Reporting in Cell, Leonard Guarente and colleagues provide a link between the NAD-dependent protein deacetylase SIRT1, forkhead transcription factor FOXO3a and mammalian longevity.

Previous work in Saccharomyces cerevisiae and Caenorhabditis elegans has shown that metabolic shifts increase the activity of SIR2 (known as Sir2 and SIR-2.1 in S. cerevisiae and C. elegans, respectively), which increases lifespan. In addition, in response to mutations in the insulin receptor, the activation of the C. elegans forkhead transcription factor DAF-16 is also known to increase longevity. However, although the data suggest that SIR2 requires DAF-16 for longevity, the mechanism that connects these two proteins has remained unknown.

Now, Guarente and co-workers show that SIRT1, the mammalian SIR2 orthologue, binds to FOXO1, FOXO3a and FOXO4, which are all growth-factor-regulated forkhead transcription factors. In vitro, FOXO3a is acetylated by its co-factor p300, which increases the transcription of FOXO3a target genes, and this effect is enhanced under stress conditions including ultra-violet light or oxidative stress. SIRT1, on the other hand, deacetylates FOXO3a and represses its activity, even under stress conditions. SIRT1 also represses FOXO3a by binding to and deacetylating p300.

Guarente and colleagues confirmed their results in vivo, by showing that in Sirt1−/− mouse embryonic stem (ES) cells Foxo3a activity was increased, and that by adding Sirt1 back to the cells the repression of Foxo3a was restored. In addition, in Sirt1 knockout mice the expression of the forkhead target genes phosphoenolpyruvate carboxykinase 1 ( Pepck ) and insulin-like growth-factor-binding protein-1 ( Igfbp1 ) was increased. And p300, Foxo3a and Foxo1 were all shown to bind to the Foxo DNA-binding site in Sirt1+/+ and Sirt1−/− mice — Sirt1 was also found to bind to the Foxo sites in Sirt1+/+ mice.

So, this work provides a link between two known regulators of lifespan in S. cerevisiae and C. elegans. Interestingly, though, the negative regulation of FOXO3a by SIRT1 in mammals seems to be opposite to the situation in C. elegans, in which it is the activation of DAF-16 that increases longevity.

But how does deacetylation of FOXO3a by SIRT1 repress its activity? The authors suggest that it might destabilize the protein, decrease its DNA-binding activity or alter its interactions with other proteins. The authors also speculate that the negative regulation of FOXO3a by SIRT1 in mammals, and the parallel repression of the tumour suppressor p53 also by SIRT1, could mitigate the effects of ageing by raising the threshold for apoptosis and cell senescence.