Aim: 

Sirtuins are NAD-dependent deacetylases that modulate metabolism, the rate of ageing and other critical physiological parameters. The role of the NAD/NADH redox ratio in the regulation of sirtuins has been proposed. To test this idea, researchers have measured NAD and NADH in several cellular models. However, in a pioneer study Krebs and co-workers showed that direct measurement of tissue content of NAD and NADH do not supply the required information: they fail to differentiate between free and bound nucleotides.

Methods: 

We have used cell culture, invertebrates (Drosophila) and vertebrates (mice) models to study the regulation of sirtuins.

Results: 

We have found that buffering NAD/NADH pair with known concentrations of lactate and pyruvate regulates sirtuin expression in 3T3 fibroblasts in culture. Ethanol, which affects NAD/NADH ratio, also up-regulates sirtuin expression in this model. In Drosophila, ethanol up-regulates sirtuin expression and these results in an increased average life span of the flies. Exercise causes a significant increase in lactate-pyruvate ratio and thus changes in NAD-NADH.

Conclusion: 

The importance of this study lies in the fact that sirtuin expression does not depend on levels of free NAD or NADH but rather on the ratio of these co-enzymes in tissues. This ratio can be modulated by many physiological manipulations like exercise or moderate ethanol intake. We have observed that these metabolic changes result in significant increases in average life span of the animals. The importance of these facts is to understand the role of oxidation in longevity.

This work has been supported by BFU2007-65803/BFI and ISCIII2006-RED13-027 from the 'Red Temática de investigación cooperativa en envejecimiento y fragilidad' (RETICEF RD06/003–027) to J.V., by grant GV/2007/263 to C.B and by grants GVPRE/2008/138 and Catholic University 2008-011-002 to J. G.