For the past several years, it has been demonstrated that the NAD-dependent protein deacetylase Sirt1 and nicotinamide phosphoribosyltransferase (Nampt)-mediated systemic NAD biosynthesis together play a critical role in the regulation of metabolism and possibly aging in mammals. Based on our recent studies on these two critical components, we have developed a hypothesis of a novel systemic regulatory network, named “NAD World”, for mammalian aging. Conceptually, in the NAD World, systemic NAD biosynthesis mediated by intra- and extracellular Nampt functions as a driver that keeps up the pace of metabolism in multiple tissues/organs, and the NAD-dependent deacetylase Sirt1 serves as a universal mediator that executes metabolic effects in a tissue-dependent manner in response to changes in systemic NAD biosynthesis. This new concept of the NAD World provides important insights into a systemic regulatory mechanism that fundamentally connects metabolism and aging and also conveys the ideas of functional hierarchy and frailty for the regulation of metabolic robustness and aging in mammals.
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Berryman, D. E., Christiansen, J. S., Johannsson, G., Thorner, M. O., & Kopchick, J. J. (2008). Role of the GH/IGF-1 axis in lifespan and healthspan: Lessons from animal models. Growth Hormone & IGF Research, 18, 455–471.
Brown-Borg, H. M. (2008). Hormonal control of aging in rodents: The somatotropic axis. Molecular and Cellular Endocrinology. doi:10.1016/j.mce.2008.07.001.
Kenyon, C. (2005). The plasticity of aging: Insights from long-lived mutants. Cell, 120, 449–460.
Tatar, M., Bartke, A., & Antebi, A. (2003). The endocrine regulation of aging by insulin-like signals. Science, 299, 1346–1351.
Blander, G., & Guarente, L. (2004). The Sir2 family of protein deacetylases. Annual Review of Biochemistry, 73, 417–435.
Imai, S., & Guarente, L. (2007). Sirtuins: A universal link between NAD, metabolism, and aging. In L. Guarente, L. Partridge, & D. Wallace (Eds.), The molecular biology of aging (pp. 39–72). New York: Cold Spring Habor Laboratory Press.
Imai, S., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 403, 795–800.
Rogina, B., & Helfand, S. L. (2004). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proceedings of the National Academy of Sciences of the United States of America, 101, 15998–16003.
Tissenbaum, H. A., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410, 227–230.
Guarente, L. (2007). Sirtuins in aging and disease. Cold Spring Harbor Symposia on Quantitative Biology, 72, 483–488.
Starai, V. J., Takahashi, H., Boeke, J. D., & Escalante-Semerena, J. C. (2004). A link between transcription and intermediary metabolism: A role for Sir2 in the control of acetyl-coenzyme A synthetase. Current Opinion in Microbiology, 7, 115–119.
Westphal, C. H., Dipp, M. A., & Guarente, L. (2007). A therapeutic role for sirtuins in diseases of aging? Trends in Biochemical Sciences, 32, 555–560.
Imai, S., & Kiess, W. (2009). Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes. Frontiers in Bioscience, 14, 2983–2995.
Bishop, N. A., & Guarente, L. (2007). Genetic links between diet and lifespan: Shared mechanisms from yeast to humans. Nature Reviews Genetics, 8, 835–844.
Haigis, M. C., & Guarente, L. P. (2006). Mammalian sirtuins—Emerging roles in physiology, aging, and calorie restriction. Genes and Development, 20, 2913–2921.
Schwer, B., & Verdin, E. (2008). Conserved metabolic regulatory functions of sirtuins. Cell Metabolism, 7, 104–112.
Rodgers, J. T., Lerin, C., Haas, W., Gygi, S. P., Spiegelman, B. M., & Puigserver, P. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature, 434, 113–118.
Rodgers, J. T., & Puigserver, P. (2007). Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proceedings of the National Academy of Sciences of the United States of America, 104, 12861–12866.
Li, X., Zhang, S., Blander, G., Tse, J. G., Krieger, M., & Guarente, L. (2007). SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Molecular Cell, 28, 91–106.
Gerhart-Hines, Z., Rodgers, J. T., Bare, O., Lerin, C., Kim, S. H., Mostoslavsky, R., et al. (2007). Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. The EMBO Journal, 26, 1913–1923.
Sun, C., Zhang, F., Ge, X., Yan, T., Chen, X., Shi, X., et al. (2007). SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B. Cell Metabolism, 6, 307–319.
Picard, F., Kurtev, M., Chung, N., Topark-Ngarm, A., Senawong, T., Oliveira, R. M., et al. (2004). Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-γ. Nature, 429, 771–776.
Qiao, L., & Shao, J. (2006). SIRT1 regulates adiponectin gene expression through foxo1-C/EBPalpha transcriptional complex. The Journal of Biological Chemistry, 281, 39915–39924.
