Advertisement

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

  • Shin-ichiro ImaiEmail author
Review Paper

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.

Keywords

NAD World Metabolism Aging Sirt1 Nampt Systemic NAD biosynthesis Pancreatic β cells Neurons Robustness Frailty 

Notes

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.

References

  1. 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.CrossRefGoogle Scholar
  2. 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. 3.
    Kenyon, C. (2005). The plasticity of aging: Insights from long-lived mutants. Cell, 120, 449–460.PubMedCrossRefGoogle Scholar
  4. 4.
    Tatar, M., Bartke, A., & Antebi, A. (2003). The endocrine regulation of aging by insulin-like signals. Science, 299, 1346–1351.PubMedCrossRefGoogle Scholar
  5. 5.
    Blander, G., & Guarente, L. (2004). The Sir2 family of protein deacetylases. Annual Review of Biochemistry, 73, 417–435.PubMedCrossRefGoogle Scholar
  6. 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. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 9.
    Tissenbaum, H. A., & Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410, 227–230.PubMedCrossRefGoogle Scholar
  10. 10.
    Guarente, L. (2007). Sirtuins in aging and disease. Cold Spring Harbor Symposia on Quantitative Biology, 72, 483–488.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    Haigis, M. C., & Guarente, L. P. (2006). Mammalian sirtuins—Emerging roles in physiology, aging, and calorie restriction. Genes and Development, 20, 2913–2921.PubMedCrossRefGoogle Scholar
  16. 16.
    Schwer, B., & Verdin, E. (2008). Conserved metabolic regulatory functions of sirtuins. Cell Metabolism, 7, 104–112.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedCrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 30.
    Ramsey, K. M., Marcheva, B., Kohsaka, A., & Bass, J. (2007). The clockwork of metabolism. Annual Review of Nutrition, 27, 219–240.PubMedCrossRefGoogle Scholar
  31. 31.
    Chen, D., Steele, A. D., Lindquist, S., & Guarente, L. (2005). Increase in activity during calorie restriction requires Sirt1. Science, 310, 1641.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 34.
    Bordone, L., & Guarente, L. (2005). Calorie restriction, SIRT1 and metabolism: Understanding longevity. Nature Reviews. Molecular Cell Biology, 6, 298–305.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 37.
    Rongvaux, A., Andris, F., Van Gool, F., & Leo, O. (2003). Reconstructing eukaryotic NAD metabolism. Bioessays, 25, 683–690.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 39.
    Ghislain, M., Talla, E., & Francois, J. M. (2002). Identification and functional analysis of the Saccharomyces cerevisiae nicotinamidase gene, PNC1. Yeast, 19, 215–324.PubMedCrossRefGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 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.CrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.CrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 48.
    Sethi, J. K. (2007). Is PBEF/visfatin/Nampt an authentic adipokine relevant to the metabolic syndrome? Current Hypertension Reports, 9, 33–38.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. 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.CrossRefGoogle Scholar
  54. 54.
    Fukuhara, A., Matsuda, M., Nishizawa, M., Segawa, K., Tanaka, M., Kishimoto, K., et al. (2007). Retraction. Science, 318, 565b.CrossRefGoogle Scholar
  55. 55.
    Bernofsky, C. (1980). Physiology aspects of pyridine nucleotide regulation in mammals. Molecular and Cellular Biochemistry, 33, 135–143.PubMedCrossRefGoogle Scholar
  56. 56.
    Yang, H., Lavu, S., & Sinclair, D. A. (2006). Nampt/PBEF/visfatin: A regulator of mammalian health and longevity? Experimental Gerontology, 41, 718–726.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 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.PubMedCrossRefGoogle Scholar
  61. 61.
    Roe, D. A. (1973). A plague of corn: The social history of pellagra. Ithaca and London: Cornell University Press.Google Scholar
  62. 62.
    Carlson, J. M., & Doyle, J. (2000). Highly optimized tolerance: Robustness and design in complex systems. Physical Review Letters, 84, 2529–2532.PubMedCrossRefGoogle Scholar
  63. 63.
    Csete, M., & Doyle, J. (2004). Bow ties, metabolism and disease. Trends in Biotechnology, 22, 446–450.PubMedCrossRefGoogle Scholar
  64. 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.PubMedCrossRefGoogle Scholar
  65. 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.PubMedCrossRefGoogle Scholar
  66. 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. 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.PubMedCrossRefGoogle Scholar
  68. 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.Google Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Department of Developmental BiologyWashington University School of MedicineSt. LouisUSA

Personalised recommendations