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J. Biol. Chem., Vol. 283, Issue 41, 27810-27819, October 10, 2008

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Life Span Extension and Neuronal Cell Protection by Drosophila Nicotinamidase^*

Vitaly Balan¹, Gregory S. Miller^¶1, Ludmila Kaplun¹, Karina Balan¹, Zhao-Zhong Chong^||, Faqi Li^||, Alexander Kaplun, Mark F. A. VanBerkum^¶, Robert Arking^¶, D. Carl Freeman^¶, Kenneth Maiese^||, and Guri Tzivion²

From the Karmanos Cancer Institute and the Departments of Pathology, ^¶Biological Sciences, and ^||Neurology, Anatomy & Cell Biology, Wayne State University, Detroit, Michigan 48201

The life span of model organisms can be modulated by environmental conditions that influence cellular metabolism, oxidation, or DNA integrity. The yeast nicotinamidase gene pnc1 was identified as a key transcriptional target and mediator of calorie restriction and stress-induced life span extension. PNC1 is thought to exert its effect on yeast life span by modulating cellular nicotinamide and NAD levels, resulting in increased activity of Sir2 family class III histone deacetylases. In Caenorhabditis elegans, knockdown of a pnc1 homolog was shown recently to shorten the worm life span, whereas its overexpression increased survival under conditions of oxidative stress. The function and regulation of nicotinamidases in higher organisms has not been determined. Here, we report the identification and biochemical characterization of the Drosophila nicotinamidase, D-NAAM, and demonstrate that its overexpression significantly increases median and maximal fly life span. The life span extension was reversed in Sir2 mutant flies, suggesting Sir2 dependence. Testing for physiological effectors of D-NAAM in Drosophila S2 cells, we identified oxidative stress as a primary regulator, both at the transcription level and protein activity. In contrast to the yeast model, stress factors such as high osmolarity and heat shock, calorie restriction, or inhibitors of TOR and phosphatidylinositol 3-kinase pathways do not appear to regulate D-NAAM in S2 cells. Interestingly, the expression of D-NAAM in human neuronal cells conferred protection from oxidative stress-induced cell death in a sirtuin-dependent manner. Together, our findings establish a life span extending the ability of nicotinamidase in flies and offer a role for nicotinamide-modulating genes in oxidative stress regulated pathways influencing longevity and neuronal cell survival.

Received for publication, June 19, 2008 , and in revised form, July 25, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01-GM067134 (to G. T.) and NS053946 (to K. M.). This work was also supported by the American Diabetes Association, the American Heart Association Bugher Foundation Award, and Wayne State University institutional support (to M. V. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Tables S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Karmanos Cancer Institute, 4100 John R., HWCRC-716, Detroit, MI 48201. Tel.: 313-576-8311; Fax: 313-576-8308; E-mail: tziviong{at}karmanos.org.

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