Wang, H., Qiang, L., & Farmer, S. R. (2008). Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Molecular and Cellular Biology, 28, 188–200.
Bordone, L., Motta, M. C., Picard, F., Robinson, A., Jhala, U. S., Apfeld, J., et al. (2006). Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biology, 4, e31.
Moynihan, K. A., Grimm, A. A., Plueger, M. M., Bernal-Mizrachi, E., Ford, E., Cras-Meneur, C., et al. (2005). Increased dosage of mammalian Sir2 in pancreatic β cells enhances glucose-stimulated insulin secretion in mice. Cell Metabolism, 2, 105–117.
Asher, G., Gatfield, D., Stratmann, M., Reinke, H., Dibner, C., Kreppel, F., et al. (2008). SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell, 134, 317–328.
Nakahata, Y., Kaluzova, M., Grimaldi, B., Sahar, S., Hirayama, J., Chen, D., et al. (2008). The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell, 134, 329–340.
Lowrey, P. L., & Takahashi, J. S. (2000). Genetics of the mammalian circadian system: Photic entrainment, circadian pacemaker mechanisms, and posttranslational regulation. Annual Review of Genetics, 34, 533–562.
Ramsey, K. M., Marcheva, B., Kohsaka, A., & Bass, J. (2007). The clockwork of metabolism. Annual Review of Nutrition, 27, 219–240.
Chen, D., Steele, A. D., Lindquist, S., & Guarente, L. (2005). Increase in activity during calorie restriction requires Sirt1. Science, 310, 1641.
Boily, G., Seifert, E. L., Bevilacqua, L., He, X. H., Sabourin, G., Estey, C., et al. (2008). SirT1 regulates energy metabolism and response to caloric restriction in mice. PLoS ONE, 3, e1759.
Bordone, L., Cohen, D., Robinson, A., Motta, M. C., van Veen, E., Czopik, A., et al. (2007). SIRT1 transgenic mice show phenotypes resembling calorie restriction. Aging Cell, 6, 759–767.
Bordone, L., & Guarente, L. (2005). Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nature Reviews. Molecular Cell Biology, 6, 298–305.
Magni, G., Amici, A., Emanuelli, M., Orsomando, G., Raffaelli, N., & Ruggieri, S. (2004). Enzymology of NAD+ homeostasis in man. Cellular and Molecular Life Sciences, 61, 19–34.
Revollo, J. R., Grimm, A. A., & Imai, S. (2007). The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin in mammals. Current Opinion in Gastroenterology, 23, 164–170.
Rongvaux, A., Andris, F., Van Gool, F., & Leo, O. (2003). Reconstructing eukaryotic NAD metabolism. Bioessays, 25, 683–690.
Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O., & Sinclair, D. A. (2003). Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae. Nature, 423, 181–185.
Ghislain, M., Talla, E., & Francois, J. M. (2002). Identification and functional analysis of the Saccharomyces cerevisiae nicotinamidase gene, PNC1. Yeast, 19, 215–324.
Collins, P. B., & Chaykin, S. (1972). The management of nicotinamide and nicotinic acid in the mouse. The Journal of Biological Chemistry, 247, 778–783.
Khan, J. A., Tao, X., & Tong, L. (2006). Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents. Nature Structural & Molecular Biology, 13, 582–588.
Kim, M. K., Lee, J. H., Kim, H., Park, S. J., Kim, S. H., Kang, G. B., et al. (2006). Crystal structure of visfatin/pre-B cell colony-enhancing factor 1/nicotinamide phosphoribosyltransferase, free and in complex with the anti-cancer agent FK-866. Journal of Molecular Biology, 362, 66–77.
Revollo, J. R., Grimm, A. A., & Imai, S. (2004). The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells. The Journal of Biological Chemistry, 279, 50754–50763.
Rongvaux, A., Shea, R. J., Mulks, M. H., Gigot, D., Urbain, J., Leo, O., et al. (2002). Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis. European Journal of Immunology, 32, 3225–3234.
van der Veer, E., Nong, Z., O’Neil, C., Urquhart, B., Freeman, D., & Pickering, J. G. (2005). Pre-B-cell colony-enhancing factor regulates NAD+-dependent protein deacetylase activity and promotes vascular smooth muscle cell maturation. Circulation Research, 97, 25–34.
Wang, T., Zhang, X., Bheda, P., Revollo, J. R., Imai, S., & Wolberger, C. (2006). Structure of Nampt/PBEF/visfatin, a mammalian NAD(+) biosynthetic enzyme. Nature Structural & Molecular Biology, 13, 661–662.
Arner, P. (2006). Visfatin—A true or false trail to type 2 diabetes mellitus. The Journal of Clinical Endocrinology and Metabolism, 91, 28–30.
Sethi, J. K. (2007). Is PBEF/visfatin/Nampt an authentic adipokine relevant to the metabolic syndrome? Current Hypertension Reports, 9, 33–38.
