26 Sep 2011

The family of histone deacetylase proteins known as sirtuins have been heralded as keys to longevity, based largely on studies in yeast, flies, and worms. New data now call these findings into question. In the September 22 Nature, researchers led by David Gems at University College London, U.K., report that the lifespan extension seen in the original C. elegans and Drosophila lines that overexpressed Sir2 was due to confounding effects from genetic background and transgene insertion. Repeating the initial experiments with new controls, Gems and colleagues report no effect from Sir2 on lifespan. In contrast, Leonard Guarente and colleagues at Massachusetts Institute of Technology, who did some of the initial Sir2 experiments, contend that, though initial lifespan claims were an overestimate, Sir2 still confers a modest extension. Though the issue remains contentious, the debate does not appear to affect the large body of research showing that sirtuins affect mammalian health and metabolism.

Guarente and colleagues first reported that Sir2 overexpression lengthened worm lifespan by up to 50 percent (see Tissenbaum and Guarente, 2001). Guarente co-chairs the scientific advisory board for Sirtris, a GlaxoSmithKline subsidiary that develops drugs based on sirtuins, and he was co-founder of Elixir Pharmaceuticals, which pursues life-extending therapies. Guarente and colleagues also found that sirtuins mediated the lifespan extension provided by calorie reduction (see, e.g., ARF related news story and ARF news story). Other studies have questioned these findings, however, leading Gems and colleagues to re-analyze the issue.

They outcrossed Sir2-overexpressing C. elegans lines into a new genetic background and found that longevity effects vanished. They traced the initial life extension instead to a sensory neuron gene mutation, many of which are known to affect lifespan (see, e.g., Hsin and Kenyon, 1999). Similarly, the U.K. group found no Sir2 lifespan effect in transgenic flies compared to appropriate controls, and found that Sir2 did not mediate the longevity effects of dietary restriction in flies. In an e-mail to ARF, Gems noted that several independent research groups have replicated these findings, and wrote, “The findings in our paper imply that increased Sir2 levels do not slow aging in worms and flies.”

In a Nature Brief Communication, Guarente and Mohan Viswanathan at MIT agree that the sensory neuron gene mutation contributed much of the lifespan extension seen in the original worm study, but report that even after extensive backcrossing, Sir2 stills lengthens life by 10 to 15 percent. The role of Sir2 in worm longevity is supported by an independent group, Guarente wrote to ARF (see Rizki et al., 2011).

Whether Sir2 does have some influence on lifespan or not, it seems clear at least that sirtuins do not hold the prominent place in longevity research they were formerly accorded. As David Lombard and Scott Pletcher at the University of Michigan, Ann Arbor, wrote in an accompanying News & Views article, “At best, therefore, these papers indicate that Sir2 overexpression is just one of more than 100 genetic manipulations currently known to increase worm and/or fly lifespan to some degree, with many others having larger effects.” The results also highlight the importance of performing adequate backcrossing in genetic studies, Lombard and Pletcher note, suggesting that eight to 10 generations of backcrossing should be the standard in both flies and worms.

What does this mean for the role of sirtuins in mammalian biology? Perhaps nothing. Sirtuins have not shown a longevity effect in mouse studies, for example. But as Carles Cantó at the Nestlé Institute of Health Sciences, Lausanne, Switzerland, and Johan Auwerx at the École Polytechnique Fédérale de Lausanne, note in a second News & Views article, “an overwhelming body of evidence indicates that sirtuins have crucial roles in metabolic homeostasis.” In mammals, the proteins have been reported to prevent metabolic disorders (see ARF related news story), reduce phosphorylated tau (see ARF related news story), and play roles in learning and memory (see ARF related news story and ARF news story), among other things. Other histone deacetylases also affect memory and are potential drug targets in neurodegenerative disease (see, e.g., ARF related news story). Sirtuins also confer neuroprotection in a worm model of Huntington’s disease (see ARF related news story). Cantó and Auwerx suggest, “the metabolic adaptations that SIRT1 induces might indirectly influence mammalian lifespan,” and conclude, “SIRT1 activation remains a promising approach to delaying general age-related physiological decline.”—Madolyn Bowman Rogers.

References:

Cantó C, Auwerx J. Don’t write sirtuins off. Nature. 2011 Sep 22;477(7365):411.

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References

News Citations

1. How Does Calorie Restriction Extend Life? 22 Nov 2002
2. Caloric Restriction Increases Metabolic Rate 22 Nov 2002
3. SIRT1 Activator Prevents Metabolic Disorders in Mice 12 Nov 2008
4. Sirtuin Inhibitor Boosts Cognition, Reduces Phospho-tau 8 Nov 2008
5. Mechanisms and Memory: The Choreography of CREB, the Balance of BDNF 16 Jul 2010
6. Research Brief: SIRTs Keep Brain Minty Fresh 25 Jul 2010
7. It’s an HDAC2 Wrap— Memory-suppressing DNA Modifier Identified 12 May 2009
8. Huntington Disease: Three Ways to Tackle Triplet Disorder 11 Apr 2005

Paper Citations

1. Tissenbaum HA, Guarente L. Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature. 2001 Mar 8;410(6825):227-30. PubMed.
2. Hsin H, Kenyon C. Signals from the reproductive system regulate the lifespan of C. elegans. Nature. 1999 May 27;399(6734):362-6. PubMed.
3. Rizki G, Iwata TN, Li J, Riedel CG, Picard CL, Jan M, Murphy CT, Lee SS. The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet. 2011 Sep;7(9):e1002235. PubMed.

Further Reading

News

1. Huntington Disease: Three Ways to Tackle Triplet Disorder 11 Apr 2005
2. It’s an HDAC2 Wrap— Memory-suppressing DNA Modifier Identified 12 May 2009
3. How Does Calorie Restriction Extend Life? 22 Nov 2002
4. Caloric Restriction Increases Metabolic Rate 22 Nov 2002
5. SIRT1 Activator Prevents Metabolic Disorders in Mice 12 Nov 2008
6. Sirtuin Inhibitor Boosts Cognition, Reduces Phospho-tau 8 Nov 2008
7. Mechanisms and Memory: The Choreography of CREB, the Balance of BDNF 16 Jul 2010
8. Research Brief: SIRTs Keep Brain Minty Fresh 25 Jul 2010