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The NAD World: A New Systemic Regulatory Network for Metabolism and Aging—Sirt1, Systemic NAD Biosynthesis, and Their Importance

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Abstract

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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References

  1. 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.

    Article  CAS  Google Scholar 

  2. 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.

  3. Kenyon, C. (2005). The plasticity of aging: Insights from long-lived mutants. Cell, 120, 449–460.

    Article  PubMed  CAS  Google Scholar 

  4. Tatar, M., Bartke, A., & Antebi, A. (2003). The endocrine regulation of aging by insulin-like signals. Science, 299, 1346–1351.

    Article  PubMed  CAS  Google Scholar 

  5. Blander, G., & Guarente, L. (2004). The Sir2 family of protein deacetylases. Annual Review of Biochemistry, 73, 417–435.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Google Scholar 

  7. 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.

    Article  PubMed  CAS  Google Scholar 

  8. 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.

    Article  PubMed  CAS  Google Scholar 

  9. Tissenbaum, H. A., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410, 227–230.

    Article  PubMed  CAS  Google Scholar 

  10. Guarente, L. (2007). Sirtuins in aging and disease. Cold Spring Harbor Symposia on Quantitative Biology, 72, 483–488.

    Article  PubMed  CAS  Google Scholar 

  11. 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.

    Article  PubMed  CAS  Google Scholar 

  12. 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.

    Article  PubMed  CAS  Google Scholar 

  13. Imai, S., & Kiess, W. (2009). Therapeutic potential of SIRT1 and NAMPT-mediated NAD biosynthesis in type 2 diabetes. Frontiers in Bioscience, 14, 2983–2995.

    PubMed  CAS  Google Scholar 

  14. Bishop, N. A., & Guarente, L. (2007). Genetic links between diet and lifespan: Shared mechanisms from yeast to humans. Nature Reviews Genetics, 8, 835–844.

    Article  PubMed  CAS  Google Scholar 

  15. Haigis, M. C., & Guarente, L. P. (2006). Mammalian sirtuins—Emerging roles in physiology, aging, and calorie restriction. Genes and Development, 20, 2913–2921.

    Article  PubMed  CAS  Google Scholar 

  16. Schwer, B., & Verdin, E. (2008). Conserved metabolic regulatory functions of sirtuins. Cell Metabolism, 7, 104–112.

    Article  PubMed  CAS  Google Scholar 

  17. 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.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. 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.

    Article  PubMed  CAS  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. 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.

    Article  PubMed  CAS  Google Scholar 

  23. Qiao, L., & Shao, J. (2006). SIRT1 regulates adiponectin gene expression through foxo1-C/EBPalpha transcriptional complex. The Journal of Biological Chemistry, 281, 39915–39924.

    Article  PubMed  CAS  Google Scholar 

  24. 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.

    Article  PubMed  CAS  Google Scholar 

  25. 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.

    Article  PubMed  CAS  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. 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.

    Article  PubMed  CAS  Google Scholar 

  28. 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.

    Article  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. Ramsey, K. M., Marcheva, B., Kohsaka, A., & Bass, J. (2007). The clockwork of metabolism. Annual Review of Nutrition, 27, 219–240.

    Article  PubMed  CAS  Google Scholar 

  31. Chen, D., Steele, A. D., Lindquist, S., & Guarente, L. (2005). Increase in activity during calorie restriction requires Sirt1. Science, 310, 1641.

    Article  PubMed  CAS  Google Scholar 

  32. 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.

    Article  PubMed  CAS  Google Scholar 

  33. 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.

    Article  PubMed  CAS  Google Scholar 

  34. Bordone, L., & Guarente, L. (2005). Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nature Reviews. Molecular Cell Biology, 6, 298–305.

    Article  PubMed  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. 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.

    Article  PubMed  CAS  Google Scholar 

  37. Rongvaux, A., Andris, F., Van Gool, F., & Leo, O. (2003). Reconstructing eukaryotic NAD metabolism. Bioessays, 25, 683–690.

