Role of the Forkhead Box O Family and Neuropeptide Y in Calorie Restriction

  • Ryoichi Mori
  • Seongjoon Park
  • Isao ShimokawaEmail author


Calorie restriction (CR) is known to extend lifespan and reduce the risk of various morbidities in lower animals to primates. The effects of CR are regulated by the expression of several age-related genes and a signaling pathway, including forkhead box O (FOXO) and neuropeptide Y (NPY). Heterozygous Foxo1-deficient mice under CR exhibit alterations in cancer development but not lifespan, indicating that FOXO1 contributes to anti-cancer effects in aging. NPY deficiency in mice under CR attenuates lifespan and adiposity but does not affect anticancer efficacy and oxidant stress tolerance, suggesting that NPY might play a role in the regulation of age-related metabolic diseases. Furthermore, intracellular organelles including mitochondria contribute to CR benefits. Recently, CR effects have been examined in individuals, leading to development of CR mimetic compounds. This review summarizes the current insights into the molecular mechanisms linking regulation of age-related genes and CR benefits in mammals.


Calorie restriction Calorie restrictionmimetics Longevity FOXO NPY 


  1. Bartke A, Brown-Borg H (2004) Life extension in the dwarf mouse. Curr Top Dev Biol 63:189–225. doi: 10.1016/s0070-2153(04)63006-7 CrossRefPubMedGoogle Scholar
  2. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444(7117):337–342. doi: 10.1038/nature05354 CrossRefPubMedGoogle Scholar
  3. Bluher M, Kahn BB, Kahn CR (2003) Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299(5606):572–574. doi: 10.1126/science.1078223 CrossRefPubMedGoogle Scholar
  4. Chao PT, Yang L, Aja S, Moran TH, Bi S (2011) Knockdown of NPY expression in the dorsomedial hypothalamus promotes development of brown adipocytes and prevents diet-induced obesity. Cell Metab 13(5):573–583. doi: 10.1016/j.cmet.2011.02.019 PubMedCentralCrossRefPubMedGoogle Scholar
  5. Chiba T, Tsuchiya T, Komatsu T, Mori R, Hayashi H, Shimokawa I (2010) Development of calorie restriction mimetics as therapeutics for obesity, diabetes, inflammatory and neurodegenerative diseases. Curr Genomics 11(8):562–567. doi: 10.2174/138920210793360934 PubMedCentralCrossRefPubMedGoogle Scholar
  6. Chiba T, Tamashiro Y, Park D, Kusudo T, Fujie R, Komatsu T, Kim SE, Park S, Hayashi H, Mori R, Yamashita H, Chung HY, Shimokawa I (2014) A key role for neuropeptide Y in lifespan extension and cancer suppression via dietary restriction. Sci Rep 4:4517. doi: 10.1038/srep04517 PubMedCentralCrossRefPubMedGoogle Scholar
  7. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, Allison DB, Cruzen C, Simmons HA, Kemnitz JW, Weindruch R (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325(5937):201–204. doi: 10.1126/science.1173635 PubMedCentralCrossRefPubMedGoogle Scholar
  8. Friedman DB, Johnson TE (1988) Three mutants that extend both mean and maximum life span of the nematode, Caenorhabditis elegans, define the age-1 gene. J Gerontol 43(4):B102–B109CrossRefPubMedGoogle Scholar
  9. Furuyama T, Kitayama K, Shimoda Y, Ogawa M, Sone K, Yoshida-Araki K, Hisatsune H, Nishikawa S, Nakayama K, Ikeda K, Motoyama N, Mori N (2004) Abnormal angiogenesis in Foxo1 (Fkhr)-deficient mice. J Biol Chem 279(33):34741–34749. doi: 10.1074/jbc.M314214200 CrossRefPubMedGoogle Scholar
  10. Holzenberger M, Dupont J, Ducos B, Leneuve P, Geloen A, Even PC, Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421(6919):182–187. doi: 10.1038/nature01298 CrossRefPubMedGoogle Scholar
  11. Hong SH, Lee KS, Kwak SJ, Kim AK, Bai H, Jung MS, Kwon OY, Song WJ, Tatar M, Yu K (2012) Minibrain/Dyrk1a regulates food intake through the Sir2-FOXO-sNPF/NPY pathway in Drosophila and mammals. PLoS Genet 8(8):e1002857. doi: 10.1371/journal.pgen.1002857 PubMedCentralCrossRefPubMedGoogle Scholar
