Skip to main content

Advertisement

SpringerLink
Log in

The roles of FoxOs in modulation of aging by calorie restriction

  • Review Article
  • Published:
Biogerontology Aims and scope Submit manuscript

Abstract

FoxO activity and modifications, such as its phosphorylation, acetylation, and methylation, may help drive the expression of genes involved in combating oxidative stress by causing the epigenetic modifications, and thus, preserve cellular function during aging and age-related diseases, such as diabetes, cancer, and Alzheimer disease. Insulin signaling has been postulated to influence the aging process by increasing resistance to oxidative stress, and slowing the accumulation of oxidative damage. Some antioxidative effects are mediated by a conserved family of forkhead box transcription factors (FoxOs), which in the absence of insulin signaling freely bind to promoters of antioxidant enzymes, superoxide dismutase, and catalase. On the other hand, calorie restriction (CR) extends the lifespans of several species via the insulin pathway, and extends longevity and healthspan in diverse species via a conserved mechanism. CR enhances adaptive stress responses at the cellular and organism levels and extends lifespan in a FoxO-independent manner. Thus, increased modification of FoxO is modulated via the hyperinsulinemia-induced PI3K/Akt pathway during aging, and CR reverses this process. Accordingly, FoxO plays an important role in maintenance of metabolic homeostasis and removal of oxidative stress in the aging process and in the effect of CR on lifespan.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Accili D, Arden KC (2004) FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117:421–426

    CAS  PubMed  Google Scholar 

  • Almeida M, Han L, Martin-Millan M, O’Brien CA, Manolagas SC (2007) Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor-to forkhead box O-mediated transcription. J Biol Chem 282:27298–27305

    CAS  PubMed  Google Scholar 

  • Aoki M, Jiang H, Vogt PK (2004) Proteasomal degradation of the FoxO1 transcriptional regulator in cells transformed by the P3k and Akt oncoproteins. Proc Natl Acad Sci USA 101:13613–13617

    CAS  PubMed Central  PubMed  Google Scholar 

  • Asada S, Daitoku H, Matsuzaki H, Saito T, Sudo T, Mukai H, Iwashita S, Kako K, Kishi T, Kasuya Y, Fukamizu A (2007) Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell Signal 19:519–527

    CAS  PubMed  Google Scholar 

  • Bakker WJ, Blazquez-Domingo M, Kolbus A, Besooyen J, Steinlein P, Beug H, Coffer PJ, Lowenberq B, von Lindern M, van Dijk TB (2004) FoxO3a regulates erythroid differentiation and induces BTG1, an activator of protein arginine methyl transferase I. J Cell Biol 164:175–184

    CAS  PubMed Central  PubMed  Google Scholar 

  • Balaban R, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and aging. Cell 120:483–495

    CAS  PubMed  Google Scholar 

  • Barthel A, Schmoll D, Kruger KD, Roth RA, Joost HG (2002) Regulation of the forkhead transcription factor FKHR (FOXO1a) by glucose starvation and AICAR, an activator of AMP-activated protein kinase. Endocrinology 143:3183–3186

    CAS  PubMed  Google Scholar 

  • Barthel A, Schmoll D, Unterman TG (2005) FoxO proteins in insulin action and metabolism. Trends Endocrinol Metab 16:183–189

    CAS  PubMed  Google Scholar 

  • Barthelemy C, Henderson CE, Pettmann B (2004) Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK. BMC Neurosci 5:48

    PubMed Central  PubMed  Google Scholar 

  • Berg BN, Simms HS (1960) Nutrition and longevity in the rat. II. Longevity and onset of disease with different levels of food intake. J Nutr 71:255–263

    CAS  PubMed  Google Scholar 

  • Biggs WH, Meisenhelder J, Hunter T, Cavenee WK, Arden KC (1999) Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci USA 96:7421–7426

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bordone L, Guarente L (2005) Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 6:298–305

