title: Life span extension and neuronal cell protection by Drosophila nicotinamidase.
abstract: 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.
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
authors.forename: Vitaly
authors.initials: V
authors.lastname: Balan
authors.affiliation: Biological Sciences, Wayne State University, Detroit, Michigan 48201.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Miller
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Kaplun
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
authors.forename: Karina
authors.initials: K
authors.lastname: Balan
authors.affiliation: Neurology, Anatomy & Cell Biology, Wayne State University, Detroit, Michigan 48201.
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Chong
authors.affiliation: Neurology, Anatomy & Cell Biology, Wayne State University, Detroit, Michigan 48201.
authors.forename: Faqi
authors.initials: F
authors.lastname: Li
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kaplun
authors.affiliation: Biological Sciences, Wayne State University, Detroit, Michigan 48201.
authors.forename: Mark F A
authors.initials: MFA
authors.lastname: VanBerkum
authors.affiliation: Biological Sciences, Wayne State University, Detroit, Michigan 48201.
authors.forename: Robert
authors.initials: R
authors.lastname: Arking
authors.affiliation: Biological Sciences, Wayne State University, Detroit, Michigan 48201.
authors.forename: D Carl
authors.initials: DC
authors.lastname: Freeman
authors.affiliation: Neurology, Anatomy & Cell Biology, Wayne State University, Detroit, Michigan 48201.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Maiese
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201. Electronic address: tziviong@karmanos.org.
authors.forename: Guri
authors.initials: G
authors.lastname: Tzivion
mesh_terms: D000818:Animals; D019556:COS Cells; D031204:Caloric Restriction; D002470:Cell Survival / Q000502:physiology; D002522:Chlorocebus aethiops; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D018869:Heat-Shock Response / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008136:Longevity / Q000502:physiology*; D008954:Models, Biological; D009154:Mutation; D009474:Neurons / Q000201:enzymology*; D009535:Nicotinamidase / Q000096:biosynthesis* / Q000235:genetics; D009997:Osmotic Pressure; D018384:Oxidative Stress / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; D006655:Histone Deacetylases; D009535:Nicotinamidase; D019869:Phosphatidylinositol 3-Kinases; D037761:Sirtuins; C447899:Sirt2 protein, Drosophila