    Article  PubMed  CAS  Google Scholar 

  38. 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.

    Article  PubMed  CAS  Google Scholar 

  39. Ghislain, M., Talla, E., & Francois, J. M. (2002). Identification and functional analysis of the Saccharomyces cerevisiae nicotinamidase gene, PNC1. Yeast, 19, 215–324.

    Article  PubMed  CAS  Google Scholar 

  40. Collins, P. B., & Chaykin, S. (1972). The management of nicotinamide and nicotinic acid in the mouse. The Journal of Biological Chemistry, 247, 778–783.

    PubMed  CAS  Google Scholar 

  41. 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.

    Article  CAS  Google Scholar 

  42. 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.

    Article  PubMed  CAS  Google Scholar 

  43. 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.

    Article  PubMed  CAS  Google Scholar 

  44. 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.

    Article  PubMed  CAS  Google Scholar 

  45. 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.

    Article  PubMed  CAS  Google Scholar 

  46. 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.

    Article  CAS  Google Scholar 

  47. Arner, P. (2006). Visfatin—A true or false trail to type 2 diabetes mellitus. The Journal of Clinical Endocrinology and Metabolism, 91, 28–30.

    Article  PubMed  CAS  Google Scholar 

  48. Sethi, J. K. (2007). Is PBEF/visfatin/Nampt an authentic adipokine relevant to the metabolic syndrome? Current Hypertension Reports, 9, 33–38.

    Article  PubMed  CAS  Google Scholar 

  49. 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.

    Article  PubMed  CAS  Google Scholar 

  50. 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.

    Article  PubMed  CAS  Google Scholar 

  51. 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.

    PubMed  CAS  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

  53. 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.

    Article  CAS  Google Scholar 

  54. Fukuhara, A., Matsuda, M., Nishizawa, M., Segawa, K., Tanaka, M., Kishimoto, K., et al. (2007). Retraction. Science, 318, 565b.

    Article  Google Scholar 

  55. Bernofsky, C. (1980). Physiology aspects of pyridine nucleotide regulation in mammals. Molecular and Cellular Biochemistry, 33, 135–143.

    Article  PubMed  CAS  Google Scholar 

  56. Yang, H., Lavu, S., & Sinclair, D. A. (2006). Nampt/PBEF/visfatin: A regulator of mammalian health and longevity? Experimental Gerontology, 41, 718–726.

    Article  PubMed  CAS  Google Scholar 

  57. 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.

    Article  PubMed  CAS  Google Scholar 

  58. 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.

    Article  PubMed  CAS  Google Scholar 

  59. 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.

    Article  PubMed  CAS  Google Scholar 

  60. 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.

    Article  PubMed  CAS  Google Scholar 

  61. Roe, D. A. (1973). A plague of corn: The social history of pellagra. Ithaca and London: Cornell University Press.

    Google Scholar 

  62. Carlson, J. M., & Doyle, J. (2000). Highly optimized tolerance: Robustness and design in complex systems. Physical Review Letters, 84, 2529–2532.

    Article  PubMed  CAS  Google Scholar 

  63. Csete, M., & Doyle, J. (2004). Bow ties, metabolism and disease. Trends in Biotechnology, 22, 446–450.

    Article  PubMed  CAS  Google Scholar 

  64. 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.

    Article  PubMed  CAS  Google Scholar 

  65. 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.

    Article  PubMed  CAS  Google Scholar 

  66. 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.

    Google Scholar 

  67. 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.

    Article  PubMed  CAS  Google Scholar 

  68. 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.

    CAS  Google Scholar 

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Acknowledgments

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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  1. Department of Developmental Biology, Washington University School of Medicine, Campus Box 8103, 660 South Euclid Avenue, St. Louis, MO, 63110, USA

    Shin-ichiro Imai

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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

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