    CAS  PubMed  Google Scholar 

  • Brenkman AB, de Keizer PL, van den Broek NJ, Jochemsen AG, Burgering BM (2008) Mdm2 induces mono-ubiquitination of FOXO4. PLoS One 3:e2819

    PubMed Central  PubMed  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96:857–868

    CAS  PubMed  Google Scholar 

  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME (2004) Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303:2011–2015

    CAS  PubMed  Google Scholar 

  • Calabrese V, Cornelius C, Cuzzocrea S, Iavicoli I, Rizzarelli E, Calabrese EJ (2011) Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol Aspects Med 32:279–304

    CAS  PubMed  Google Scholar 

  • Calvanese V, Lara E, Kahn A, Fraga MF (2009) The role of epigenetics in aging and age-related diseases. Ageing Res Rev 8:268–276

    CAS  PubMed  Google Scholar 

  • Cameron AR, Anton S, Melville L, Houston NP, Dayal S, McDougall GJ, Stewart D, Rena G (2008) Black tea polyphenols mimic insulin/insulin-like growth factor-1 signaling to the longevity factor FoxO1a. Aging Cell 7:69–77

    CAS  PubMed  Google Scholar 

  • Campisi J, di Fagagna FD (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740

    CAS  PubMed  Google Scholar 

  • Canto’ C, Auwerx J (2009) Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab 20:325–331

    Google Scholar 

  • Castrillon DH, Miao L, Kollipara R, Horner JW, DePinho PA (2003) Suppression of ovarian follicle activation in mice by the transcription factor Foxo3a. Science 301:215–218

    CAS  PubMed  Google Scholar 

  • 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 11:562–567

    CAS  PubMed Central  PubMed  Google Scholar 

  • Choi KM, Lee HL, Kwon YY, Kang MS, Lee SK, Lee CK (2013) Enhancement of mitochondrial function correlates with the extension of lifespan by caloric restriction and caloric restriction mimetics in yeast. Biochem Biophys Res Commun 441:236–242

    CAS  PubMed  Google Scholar 

  • Chung HY, Lee EK, Choi YJ, Kim JM, Kim DH, Zou Y, Kim CH, Lee J, Kim HS, Kim ND, Jung JH, Yu BP (2011) Molecular inflammation as an underlying mechanism of the aging process and age-related diseases. J Dent Res 90:830–840

    CAS  PubMed  Google Scholar 

  • Clavel S, Coldefy AS, Kurkdjian E, Salles J, Margaritis I, Derijard B (2006) Atrophy-related ubiquitin ligases, atrogin-1, and MuRF1 are up-regulated in aged rat tibialis anterior muscle. Mech Aging Dev 127:794–801

    CAS  PubMed  Google Scholar 

  • Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A (2006) Opposing activities protect against age-onset proteotoxicity. Science 313:1604–1610

    CAS  PubMed  Google Scholar 

  • Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233

    CAS  PubMed  Google Scholar 

  • Daitoku H, Yamagata K, Matsuzaki H, Hatta M, Fukamizu A (2003) Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes 52:642–649

    CAS  PubMed  Google Scholar 

  • Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyaqishi M, Nakajima T, Fukamizu A (2004) Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA 101:10042–10047

    CAS  PubMed Central  PubMed  Google Scholar 

  • del Peso L, Gonzalez VM, Hernandez R, Barr FG, Nunez G (1999) Regulation of the forkhead transcription factor FKHR, but not the PAX3-FKHR fusion protein, by the serine/threonine kinase Akt. Oncogene 18:7328–7333

    PubMed  Google Scholar 

  • Delpuech O, Griffiths B, East P, Essafi A, Lam EW, Burgering B, Downward J, Schulze A (2007) Induction of Mxi1-SR(alpha) by FOXO3a contributes to repression of Myc-dependent gene expression. Mol Cell Biol 27:4917–4930

    CAS  PubMed Central  PubMed  Google Scholar 

  • Demetrius L (2005) Of mice and men. When it comes to studying ageing and the means to slow it down, mice are not just small humans. EMBO Rep 6:39–44

    Google Scholar 

  • Demetrius L (2006) Aging in mouse and human systems: a comparative study. Ann NY Acad Sci 1067:66–82

    CAS  PubMed  Google Scholar 

  • Dixit M, Bess E, Fisslthaler B, Hartel FV, Noll T, Busse R, Fleminq I (2007) Shear stress-induced activation of the AMP-activated protein kinase regulates FoxO1a and angiopoietin-2 in endothelial cells. Cardiovasc Res 77:160–168

    PubMed  Google Scholar 

  • Dowell P, Otto TC, Adi S, Lane MD (2003) Convergence of peroxisome proliferator-activated receptor gamma and Foxo1 signaling pathways. J Biol Chem 278:45485–45491

    CAS  PubMed  Google Scholar 

  • Edstrom E, Altun M, Hagglund M, Ulfhake B (2006) Atrogin-1/MAFbx and MuRF1 are downregulated in aging-related loss of skeletal muscle. J Gerontol A Biol Sci Med Sci 61:663–674

    PubMed  Google Scholar 

  • Essers MA, Weijzen S, deVries-Smits AM, Saarloos I, de Ruiter ND, Bos JL, Burgering BM (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23:4802–4812

    CAS  PubMed Central  PubMed  Google Scholar 

  • Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308:1181–1184

    CAS  PubMed  Google Scholar 

  • Evans-Anderson HJ, Alfieri CM, Yutzey KE (2008) Regulation of cardiomyocyte proliferation and myocardial growth during development by FOXO transcription factors. Circ Res 102:686–694

    CAS  PubMed  Google Scholar 

  • Fischle W, Wang Y, Allis CD (2003) Histone and chromatin cross-talk. Curr Opin Cell Biol 15:172–183

    CAS  PubMed  Google Scholar 

  • Fontana L, Partridge L, Longo VD (2010) Extending healthy life span-from yeast to humans. Science 328:321–326

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fraga ME, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suñer D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA 102:10604–10609

    CAS  PubMed Central  PubMed  Google Scholar 

  • Frescas D, Valenti L, Accili D (2005) Nuclear trapping of the forkhead transcription factor FoxO1 via Sirt-dependent deacetylation promotes expression of glucogenetic genes. J Biol Chem 280:20589–20595

    CAS  PubMed  Google Scholar 

  • Fu W, Ma Q, Chen L, Li P, Zhanq M, Ramamoorthy S, Nawaz Z, Shimojima T, Wanq H, Yanq Y, Shen Z, Zhanq Y, Zhanq X, Nicosia SV, Zhanq Y, Pledqer JW, Chen J, Bai W (2009) MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation. J Biol Chem 284:13987–14000

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fukuoka M, Daitoku H, Hatta M, Matsuzaki H, Umemura S, Fukamizu A (2003) Negative regulation of forkhead transcription factor AFX (Foxo4) by CBP-induced acetylation. Int J Mol Med 12:503–508

    CAS  PubMed  Google Scholar 

  • Furukawa-Hibi Y, Yoshida-Araki K, Ohta T, Ikeda K, Motoyama N (2002) FOXO forkhead transcription factors induce G(2)-M checkpoint in response to oxidative stress. J Biol Chem 277:26729–26732

    CAS  PubMed  Google Scholar 

  • Furukawa-Hibi Y, Kobayashi Y, Chen C, Motoyama N (2005) FOXO transcription factors in cell-cycle regulation and the response to oxidative stress. Antioxid Redox Signal 7:752–760

    CAS  PubMed  Google Scholar 

  • Furuyama T, Nakazawa T, Nakano I, Mori N (2000) Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem J 349:629–634

    CAS  PubMed Central  PubMed  Google Scholar 

  • Furuyama T, Yamashita H, Kitayama K, Higami Y, Shimokawa I, Mori N (2002) Effects of aging and caloric restriction on the gene expression of Foxo1, 3, and 4 (FKHR, FKHRL1, and AFX) in the rat skeletal muscles. Microsc Res Tech 59:331–334

    CAS  PubMed  Google Scholar 

  • Galgani JE, Uauy RD, Aguirre CA, Diaz EO (2008) Effect of the dietary fat quality on insulin sensitivity. Br J Nutr 100:471–479

    CAS  PubMed  Google Scholar 

  • Giannakou ME, Partridge L (2004) The interaction between FOXO and SIRT1: tipping the balance towards survival. Trends Cell Biol 14:408–412

    CAS  PubMed  Google Scholar 

  • Giannakou ME, Goss M, Partridge L (2008) Role of dFOXO in lifespan extension by dietary restriction in Drosophila melanogaster: not required, but its activity modulates the response. Aging Cell 7:187–198

  • Goldberg RB (2009) Cytokine and cytokine-like inflammation markers, endothelial dysfunction, and imbalanced coagulation in development of diabetes and its complications. J Clin Endocrinol Metab 94:3171–3182

    CAS  PubMed  Google Scholar 

  • Gomis RR, Alarcon C, He W, Wang Q, Seoane J, Lash A, Massague J (2006) A FoxO-Smad synexpression group in human keratinocytes. Proc Natl Acad Sci USA 103:12747–12752

    CAS  PubMed Central  PubMed  Google Scholar 

  • Greer EL, Oskoui PR, Banko MR, Maniar JM, Gvgi MP, Gvgi SP, Brunet A (2007a) The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J Biol Chem 282:30107–30119

    CAS  PubMed  Google Scholar 

  • Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gvgi SP, Brunet A (2007b) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17:1646–1656

    CAS  PubMed Central  PubMed  Google Scholar 

  • Guarente L, Picard F (2005) Calorie restriction–the SIR2 connection. Cell 120:473–482

    CAS  PubMed  Google Scholar 

  • Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T (1999) Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on IGF binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem 274:17184–17192

    CAS  PubMed  Google Scholar 

  • Hardie DG (2009) AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes (Lond) 32:S7–S12

    Google Scholar 

  • Hayashi H, Yamaza H, Komatsu T, Park S, Chiba T, Higami Y, Nagayasu T, Shimokawa I (2008) Calorie restriction minimizes activation of insulin signaling in response to glucose: potential involvement of the growth hormone-insulin-like growth factor 1 axis. Exp Gerontol 43:827–832

  • He XY, Zhao XL, Gu Q, Shen JP, Hu Y, Hu RM (2012) Calorie restriction from a young age preserves the functions of pancreatic β cells in aging rats. Tohoku J Exp Med 227:245–252

    CAS  PubMed  Google Scholar 

  • Hedrick SM (2009) The cunning little vixen: FoxO and the cycle of life and death. Nat Immunol 10:1057–1063

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hoekman MF, Jacobs FM, Smidt MP, Burbach JP (2006) Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain. Gene Expr Patterns 6:134–140

    CAS  PubMed  Google Scholar 

  • Hsu AL, Murphy CT, Kenyon C (2003) Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science 300:1142–1145

    CAS  PubMed  Google Scholar 

  • Huang H, Reqan KM, Wanq F, Wanq D, Smith DI, van Deursen JM, Tindall DJ (2005) Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci USA 102:1649–1654

    CAS  PubMed Central  PubMed  Google Scholar 

  • Huang H, Regan KM, Lou Z, Chen J, Tindall DJ (2006) CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science 314:294–297

    CAS  PubMed  Google Scholar 

  • Jacobs FM, van der Heide LP, Wijchers PJ, Burbach JP, Hoekman MF, Smidt MP (2003) FoxO6, a novel member of the FoxO class of transcription factors with distinct shuttling dynamics. J Biol Chem 278:35959–35967

    CAS  PubMed  Google Scholar 

  • Jian B, Yang S, Chen D, Chaudry I, Raju R (2011) Influence of aging and hemorrhage injury on Sirt1 expression: possible role of myc-Sirt1 regulation in mitochondrial function. Biochim Biophys Acta 12:1446–1451

    Google Scholar 

  • Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293

    CAS  PubMed  Google Scholar 

  • Kato S, Ding J, Pisck E, Jhala US, Du K (2008) COP1 functions as a FoxO1 ubiquitin E3 ligase to regulate FoxO1-mediated gene expression. J Biol Chem 283:35464–35473

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kim DH, Kim JY, Yu BP, Chung HY (2008) The activation of NF-κB through Akt-induced FoxO1 phosphorylation during aging and its modulation by calorie restriction. Biogerontology 9:33–47

    CAS  PubMed  Google Scholar 

  • Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH (2011) FoxO6 integrates insulin signaling with gluconeogenesis in the liver. Diabetes 60:2763–2774

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kobayashi Y, Furukawa-Hibi Y, Chen C, Horio Y, Isobe K, Ikeda K, Motoyama N (2005) SIRT1 is critical regulator of FoxO-mediated transcription in response to oxidative stress. Int J Mol Med 16:237–243

    CAS  PubMed  Google Scholar 

  • Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM (1999) Direct control of the forkhead transcription factor AFX by protein kinase B. Nature 398:630–634

    CAS  PubMed  Google Scholar 

  • Kops GJ, Dansn TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ, Huang TT, Bos JL, Medema RH, Burgering BM (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316–321

    CAS  PubMed  Google Scholar 

  • Kouzarides T (2002) Histone methylation in transcriptional control. Curr Opin Genet Dev 12:198–209

    CAS  PubMed  Google Scholar 

  • Lane MA, Ball SS, Ingram DK, Cutler RG, Engel J, Read V, Roth GS (1995) Diet restriction in rhesus monkeys lowers fasting and glucose stimulated glucoregulatory end points. Am J Physiol 268:941–948

    Google Scholar 

  • Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB, DiBacco S, de la lglesia N, Gygi S, Blackwell TK, Bonni A (2006) A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125:987–1001

    CAS  PubMed  Google Scholar 

  • Li M, Chiu JF, Mossman BT, Fukaqawa NK (2006) Down-regulation of manganese-superoxide dismutase through phosphorylation of FOXO3a by Akt in explanted vascular smooth muscle cells from old rats. J Biol Chem 281:40429–40439

    CAS  PubMed  Google Scholar 

  • Li Y, Daniel M, Tollefsbol TO (2011) Epigenetic regulation of calorie restriction in aging. BMC Med 9:98

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 278:1319–1322

    CAS  PubMed  Google Scholar 

  • Lin SJ, Ford E, Haigis M, Liszt G, Guarente L (2004) Calorie restriction extends yeast life span by lowering the level of NADH. Genes Dev 18:12–16

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liu ZP, Wang Z, Yanagisawa H, Olson EN (2005) Phenotypic modulation of smooth muscle cells through interaction of FoxO4 and myocardin. Dev Cell 9:261–270

    PubMed  Google Scholar 

  • Longo VD, Finch CE (2003) Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 299:1342–1346

    PubMed  Google Scholar 

  • Masoro EJ (2005) Overview of caloric restriction and ageing. Mech Ageing Dev 126:913–922

  • Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A (2003) Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA 100:11285–11290

    CAS  PubMed Central  PubMed  Google Scholar 

  • Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A (2005) Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci USA 102:11278–11283

    CAS  PubMed Central  PubMed  Google Scholar 

  • Miyauchi H, Minamino T, Tateno K, Kunieda T, Toko H, Komuro I (2004) Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J 23:212–220

