the original experiments.

Researchers from the Institute of Healthy Ageing at University College London (UK), led by David Gems and Linda Partridge, in collaboration with several other laboratories, decided to take a closer look, re-examining the effects of Sir2 on longevity in C. elegans and D. melanogaster. They found that standardizing the genetic backgrounds of the experimental animals and using appropriate experimental controls eliminated the increased longevity in the sirtuin mutants of both species (Nature 477, 482–485; 2011). The authors stress that their findings “underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects of lifespan.”

The report won't be the last to address the question of sirtuins and longevity. Members of the laboratories that contributed the original reports acknowledge some flaws in those experiments but provide new results that confirm an effect (though smaller than that originally reported, at least for C. elegans) of Sir2 on longevity.

Speaking with Nature News, Gems agreed that sirtuin research should not be abandoned: “They are very interesting proteins...and have very interesting metabolic effects.”