Cell Life Versus Cell Longevity: The Mysteries Surrounding the NAD+ Precursor Nicotinamide

Abstract

Nicotinamide, the amide form of niacin (vitamin B 3 ), is the precursor for the coenzyme β-nicotinamide adenine dinucleotide (NAD + ) and plays a significant role during the enhancement of cell survival as well as cell longevity. Yet, these abilities of nicotinamide appear to be diametrically opposed. Here we describe the development of nicotinamide as a novel agent that is critical for modulating cellular metabolism, plasticity, longevity, and inflammatory microglial function as well as for influencing cellular life span. The capacity of nicotinamide to govern not only intrinsic cellular integrity, but also extrinsic cellular inflammation rests with the modulation of a host of cellular targets that involve mitochondrial membrane potential, poly(ADP-ribose) polymerase, protein kinase B (Akt), Forkhead transcription factors, Bad, caspases, and microglial activation. Further knowledge acquired in regards to the ability of nicotinamide to foster cellular survival and regulate cellular lifespan should significantly promote the development of therapies against a host of disorders, such as aging, Alzheimer's disease, diabetes, cerebral ischemia, Parkinson's disease, and cancer. KeywordsAkt; Alzheimer's disease; apoptosis; caspases; diabetes; erythropoietin; Huntington's disease; microglia; NAD + ; Parkinson's disease; stroke; vitamin B 3 NICOTINAMIDE, NAD + PRECURSOR, AND CELLULAR METABOLISMAs the amide form of niacin or vitamin B 3 , nicotinamide is the precursor for the coenzyme β-nicotinamide adenine dinucleotide (NAD + ) and is essential for the synthesis of nicotinamide adenine dinucleotide phosphate (NADP + ) [1,2]. Nicotinamide and nicotinic acid can be obtained either through synthesis in the body or through a dietary source [3]. The predominant form of niacin in dietary plant sources is nicotinic acid that is rapidly absorbed through the gastrointestinal epithelium. Nicotinamide is formed through the conversion of nicotinic acid in the liver or through the hydrolysis of NAD + . Once nicotinamide is obtained in the body, it is utilized to synthesize NAD + [4].Nicotinamide through NAD + plays a critical physiological role in cellular metabolism and can be directly utilized by cells to synthesize NAD + [4]. Nicotinamide also participates in energy metabolism through the tricarboxylic acid cycle by utilizing NAD + in the mitochondrial respiratory electron transport chain for the production of ATP, DNA synthesis, and DNA repair *Address correspondence to this author at the Department of Neurology, 8C-1 UHC, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI 48201, USA; Fax: 313-966-0486; E-mail: kmaiese@med.wayne.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript [5][6][7]. Furthermore, nicotinamide can significantly increase NAD + levels in vulnerable regions of the ischemic brain, suggesting that nicotinamide may offer cytoprotection of injured tissue through the maintenance of NAD + levels [8]. Administration of nicotinamide can signif...

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