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mohsenzadegan M, Mirshafiey A (2012) The immunopathogenic role of reactive oxygen species in Alzheimer disease. Iran J Allergy Asthma Immunol 11:203–216

    CAS  PubMed  Google Scholar 

  • Morley JF, Brignull HR, Weyers JJ, Morimoto RI (2002) The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans. Proc Natl Acad Sci USA 99:10417–10422

    PubMed Central  PubMed  Google Scholar 

  • Morris BJ (2005) A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer. J Hypertens 23:1285–1309

    CAS  PubMed  Google Scholar 

  • Moskalev AA, Smit-McBride Z, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Tacutu R, Fraifeld VE (2012) Gadd45 proteins: relevance to aging, longevity and age-related pathologies. Ageing Res Rev 11:51–66

  • Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L (2004) Mammalian SIRT1 represses forkhead transcription factors. Cell 116:551–563

    CAS  PubMed  Google Scholar 

  • Murakami S (2006) Stress resistance in long-lived mouse models. Exp Gerontol 41:1014–1019

    CAS  PubMed  Google Scholar 

  • Nasrin N, Ogg S, Cahill CM, Biggs W, Nui S, Dore J, Calvo D, Shi Y, Ruvkun G, Alexander-Bridges MC (2000) DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells. Proc Natl Acad Sci USA 97:10412–10417

    CAS  PubMed Central  PubMed  Google Scholar 

  • Navab M, Gharavi N, Watson AD (2008) Inflammation and metabolic disorders. Curr Opin Clin Nutr Metab Care 11:459–464

    CAS  PubMed  Google Scholar 

  • Ni Z, Ebata A, Alipanahiramandi E, Lee SS (2012) Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. Aging Cell 11:315–325

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nisoli E, Tonello C, Cardile A, Cozzi V, Bracale R, Tedesco L, Falcone S, Valerio A, Cantoni O, Clementi E, Moncada S, Carruba MO (2005) Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science 310:314–317

    CAS  PubMed  Google Scholar 

  • Obexer P, Geiger K, Ambros PF, Meister B, Ausserlechner MJ (2007) FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells. Cell Death Differ 14:534–547

    CAS  PubMed  Google Scholar 

  • Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA (2005) JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. Proc Natl Acad Sci USA 102:4494–4499

    CAS  PubMed Central  PubMed  Google Scholar 

  • Owusu-Ansah E, Banerjee U (2009) Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461:537–541

    CAS  PubMed  Google Scholar 

  • Owusu-Ansah E, Song W, Perrimon N (2013) Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155:699–712

    CAS  PubMed  Google Scholar 

  • Panici JA, Harper JM, Miller RA, Bartke A, Spong A, Masternak MM (2010) Early life growth hormone treatment shortens longevity and decreases cellular stress resistance in long-lived mutant mice. FASEB J 24:5073–5079

    CAS  PubMed Central  PubMed  Google Scholar 

  • Perrot V, Rechler MM (2005) The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription. Mol Endocrinol 19:2283–2298

    CAS  PubMed  Google Scholar 

  • Plas DR, Thompson CB (2003) Akt activation promotes degradation of tuberin and FOXO3 via the proteasome. J Biol Chem 278:12361–12366

    CAS  PubMed  Google Scholar 

  • Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423:550–555

    CAS  PubMed  Google Scholar 

  • Redman LM, Ravussin E (2011) Caloric restriction in humans: impact on physiological, psychological, and behavioral outcomes. Antioxid Redox Signal 14:275–287

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ribarič S (2012) Diet and aging. Oxid Med Cell Longev 2012:741468

    PubMed Central  PubMed  Google Scholar 

  • Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136

    CAS  PubMed Central  PubMed  Google Scholar 

  • Salminen A, Kaarniranta K (2012) AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Aging Res Rev 11:230–241

  • Salminen A, Ojala J, Huuskonen J, Kauppinen A, Suuronen T, Kaarniranta K (2008) Interaction of aging-associated signaling cascades: inhibition of NF-kB signaling by longevity factors FoxOs and SIRT1. Cell Mol Life Sci 65:1049–1058

    CAS  PubMed  Google Scholar 

  • Senapedis WT, Kennedy CJ, Boyle PM, Silver PA (2011) Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain. Mol Biol Cell 22:1791–1805

    CAS  PubMed Central  PubMed  Google Scholar 

  • Seoane J, Le HV, Shen L, Anderson SA, Massague J (2004) Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell 117:211–223

    CAS  PubMed  Google Scholar 

  • Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction, and aging. Science 273:59–63

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sohal RS, Orr WC (2012) The redox stress hypothesis of aging. Free Radic Biol Med 52:539–555

  • Stankovic M, Mladenovic D, Ninkovic M, Vucevic D, Tomasevic T, Radosavljevic T (2013) Effects of caloric restriction on oxidative stress parameters. Gen Physiol Biophys 32:277–283

    CAS  PubMed  Google Scholar 

  • Steinberg GR, Kemp BE (2009) AMPK in health and disease. Physiol Rev 89:1025–1078

    CAS  PubMed  Google Scholar 

  • Stenvinkel P, Karimi M, Johansson S, Axelsson J, Suliman M, Lindholm B, Heimbürger O, Barany P, Alvestrand A, Nordfors L, Qureshi AR, Ekström TJ, Schalling M (2007) Impact of inflammation on epigenetic DNA methylation: a novel risk factor for cardiovascular disease? J Intern Med 261:488–499

    CAS  PubMed  Google Scholar 

  • Takayama H, Misu H, Iwama H, Chikamoto K, Saito Y, Murao K, Teraguchi A, Lan F, Kikuchi A, Saito R, Tajima N, Shirasaki T, Matsugo S, Miyamoto KI, Kaneko S, Takamura T (2014) Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. J Biol Chem 289:335–345

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tereshina EV (2009) Metabolic abnormalities as a basis for age-dependent diseases and aging? State of the art. Adv Gerontol 22:129–138

    CAS  PubMed  Google Scholar 

  • Tsai KL, Sun YJ, Huang CY, Yang JY, Hung MC, Hsiao CD (2007) Crystal structure of the human FOXO3a-DBD/DNA complex suggests the effects of posttranslational modification. Nucleic Acids Res 35:6984–6994

    CAS  PubMed Central  PubMed  Google Scholar 

  • van der Heide LP, Smidt MP (2005) Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends Biochem Sci 30:81–86

    PubMed  Google Scholar 

  • van der Heide LP, Hoekman MFM, Smidt MP (2004) The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J 380:297–309

    Google Scholar 

  • van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8:440–450

    PubMed  Google Scholar 

  • Van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM (2004) FoxO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2 (SIRT1). J Biol Chem 279:28873–28879

    PubMed  Google Scholar 

  • van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F, Maurice MM, Burqweing BM (2006) FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nat Cell Biol 8:1064–1073

    PubMed  Google Scholar 

  • Vaquero A, Reinberg D (2009) Calorie restriction and the exercise of chromatin. Genes Dev 23:1849–1869

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang F, Nguyen M, Qin FX, Tong Q (2007) SIRT2 deacetylates FOXO3a in response to oxidative stress and caloric restriction. Aging Cell 6:505–514

    CAS  PubMed  Google Scholar 

  • Willcox DC, Willcox BJ, Todoriki H, Curb JD, Suzuki M (2006) Caloric restriction and human longevity: what can we learn from the Okinawans? Biogerontology 7:173–177

    PubMed  Google Scholar 

  • Xie Q, Hao Y, Tao L, Peng S, Rao C, Chen H, You H, Dong MQ, Yuan Z (2012) Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death. EMBO Rep 13:371–377