Stephens, J. M., & Vidal-Puig, A. J. (2006). An update on visfatin/pre-B cell colony-enhancing factor, an ubiquitously expressed, illusive cytokine that is regulated in obesity. Current Opinion in Lipidology, 17, 128–131.
Revollo, J. R., Körner, A., Mills, K. F., Satoh, A., Wang, T., Garten, A., et al. (2007). Nampt/PBEF/visfatin regulates insulin secretion in β cells as a systemic NAD biosynthetic enzyme. Cell Metabolism, 6, 363–375.
Samal, B., Sun, Y., Stearns, G., Xie, C., Suggs, S., & McNiece, I. (1994). Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor. Molecular and Cellular Biology, 14, 1431–1437.
Fukuhara, A., Matsuda, M., Nishizawa, M., Segawa, K., Tanaka, M., Kishimoto, K., et al. (2005). Visfatin: A protein secreted by visceral fat that mimics the effects of insulin. Science, 307, 426–430.
Li, Y., Zhang, Y., Dorweiler, B., Cui, D., Wang, T., Woo, C. W., et al. (2008). Extracellular Nampt promotes macrophages survival via a non-enzymatic interleukin-6/STAT3 signaling mechanism. The Journal of Biological Chemistry, 280, 34833–34843.
Fukuhara, A., Matsuda, M., Nishizawa, M., Segawa, K., Tanaka, M., Kishimoto, K., et al. (2007). Retraction. Science, 318, 565b.
Bernofsky, C. (1980). Physiology aspects of pyridine nucleotide regulation in mammals. Molecular and Cellular Biochemistry, 33, 135–143.
Yang, H., Lavu, S., & Sinclair, D. A. (2006). Nampt/PBEF/visfatin: A regulator of mammalian health and longevity? Experimental Gerontology, 41, 718–726.
Ramsey, K. M., Mills, K. F., Satoh, A., & Imai, S. (2008). Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in β cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell, 7, 78–88.
Basu, R., Breda, E., Oberg, A. L., Powell, C. C., Dalla Man, C., Basu, A., et al. (2003). Mechanisms of the age-associated deterioration in glucose tolerance: Contribution of alterations in insulin secretion, action, and clearance. Diabetes, 52, 1738–1748.
Iozzo, P., Beck-Nielsen, H., Laakso, M., Smith, U., Yki-Jarvinen, H., & Ferrannini, E. (1999). Independent influence of age on basal insulin secretion in nondiabetic humans. European Group for the Study of Insulin Resistance. The Journal of Clinical Endocrinology and Metabolism, 84, 863–868.
Muzumdar, R., Ma, X., Atzmon, G., Vuguin, P., Yang, X., & Barzilai, N. (2004). Decrease in glucose-stimulated insulin secretion with aging is independent of insulin action. Diabetes, 53, 441–446.
Roe, D. A. (1973). A plague of corn: The social history of pellagra. Ithaca and London: Cornell University Press.
Carlson, J. M., & Doyle, J. (2000). Highly optimized tolerance: Robustness and design in complex systems. Physical Review Letters, 84, 2529–2532.
Csete, M., & Doyle, J. (2004). Bow ties, metabolism and disease. Trends in Biotechnology, 22, 446–450.
Zhou, T., Carlson, J. M., & Doyle, J. (2002). Mutation, specialization, and hypersensitivity in highly optimized tolerance. Proceedings of the National Academy of Sciences of the United States of America, 99, 2049–2054.
Yang, H., Yang, T., Baur, J. A., Perez, E., Matsui, T., Carmona, J. J., et al. (2007). Nutrient-sensitive mitochondrial NAD(+) levels dictate cell survival. Cell, 130, 1095–1107.
Gardner, E. M. (2005). Caloric restriction decreases survival of aged mice in response to primary influenza infection. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 60, 688–694.
Ritz, B. W., Aktan, I., Nogusa, S., & Gardner, E. M. (2008). Energy restriction impairs natural killer cell function and increases the severity of influenza infection in young adult male C57BL/6 mice. The Journal of Nutrition, 138, 2269–2275.
Roecker, E. B., Kemnitz, J. W., Ershler, W. B., & Weindruch, R. (1996). Reduced immune responses in rhesus monkeys subjected to dietary restriction. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 51, B276–B279.
I thank all members of the Imai lab for their helpful discussions and comments. I apologize to those whose work is not cited due to the focus of this review and space limitations. This work was supported by grants from the National Institute on Aging (AG024150), Ellison Medical Foundation, and Longer Life Foundation to S. I.
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Imai, Si. The NAD World: A New Systemic Regulatory Network for Metabolism and Aging—Sirt1, Systemic NAD Biosynthesis, and Their Importance. Cell Biochem Biophys 53, 65–74 (2009). https://doi.org/10.1007/s12013-008-9041-4