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Development of Calorie Restriction Mimetics as Therapeutics for Obesity, Diabetes, Inflammatory and Neurodegenerative Diseases

By Takuya Chiba, Tomoshi Tsuchiya, Toshimitsu Komatsu, Ryoichi Mori, Hiroko Hayashi and Isao Shimokawa


Calorie restriction (CR) is the most robust intervention that decreases morbidity and mortality, and thereby increases the lifespan of many organisms. Although the signaling pathways involved in the beneficial effects of CR are not yet fully understood. Several candidate pathways and key molecules have been identified. The effects of CR are highly conserved from lower organisms such as yeast to higher mammals such as rodents and monkeys. Recent studies have also demonstrated beneficial effects of CR in humans, although we need much longer studies to evaluate whether CR also increases the lifespan of humans. In reality, it is difficult for us to conduct CR interventions in humans because the subjects must be kept in a state of hunger and the duration of this state needed to achieve a clinically meaningful effect is still unknown. Thus, research in this field is focusing on the development of molecules that mimic the beneficial effects of CR without reducing food intake. Some of these candidate molecules include plant-derived functional chemicals (phyto-chemicals), synthetic small molecules, and endocrine molecules such as adipokines. Several studies have already shown that this research field may yield novel drugs for the treatment of age-related diseases such as diabetes. In this article, we describe the target pathways, candidate molecules, and strategies to develop CR mimetics

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  1. (2008). A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genet.,
  2. (2001). A role for ghrelin in the central regulation of feeding. Nature,
  3. (1999). A role for leptin in the antiaging action of dietary restriction: a hypothesis. Aging
  4. (2005). A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life
  5. (2004). Additive regulation of hepatic gene expression by dwarfism and caloric restriction.
  6. (2009). AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature,
  7. (2002). Anti-aging effects of caloric restriction: Involvement of neuroendocrine adaptation by peripheral signaling.
  8. (2007). Association of LKB1 with a WDrepeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction.
  9. (2002). Biomarkers of caloric restriction may predict longevity in humans. Science,
  10. (2010). Caloric restriction: from soup to nuts. Ageing Res. Rev.,
  11. (2006). Calorie restriction mimetics: an emerging research field. Aging Cell,
  12. (2010). Cell biology. Burn out or fade away? Science,
  13. (2010). Development of a bioassay to screen for chemicals mimicking the anti-aging effects of calorie restriction.
  14. (2010). Dietary restriction: standing up for sirtuins. Science,
  15. (2007). Downregulation of AMP-activated protein kinase by calorie restriction in rat li.
  16. (2004). DRESSA: biosensing of dioxin and dioxin-like chemicals using secreted alkaline phosphatase.
  17. (2006). Effect of leptin on hypothalamic gene expression in calorie-restricted rats.
  18. (2005). Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.
  19. (2007). Effects of resveratrol on lifespan
  20. (2010). Extending healthy life span--from yeast to humans. Science,
  21. (2006). Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev.,
  22. (1998). Finding DNA regulatory motifs within unaligned noncoding sequences clustered by whole-genome mRNA quantitation.
  23. (1988). Food restriction in rodents: an evaluation of its role in the study of aging.
  24. (2003). Genetics: influence of TOR kinase on lifespan
  25. (1999). Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature,
  26. (2006). Hepatic gene expression profile of lipid metabolism in rats: Impact of caloric restriction and growth hormone/insulin-like growth factor-1 suppression.
  27. (2006). High levels of dioxin-like potential in cigarette smoke evidenced by in vitro and in vivo biosensing. Cancer Res.,
  28. (2003). Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension,
  29. (2003). Hypothalamic neuropeptide Y/Y1 receptor pathway activated by a reduction in circulating leptin, but not by an increase in circulating ghrelin, contributes to hyperphagia associated with triiodothyronine-induced thyrotoxicosis. Neuroendocrinology,
  30. (2010). Identification and characterization of an insulin receptor substrate 4-interacting pro-566 Current Genomics,
  31. (2005). Identification of potential caloric restriction mimetics by microarray profiling.
  32. (2007). Involvement of insulin-like growth factor-1 in the effect of caloric restriction: regulation of plasma adiponectin
  33. (2007). Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell,
  34. (2009). Metabolic and behavioral compensations in response to caloric restriction: implications for the maintenance of weight loss. PLoS One,
  35. (2010). Metformin supplementation and life span in Fischer-344 rats.
  36. (2004). Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors.
  37. (2007). mTOR signaling: implications for cancer and anticancer
  38. (2010). P.S.; Calorie Restriction Mimetics: Elixirs for a Healthy Life Current Genomics,
  39. (2008). Pituitary growth hormone suppression reduces resistin expression and enhances insulin effectiveness: Relationship with caloric restriction.
  40. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature,
  41. (2004). Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway.
  42. (2005). Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science,
  43. (2008). Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. Cell Metab.,
  44. (2006). Resveratrol improves health and survival of mice on a high-calorie diet. Nature,
  45. (1999). Revisiting the role of fat mass in the life extension induced by caloric restriction.
  46. (2009). Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science,
  47. (2007). Role of insulin and growth hormone/insulin-like growth factor-I signaling in lifespan extension: Rodent longevity models for studying aging and calorie restriction.
  48. (2007). Screening candidate longevity therapeutics using gene-expression arrays. Gerontology,
  49. (2010). Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science,
  50. (2009). Similar metabolic responses to calorie restriction in lean and obese Zucker rats.
  51. (2010). SIRT1 activation by small molecules - kinetic and biophysical evidence for direct interaction of enzyme and
  52. (2010). SIRT1 Regulates ThyroidStimulating Hormone Release by Enhancing PIP5Kc Activity through Deacetylation of Specific Lysine Residues in Mammals. PLoS One,
  53. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature,
  54. (2007). Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature,
  55. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature,
  56. (2010). SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.
  57. (2007). Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic
  58. (2005). The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science,
  59. (2005). The role of insulin and IGF-1 signaling in longevity. Cell Mol Life Sci.,
  60. (2004). The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life
  61. (2008). Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev.,
  62. (2005). Toward a unified theory of caloric restriction and longevity regulation. Mech. Ageing Dev.,
  63. (2000). Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature,