Physiological links of circadian clock and biological clock of aging

Abstract

Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold selfsustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.

Keywords

circadian rhythms / SCN / longevity

References

[1] AbrahamsonEE, MooreRY (2001) Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res916:172–191

[2] AbrahamsonEE, LeakRK, MooreRY (2001) The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. NeuroReport12:435–440

[3] AdamovichY, LadeuixB, GolikM, KoenersMP, AsherG (2017) Rhythmic oxygen levels reset circadian clocks through HIF1alpha. Cell Metab. doi:10.1016/j.cmet.2016.09.014

[4] AidaR, MoriyaT, ArakiM, AkiyamaM, WadaK, WadaE, ShibataS (2002) Gastrin-releasing peptide mediates photic entrainable signals to dorsal subsets of suprachiasmatic nucleus via induction of period gene in mice. Mol Pharmacol61:26–34

[5] AntleMC, SilverR (2005) Orchestrating time: arrangements of the brain circadian clock. Trends Neurosci28:145–151

[6] AntochMP, GorbachevaVY, VykhovanetsO, ToshkovIA, KondratovRV, KondratovaAA, LeeC, NikitinAY (2008) Disruption of the circadian clock due to the clock mutation has discrete effects on aging and carcinogenesis. Cell Cycle7:1197–1204

[7] ArnulfI, NielsenJ, LohmannE, SchieferJ, WildE, JennumP, KonofalE, WalkerM, OudietteD, TabriziS (2008) Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol65:482–488

[8] AsherG, Sassone-CorsiP (2015) Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock. Cell161:84–92

[9] AsherG, GatfieldD, StratmannM, ReinkeH, DibnerC, KreppelF, MostoslavskyR, AltFW, SchiblerU (2008) SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell134:317–328

[10] Aston-JonesG, ChenS, ZhuY, OshinskyML (2001) A neural circuit for circadian regulation of arousal. Nat Neurosci4:732–738

[11] AzizA, FronczekR, Maat-SchiemanM, UnmehopaU, RoelandseF, OvereemS, van DuinenS, LammersGJ, SwaabD, RoosR (2008) Hypocretin and melanin-concentrating hormone in patients with Huntington disease. Brain Pathol18:474–483

[12] BaroneP, AntoniniA, ColosimoC, MarconiR, MorganteL, AvarelloTP, BottacchiE, CannasA, CeravoloG, CeravoloR (2009) The PRIAMO study: a multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease. Mov Dis24:1641–1649

[13] BarzilaiN, CrandallJP, KritchevskySB, EspelandMA (2016) Metformin as a tool to target aging. Cell Metab23:1060–1065

[14] BassJ, TakahashiJS (2010) Circadian integration of metabolism and energetics. Science330:1349–1354

[15] BollingerT, SchiblerU (2014) Circadian rhythms—from genes to physiology and disease. Swiss Med Wkly144:w13984

[16] BonkowskiMS, SinclairDA (2016) Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds. Nat Rev Mol Cell Biol17:679–690

[17] BraakH, GhebremedhinE, RubU, BratzkeH, Del TrediciK (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res318:121–134

[18] BrayMS, YoungME (2007) Circadian rhythms in the development of obesity: potential role for the circadian clock within the adipocyte. Obes Rev8:169–181

[19] BreenDP, VuonoR, NawarathnaU, FisherK, ShneersonJM, ReddyAB, BarkerRA (2014) Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol71:589–595

[20] CaiY, LiuS, SothernRB, XuS, ChanP (2010) Expression of clock genes Per1 and Bmal1 in total leukocytes in health and Parkinson’s disease. Eur J Neurol17:550–554

[21] CaoR, RobinsonB, XuH, GkogkasC, KhoutorskyA, AlainT, YanagiyaA, NevarkoT, LiuAC, AmirS (2013) Translational control of entrainment and synchrony of the suprachiasmatic circadian clock by mTOR/4E-BP1 signaling. Neuron79:712–724

[22] ChangHC, GuarenteL (2013) SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging. Cell153:1448–1460

[23] ChangHC, GuarenteL (2014) SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab25:138–145

[24] ChawlaA, LazarMA (1993) Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation. J Biol Chem268:16265–16269

[25] ChoH, ZhaoX, HatoriM, YuRT, BarishGD, LamMT, ChongLW, DiTacchioL, AtkinsAR, GlassCK (2012) Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature485:123–127

[26] ChoiHJ, LeeCJ, SchroederA, KimYS, JungSH, KimJS, KimDY, SonEJ, HanHC, HongSK (2008) Excitatory actions of GABA in the suprachiasmatic nucleus. J Neurosci28:5450–5459

