Life span extension and neuronal cell protection by Drosophila nicotinamidase.
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.
Balan
Vitaly
V
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
Miller
Gregory S
GS
Biological Sciences, Wayne State University, Detroit, Michigan 48201.
Kaplun
Ludmila
L
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
Balan
Karina
K
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
Chong
Zhao-Zhong
ZZ
Neurology, Anatomy & Cell Biology, Wayne State University, Detroit, Michigan 48201.
Li
Faqi
F
Neurology, Anatomy & Cell Biology, Wayne State University, Detroit, Michigan 48201.
Kaplun
Alexander
A
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201.
VanBerkum
Mark F A
MFA
Biological Sciences, Wayne State University, Detroit, Michigan 48201.
Arking
Robert
R
Biological Sciences, Wayne State University, Detroit, Michigan 48201.
Freeman
D Carl
DC
Biological Sciences, Wayne State University, Detroit, Michigan 48201.
Maiese
Kenneth
K
Neurology, Anatomy & Cell Biology, Wayne State University, Detroit, Michigan 48201.
Tzivion
Guri
G
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Pathology, Wayne State University, Detroit, Michigan 48201. Electronic address: tziviong@karmanos.org.
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*
D029721:Drosophila Proteins; D006655:Histone Deacetylases; D009535:Nicotinamidase; D019869:Phosphatidylinositol 3-Kinases; D037761:Sirtuins; C447899:Sirt2 protein, Drosophila