  12. Hosaka T, Biggs WH 3rd, Tieu D, Boyer AD, Varki NM, Cavenee WK, Arden KC (2004) Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification. Proc Natl Acad Sci U S A 101(9):2975–2980. doi: 10.1073/pnas.0400093101 PubMedCentralCrossRefPubMedGoogle Scholar
  13. Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE ESY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJ, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, Sinclair DA (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339(6124):1216–1219. doi: 10.1126/science.1231097 PubMedCentralCrossRefPubMedGoogle Scholar
  14. Ingram DK, Zhu M, Mamczarz J, Zou S, Lane MA, Roth GS, deCabo R (2006) Calorie restriction mimetics: an emerging research field. Aging Cell 5(2):97–108. doi: 10.1111/j.1474-9726.2006.00202.x CrossRefPubMedGoogle Scholar
  15. Ishihara A, Kanatani A, Mashiko S, Tanaka T, Hidaka M, Gomori A, Iwaasa H, Murai N, Egashira S, Murai T, Mitobe Y, Matsushita H, Okamoto O, Sato N, Jitsuoka M, Fukuroda T, Ohe T, Guan X, MacNeil DJ, Van der Ploeg LH, Nishikibe M, Ishii Y, Ihara M, Fukami T (2006) A neuropeptide Y Y5 antagonist selectively ameliorates body weight gain and associated parameters in diet-induced obese mice. Proc Natl Acad Sci U S A 103(18):7154–7158. doi: 10.1073/pnas.0510320103 PubMedCentralCrossRefPubMedGoogle Scholar
  16. Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R (1993) A C. elegans mutant that lives twice as long as wild type. Nature 366(6454):461–464. doi: 10.1038/366461a0 CrossRefPubMedGoogle Scholar
  17. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G (1997) daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277(5328):942–946CrossRefPubMedGoogle Scholar
  18. Lane MA, Black A, Handy A, Tilmont EM, Ingram DK, Roth GS (2001) Caloric restriction in primates. Ann N Y Acad Sci 928:287–295CrossRefPubMedGoogle Scholar
  19. Lin K, Dorman JB, Rodan A, Kenyon C (1997) daf-16: an HNF-3/forkhead family member that can function to double the life-span of Caenorhabditis elegans. Science 278(5341):1319–1322CrossRefPubMedGoogle Scholar
  20. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192. doi: 10.1038/ncomms3192 PubMedCentralCrossRefPubMedGoogle Scholar
  21. Martins L, Fernandez-Mallo D, Novelle MG, Vazquez MJ, Tena-Sempere M, Nogueiras R, Lopez M, Dieguez C (2012) Hypothalamic mTOR signaling mediates the orexigenic action of ghrelin. PLoS One 7(10):e46923. doi: 10.1371/journal.pone.0046923 PubMedCentralCrossRefPubMedGoogle Scholar
  22. Mattison JA, Roth GS, Beasley TM, Tilmont EM, Handy AM, Herbert RL, Longo DL, Allison DB, Young JE, Bryant M, Barnard D, Ward WF, Qi W, Ingram DK, de Cabo R (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489(7415):318–321. doi: 10.1038/nature11432 CrossRefPubMedGoogle Scholar
  23. McCay CM, Crowell MF, Maynard LA (1935) The effect of retarded growth upon the length of life span and upon the ultimate body size. J Nutr 10(1):63–79Google Scholar
  24. Michalkiewicz M, Knestaut KM, Bytchkova EY, Michalkiewicz T (2003) Hypotension and reduced catecholamines in neuropeptide Y transgenic rats. Hypertension 41(5):1056–1062. doi: 10.1161/01.hyp.0000066623.64368.4e CrossRefPubMedGoogle Scholar
  25. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66(2):191–201. doi: 10.1093/gerona/glq178 CrossRefPubMedGoogle Scholar
  26. Nakae J, Oki M, Cao Y (2008) The FoxO transcription factors and metabolic regulation. FEBS Lett 582(1):54–67. doi: 10.1016/j.febslet.2007.11.025 CrossRefPubMedGoogle Scholar
  27. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389(6654):994–999. doi: 10.1038/40194 CrossRefPubMedGoogle Scholar