[27] ChouTC, BjorkumAA, GausSE, LuJ, ScammellTE, SaperCB (2002) Afferents to the ventrolateral preoptic nucleus. J Neurosci22:977–990

[28] ChouTC, ScammellTE, GooleyJJ, GausSE, SaperCB, LuJ (2003) Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J Neurosci23:10691–10702

[29] ChoudharyC, WeinertBT, NishidaY, VerdinE, MannM (2014) The growing landscape of lysine acetylation links metabolism and cell signalling. Nat Rev Mol Cell Biol15:536–550

[30] ColmanRJ, AndersonRM, JohnsonSC, KastmanEK, KosmatkaKJ, BeasleyTM, AllisonDB, CruzenC, SimmonsHA, KemnitzJW (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science325:201–204

[31] ColmanRJ, BeasleyTM, KemnitzJW, JohnsonSC, WeindruchR, AndersonRM (2014) Caloric restriction reduces age-related and all-cause mortality in rhesus monkeys. Nat Commun5:3557

[32] ColwellCS (2011) Linking neural activity and molecular oscillations in the SCN. Nat Rev Neurosci12:553–569

[33] DavidsonAJ, StraumeM, BlockGD, MenakerM (2006) Daily timed meals dissociate circadian rhythms in hepatoma and healthy host liver. Int J Cancer118:1623–1627

[34] De JeuM, PennartzC (2002) Circadian modulation of GABA function in the rat suprachiasmatic nucleus: excitatory effects during the night phase. J Neurophysiol87:834–844

[35] DibnerC, SchiblerU, AlbrechtU (2010) The mammalian circadian timing system: organization and coordination of central and peripheral clocks. Annu Rev Physiol72:517–549

[36] DubrovskyYV, SamsaWE, KondratovRV (2010) Deficiency of circadian protein CLOCK reduces lifespan and increases agerelated cataract development in mice. Aging2:936–944

[37] DuffyJF, CzeislerCA (2002) Age-related change in the relationship between circadian period, circadian phase, and diurnal preference in humans. Neurosci Lett318:117–120

[38] Eckel-MahanKL, PatelVR, de MateoS, Orozco-SolisR, CegliaNJ, SaharS, Dilag-PenillaSA, DyarKA, BaldiP, Sassone-CorsiP (2013) Reprogramming of the circadian clock by nutritional challenge. Cell155:1464–1478

[39] EverettLJ, LazarMA (2014) Nuclear receptor Rev-erbalpha: up, down, and all around. Trends Endocrinol Metab25:586–592

[40] FahrenkrugJ, PopovicN, GeorgB, BrundinP, HannibalJ (2007) Decreased VIP and VPAC2 receptor expression in the biological clock of the R6/2 Huntington’s disease mouse. J Mol Neurosci31:139–148

[41] FarajniaS, MichelS, DeboerT, vanderLeestHT, HoubenT, RohlingJH, RamkisoensingA, YasenkovR, MeijerJH (2012) Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. J Neurosci32:5891–5899

[42] FifelK, CooperHM (2014) Loss of dopamine disrupts circadian rhythms in a mouse model of Parkinson’s disease. Neurobiol Dis71:359–369

[43] FilipskiE, KingVM, LiX, GrandaTG, MormontMC, ClaustratB, HastingsMH, LeviF (2003) Disruption of circadian coordination accelerates malignant growth in mice. Pathol Biol51:216–219

[44] FontanaL, PartridgeL (2015) Promoting health and longevity through diet: from model organisms to humans. Cell161:106–118

[45] FronczekR, OvereemS, LeeSY, HegemanIM, van PeltJ, van DuinenSG, LammersGJ, SwaabDF (2007) Hypocretin (orexin) loss in Parkinson’s disease. Brain130:1577–1585

[46] FroyO (2013) Circadian aspects of energy metabolism and aging. Ageing Res Rev12:931–940

[47] FuL, PelicanoH, LiuJ, HuangP, LeeC (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell111:41–50

[48] GaberyS, MurphyK, SchultzK, LoyCT, McCuskerE, KirikD, HallidayG, PetersenA (2010) Changes in key hypothalamic neuropeptide populations in Huntington disease revealed by neuropathological analyses. Acta Neuropathol120:777–788

[49] GibsonEM, WilliamsWP 3rd, KriegsfeldLJ (2009) Aging in the circadian system: considerations for health, disease prevention and longevity. Exp Gerontol44:51–56

[50] GolombekDA, RosensteinRE (2010) Physiology of circadian entrainment. Physiol Rev90:1063–1102

