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Life span extension and neuronal cell protection by Drosophila nicotinamidase.
J Biol Chem. 2008 Oct 10; 283(41):27810-9.JB

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+Show Affiliations

Karmanos Cancer Institute, Detroit, Michigan 48201, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18678867

Citation

Balan, Vitaly, et al. "Life Span Extension and Neuronal Cell Protection By Drosophila Nicotinamidase." The Journal of Biological Chemistry, vol. 283, no. 41, 2008, pp. 27810-9.
Balan V, Miller GS, Kaplun L, et al. Life span extension and neuronal cell protection by Drosophila nicotinamidase. J Biol Chem. 2008;283(41):27810-9.
Balan, V., Miller, G. S., Kaplun, L., Balan, K., Chong, Z. Z., Li, F., Kaplun, A., VanBerkum, M. F., Arking, R., Freeman, D. C., Maiese, K., & Tzivion, G. (2008). Life span extension and neuronal cell protection by Drosophila nicotinamidase. The Journal of Biological Chemistry, 283(41), 27810-9. https://doi.org/10.1074/jbc.M804681200
Balan V, et al. Life Span Extension and Neuronal Cell Protection By Drosophila Nicotinamidase. J Biol Chem. 2008 Oct 10;283(41):27810-9. PubMed PMID: 18678867.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Life span extension and neuronal cell protection by Drosophila nicotinamidase. AU - Balan,Vitaly, AU - Miller,Gregory S, AU - Kaplun,Ludmila, AU - Balan,Karina, AU - Chong,Zhao-Zhong, AU - Li,Faqi, AU - Kaplun,Alexander, AU - VanBerkum,Mark F A, AU - Arking,Robert, AU - Freeman,D Carl, AU - Maiese,Kenneth, AU - Tzivion,Guri, Y1 - 2008/08/04/ PY - 2008/8/6/pubmed PY - 2008/11/11/medline PY - 2008/8/6/entrez SP - 27810 EP - 9 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 283 IS - 41 N2 - 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. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18678867/Life_span_extension_and_neuronal_cell_protection_by_Drosophila_nicotinamidase_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=18678867 DB - PRIME DP - Unbound Medicine ER -