  28. Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One 5(1):e8758. doi: 10.1371/journal.pone.0008758 PubMedCentralCrossRefPubMedGoogle Scholar
  29. Paik JH, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z, Miao L, Tothova Z, Horner JW, Carrasco DR, Jiang S, Gilliland DG, Chin L, Wong WH, Castrillon DH, DePinho RA (2007) FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128(2):309–323. doi: 10.1016/j.cell.2006.12.029 PubMedCentralCrossRefPubMedGoogle Scholar
  30. Park S, Fujishita C, Komatsu T, Kim SE, Chiba T, Mori R, Shimokawa I (2014) NPY antagonism reduces adiposity and attenuates age-related imbalance of adipose tissue metabolism. FASEB J. doi: 10.1096/fj.14-258384 Google Scholar
  31. Przybysz AJ, Choe KP, Roberts LJ, Strange K (2009) Increased age reduces DAF-16 and SKN-1 signaling and the hormetic response of Caenorhabditis elegans to the xenobiotic juglone. Mech Ageing Dev 130(6):357–369. doi: 10.1016/j.mad.2009.02.004 PubMedCentralCrossRefPubMedGoogle Scholar
  32. Ruohonen ST, Vahatalo LH, Savontaus E (2012) Diet-induced obesity in mice overexpressing neuropeptide y in noradrenergic neurons. Int J Pept 2012:452524. doi: 10.1155/2012/452524 PubMedCentralCrossRefPubMedGoogle Scholar
  33. Sainsbury A, Zhang L (2012) Role of the hypothalamus in the neuroendocrine regulation of body weight and composition during energy deficit. Obes Rev 13(3):234–257. doi: 10.1111/j.1467-789X.2011.00948.x CrossRefPubMedGoogle Scholar
  34. Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6(4):280–293. doi: 10.1016/j.cmet.2007.08.011 CrossRefPubMedGoogle Scholar
  35. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671. doi: 10.1038/35007534 PubMedGoogle Scholar
  36. Shimokawa I, Higami Y, Utsuyama M, Tuchiya T, Komatsu T, Chiba T, Yamaza H (2002) Life span extension by reduction in growth hormone-insulin-like growth factor-1 axis in a transgenic rat model. Am J Pathol 160(6):2259–2265. doi: 10.1016/s0002-9440(10)61173-x PubMedCentralCrossRefPubMedGoogle Scholar
  37. Son TG, Camandola S, Mattson MP (2008) Hormetic dietary phytochemicals. Neuromolecular Med 10(4):236–246. doi: 10.1007/s12017-008-8037-y PubMedCentralCrossRefPubMedGoogle Scholar
  38. Spindler SR, Li R, Dhahbi JM, Yamakawa A, Mote P, Bodmer R, Ocorr K, Williams RT, Wang Y, Ablao KP (2012) Statin treatment increases lifespan and improves cardiac health in Drosophila by decreasing specific protein prenylation. PLoS One 7(6):e39581. doi: 10.1371/journal.pone.0039581 PubMedCentralCrossRefPubMedGoogle Scholar
  39. Spindler SR, Mote PL, Li R, Dhahbi JM, Yamakawa A, Flegal JM, Jeske DR, Lublin AL (2013) beta1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice. Age (Dordr) 35(6):2099–2109. doi: 10.1007/s11357-012-9498-3 CrossRefGoogle Scholar
  40. Stanley S, Wynne K, McGowan B, Bloom S (2005) Hormonal regulation of food intake. Physiol Rev 85(4):1131–1158. doi: 10.1152/physrev.00015.2004 CrossRefPubMedGoogle Scholar
  41. Yamaza H, Komatsu T, Wakita S, Kijogi C, Park S, Hayashi H, Chiba T, Mori R, Furuyama T, Mori N, Shimokawa I (2010) FoxO1 is involved in the antineoplastic effect of calorie restriction. Aging Cell 9(3):372–382. doi: 10.1111/j.1474-9726.2010.00563.x CrossRefPubMedGoogle Scholar
  42. Zarjevski N, Cusin I, Vettor R, Rohner-Jeanrenaud F, Jeanrenaud B (1993) Chronic intracerebroventricular neuropeptide-Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 133(4):1753–1758. doi: 10.1210/endo.133.4.8404618 PubMedGoogle Scholar

Copyright information

© Springer Japan 2015

Authors and Affiliations

  1. 1.Department of Pathology, Graduate School of Biomedical SciencesNagasaki UniversityNagasakiJapan

Personalised recommendations