[51] GomesAP, PriceNL, LingAJ, MoslehiJJ, MontgomeryMK, RajmanL, WhiteJP, TeodoroJS, WrannCD, HubbardBP (2013) Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell155:1624–1638

[52] GoodmanAO, BarkerRA (2010) How vital is sleep in Huntington’s disease?J Neurol257:882–897

[53] GuarenteL (2013) Calorie restriction and sirtuins revisited. Genes Dev27:2072–2085

[54] HamadaT, AntleMC, SilverR (2004) Temporal and spatial expression patterns of canonical clock genes and clock-controlled genes in the suprachiasmatic nucleus. Eur J Neurosci19:1741–1748

[55] HarrisonDE, StrongR, SharpZD, NelsonJF, AstleCM, FlurkeyK, NadonNL, WilkinsonJE, FrenkelK, CarterCS (2009) Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature460:392–395

[56] HerskovitsAZ, GuarenteL (2014) SIRT1 in neurodevelopment and brain senescence. Neuron81:471–483

[57] HirayamaJ, SaharS, GrimaldiB, TamaruT, TakamatsuK, NakahataY, Sassone-CorsiP (2007) CLOCK-mediated acetylation of BMAL1 controls circadian function. Nature450:1086–1090

[58] HofmanMA, SwaabDF (1994) Alterations in circadian rhythmicity of the vasopressin-producing neurons of the human suprachiasmatic nucleus (SCN) with aging. Brain Res651:134–142

[59] HofmanMA, SwaabDF (1995) Influence of aging on the seasonal rhythm of the vasopressin-expressing neurons in the human suprachiasmatic nucleus. Neurobiol Aging16:965–971

[60] HofmanMA, SwaabDF (2006) Living by the clock: the circadian pacemaker in older people. Ageing Res Rev5:33–51

[61] HofmanMA, ZhouJN, SwaabDF (1996) No evidence for a diurnal vasoactive intestinal polypeptide (VIP) rhythm in the human suprachiasmatic nucleus. Brain Res722:78–82

[62] HosodaH, KatoK, AsanoH, ItoM, KatoH, IwamotoT, SuzukiA, MasushigeS, KidaS (2009) CBP/p300 is a cell type-specific modulator of CLOCK/BMAL1-mediated transcription. Mol Brain2:34

[63] HurdMW, RalphMR (1998) The significance of circadian organization for longevity in the golden hamster. J Biol Rhythms13:430–436

[64] IranzoA (2013) Parkinson disease and sleep: sleep-wake changes in the premotor stage of Parkinson disease; impaired olfaction and other prodromal features. Curr Neurol Neurosci Rep13:373

[65] Jung-HynesB, ReiterRJ, AhmadN (2010) Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer. J Pineal Res48:9–19

[66] KaeberleinM, RabinovitchPS, MartinGM (2015) Healthy aging: the ultimate preventative medicine. Science350:1191–1193

[67] KalsbeekA, PalmIF, La FleurSE, ScheerFA, Perreau-LenzS, RuiterM, KreierF, CailottoC, BuijsRM (2006) SCN outputs and the hypothalamic balance of life. J Biol Rhythms21:458–469

[68] KhapreRV, KondratovaAA, PatelS, DubrovskyY, WrobelM, AntochMP, KondratovRV (2014) BMAL1-dependent regulation of the mTOR signaling pathway delays aging. Aging6:48–57

[69] KolkerDE, FukuyamaH, HuangDS, TakahashiJS, HortonTH, TurekFW (2003) Aging alters circadian and light-induced expression of clock genes in golden hamsters. J Biol Rhythms18:159–169

[70] KondratovRV, KondratovaAA, GorbachevaVY, VykhovanetsOV, AntochMP (2006) Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev20:1868–1873

[71] KondratovaAA, KondratovRV (2012) The circadian clock and pathology of the ageing brain. Nat Rev Neurosci13:325–335

[72] KudoT, LohDH, TruongD, WuY, ColwellCS (2011) Circadian dysfunction in a mouse model of Parkinson’s disease. Exp Neurol232:66–75

[73] LamiaKA, SachdevaUM, DiTacchioL, WilliamsEC, AlvarezJG, EganDF, VasquezDS, JuguilonH, PandaS, ShawRJ (2009) AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science326:437–440

[74] Lande-DinerL, BoyaultC, KimJY, WeitzCJ (2013) A positive feedback loop links circadian clock factor CLOCK-BMAL1 to the basic transcriptional machinery. Proc Natl Acad Sci USA110:16021–16026

[75] LeeCC (2005) The circadian clock and tumor suppression by mammalian period genes. Methods Enzymol393:852–861