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yalcin S, Marinkovic D, Mungamuri SK, Zhang X, Tong W, Sellers R, Ghaffari S (2010) ROS-mediated amplification of Akt/mTOR signaling pathway leads to myeloproliferative syndrome in Foxo3-/- mice. EMBO J 29:4118–4131

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, Mukai H, Kasuya Y, Fukamizu A (2008) Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell 32:221–231

    CAS  PubMed  Google Scholar 

  • Yamamura Y, Lee WL, Inoue K, Ida H, Ito Y (2006) RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells. J Biol Chem 281:5267–5276

    CAS  PubMed  Google Scholar 

  • 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 9:372–382

    CAS  PubMed  Google Scholar 

  • Yan L, Lavin VA, Moser LR, Cui Q, Kanies C, Yang E (2008) PP2A regulates the pro- apoptotic activity of FOXO1. J Biol Chem 283:7411–7420

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang Y, Hou H, Haller EM, Nicosia SV, Bai W (2005) Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J 24:1021–1032

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yellaturu CR, Bhanoori M, Neeli I, Rao GN (2002) N-Ethylmaleimide inhibits platelet-derived growth factor BB-stimulated Akt phosphorylation via activation of protein phosphatase 2A. J Biol Chem 277:40148–40155

    CAS  PubMed  Google Scholar 

  • Yiu WH, Mead PA, Jun HS, Mansfield BC, Chou JY (2010) Oxidative stress mediates nephropathy in type Ia glycogen storage disease. Lab Invest 90:620–629

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yu BP (1994) Modulation of aging processes by dietary restriction. CRC Press, Boca Raton, pp 1–36

    Google Scholar 

  • Yu BP (1996) Aging and oxidative stress: modulation by dietary restriction. Free Radic Biol Med 21:651–668

    CAS  PubMed  Google Scholar 

  • Yu BP (2005) Calorie restriction as a potent anti-aging intervention: suppression of oxidative stress. In: Rattan S (ed) Aging intervention and therapies. World Scientific, Singapore, pp 193–217

    Google Scholar 

  • Yu BP, Chung HY (2006) The inflammatory process in aging. Rev Clin Gerontol 16:179–187

    Google Scholar 

  • Zhao X, Gan L, Pan H, Kan D, Majeski M, Adam SA, Unterman TG (2004) Multiple elements regulate nuclear/cytoplasmic shuttling of FOXO1: characterization of phosphorylation- and 14-3-3-dependent and -independent mechanisms. Biochem J 378:839–849

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (MEST) (Grant No. 2009-0083538). This work was carried out with the support of “Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ006522132013)” Rural Development Administration, Republic of Korea. We also take this opportunity to thank the Aging Tissue Bank (Busan, Korea) for supplying research materials.

Conflict of interest

The authors have no conflicts of interests.

Author information

Authors and Affiliations

  1. Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), College of Pharmacy, Pusan National University, San 30, Jangjun-dong, Gumjung-gu, Busan, 609-735, Korea

    Dae Hyun Kim, Min Hi Park, Eun Kyeong Lee, Yeon Ja Choi, Ki Wung Chung, Kyoung Mi Moon, Min Jo Kim, Hye Jin An, June Whoun Park, Nam Deuk Kim & Hae Young Chung

  2. Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Byung Pal Yu

Authors
  1. Dae Hyun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Hi Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eun Kyeong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yeon Ja Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ki Wung Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kyoung Mi Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Min Jo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hye Jin An
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. June Whoun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nam Deuk Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Byung Pal Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hae Young Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hae Young Chung.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, D.H., Park, M.H., Lee, E.K. et al. The roles of FoxOs in modulation of aging by calorie restriction. Biogerontology 16, 1–14 (2015). https://doi.org/10.1007/s10522-014-9519-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10522-014-9519-y

Keywords

Search

Navigation