[76] LeeC, EtchegarayJP, CagampangFR, LoudonAS, ReppertSM (2001) Posttranslational mechanisms regulate the mammalian circadian clock. Cell107:855–867

[77] LeeJH, BliwiseDL, AnsariFP, GoldsteinFC, CellarJS, LahJJ, LeveyAI (2007) Daytime sleepiness and functional impairment in Alzheimer disease. Am J Geriatr Psychiatry15:620–626

[78] LiH, SatinoffE (1998) Fetal tissue containing the suprachiasmatic nucleus restores multiple circadian rhythms in old rats. Am J Physiol275:R1735–R1744

[79] LiXM, DelaunayF, DulongS, ClaustratB, ZamperaS, FujiiY, TeboulM, BeauJ, LeviF (2010) Cancer inhibition through circadian reprogramming of tumor transcriptome with meal timing. Cancer Res70:3351–3360

[80] LiJ, KimSG, BlenisJ (2014) Rapamycin: one drug, many effects. Cell Metab19:373–379

[81] LiptonJO, YuanED, BoyleLM, Ebrahimi-FakhariD, KwiatkowskiE, NathanA, GuttlerT, DavisF, AsaraJM, SahinM (2015) The circadian protein BMAL1 regulates translation in response to S6K1-mediated phosphorylation. Cell161:1138–1151

[82] LopezM, NogueirasR, Tena-SempereM, DieguezC (2016) Hypothalamic AMPK: a canonical regulator of whole-body energy balance. Nat Rev Endocrinol12:421–432

[83] Lopez-OtinC, BlascoMA, PartridgeL, SerranoM, KroemerG (2013) The hallmarks of aging. Cell153:1194–1217

[84] Lopez-OtinC, GalluzziL, FreijeJM, MadeoF, KroemerG (2016) Metabolic control of longevity. Cell166:802–821

[85] MarchevaB, RamseyKM, BuhrED, KobayashiY, SuH, KoCH, IvanovaG, OmuraC, MoS, VitaternaMH (2010) Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature466:627–631

[86] MasriS, RigorP, CervantesM, CegliaN, SebastianC, XiaoCY, Roqueta-RiveraM, DengCX, OsborneTF, MostoslavskyR (2014) Partitioning circadian transcription by SIRT6 leads to segregated control of cellular metabolism. Cell158:659–672

[87] MattisJ, SehgalA (2016) Circadian rhythms, sleep, and disorders of aging. Trends Endocrinol Metab27:192–203

[88] Meyer-SpascheA, ReedHE, PigginsHD (2002) Neurotensin phaseshifts the firing rate rhythm of neurons in the rat suprachiasmatic nuclei in vitro. Eur J Neurosci16:339–344

[89] MooreRY, SpehJC (1993) GABA is the principal neurotransmitter of the circadian system. Neurosci Lett150:112–116

[90] MorinLP, AllenCN (2006) The circadian visual system, 2005. Brain Res Rev51:1–60

[91] MorinLP, ShiversKY, BlanchardJH, MuscatL (2006) Complex organization of mouse and rat suprachiasmatic nucleus. Neuroscience137:1285–1297

[92] MortonAJ, WoodNI, HastingsMH, HurelbrinkC, BarkerRA, MaywoodES (2005) Disintegration of the sleep-wake cycle and circadian timing in Huntington’s disease. J Neurosci25:157–163

[93] NadonNL (2006) Exploiting the rodent model for studies on the pharmacology of lifespan extension. Aging Cell5:9–15

[94] NakahataY, KaluzovaM, GrimaldiB, SaharS, HirayamaJ, ChenD, GuarenteLP, Sassone-CorsiP (2008) The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell134:329–340

[95] NakahataY, SaharS, AstaritaG, KaluzovaM, Sassone-CorsiP (2009) Circadian control of the NAD+ salvage pathway by CLOCK-SIRT1. Science324:654–657

[96] NakamuraW, YamazakiS, TakasuNN, MishimaK, BlockGD (2005) Differential response of Period 1 expression within the suprachiasmatic nucleus. J Neurosci25:5481–5487

[97] NakamuraTJ, NakamuraW, YamazakiS, KudoT, CutlerT, ColwellCS, BlockGD (2011) Age-related decline in circadian output. J Neurosci31:10201–10205

[98] NovakCM, NunezAA (2000) A sparse projection from the suprachiasmatic nucleus to the sleep active ventrolateral preoptic area in the rat. NeuroReport11:93–96

[99] OzturkN, LeeJH, GaddameedhiS, SancarA (2009) Loss of cryptochrome reduces cancer risk in p53 mutant mice. Proc Natl Acad Sci USA106:2841–2846

[100] PandaS, HogeneschJB, KaySA (2002) Circadian rhythms from flies to human. Nature417:329–335

[101] PeekCB, LevineDC, CedernaesJ, TaguchiA, KobayashiY, TsaiSJ, BonarNA, McNultyMR, RamseyKM, BassJ (2017) Circadian clock interaction with HIF1alpha mediates oxygenic metabolism and anaerobic glycolysis in skeletal muscle. Cell Metab. doi:10.1016/j.cmet.2016.09.010

[102] PenevPD, KolkerDE, ZeePC, TurekFW (1998) Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic heart disease. Am J Physiol275:H2334–H2337

[103] PreitnerN, DamiolaF, Lopez-MolinaL, ZakanyJ, DubouleD, AlbrechtU, SchiblerU (2002) The orphan nuclear receptor REVERBalpha controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell110:251–260

[104] PulivarthySR, TanakaN, WelshDK, De HaroL, VermaIM, PandaS (2007) Reciprocity between phase shifts and amplitude changes in the mammalian circadian clock. Proc Natl Acad Sci USA104:20356–20361

[105] PuramRV, KowalczykMS, de BoerCG, SchneiderRK, MillerPG, McConkeyM, TothovaZ, TejeroH, HecklD, JarasM (2016) Core circadian clock genes regulate leukemia stem cells in AML. Cell165:303–316

[106] QuZ, ZhangH, HuangM, ShiG, LiuZ, XieP, LiH, WangW, XuG, ZhangY (2016) Loss of ZBTB20 impairs circadian output and leads to unimodal behavioral rhythms. eLife5:e17171

[107] RamadoriG, FujikawaT, FukudaM, AndersonJ, MorganDA, MostoslavskyR, StuartRC, PerelloM, ViannaCR, NillniEA (2010) SIRT1 deacetylase in POMC neurons is required for homeostatic defenses against diet-induced obesity. Cell Metab12:78–87

[108] RamadoriG, FujikawaT, AndersonJ, BerglundED, FrazaoR, MichanS, ViannaCR, SinclairDA, EliasCF, CoppariR (2011) SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. Cell Metab14:301–312

[109] RamseyKM, YoshinoJ, BraceCS, AbrassartD, KobayashiY, MarchevaB, HongHK, ChongJL, BuhrED, LeeC (2009) Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science324:651–654

[110] ReddyAB, ReyG (2014) Metabolic and nontranscriptional circadian clocks: eukaryotes. Annu Rev Biochem83:165–189

[111] ReppertSM, WeaverDR (2002) Coordination of circadian timing in mammals. Nature418:935–941

[112] RieraCE, DillinA (2015) Tipping the metabolic scales towards increased longevity in mammals. Nat Cell Biol17:196–203

[113] RoozendaalB, van GoolWA, SwaabDF, HoogendijkJE, MirmiranM (1987) Changes in vasopressin cells of the rat suprachiasmatic nucleus with aging. Brain Res409:259–264

[114] RudicRD, McNamaraP, CurtisAM, BostonRC, PandaS, HogeneschJB, FitzgeraldGA (2004) BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol2:e377

[115] SaharS, Sassone-CorsiP (2009) Metabolism and cancer: the circadian clock connection. Nat Rev Cancer9:886–896

[116] SatlinA, VolicerL, StopaEG, HarperD (1995) Circadian locomotor activity and core-body temperature rhythms in Alzheimer’s disease. Neurobiol Aging16:765–771

[117] SatoTK, PandaS, MiragliaLJ, ReyesTM, RudicRD, McNamaraP, NaikKA, FitzGeraldGA, KaySA, HogeneschJB (2004) A functional genomics strategy reveals Rora as a component of the mammalian circadian clock. Neuron43:527–537

[118] SatohA, BraceCS, RensingN, CliftenP, WozniakDF, HerzogED, YamadaKA, ImaiS (2013) Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab18:416–430

[119] ScarbroughK, Losee-OlsonS, WallenEP, TurekFW (1997) Aging and photoperiod affect entrainment and quantitative aspects of locomotor behavior in Syrian hamsters. Am J Physiol272: R1219–R1225

[120] ShimbaS, IshiiN, OhtaY, OhnoT, WatabeY, HayashiM, WadaT, AoyagiT, TezukaM (2005) Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc Natl Acad Sci USA102:12071–12076

[121] ShinoharaK, HirumaH, FunabashiT, KimuraF (2000) GABAergic modulation of gap junction communication in slice cultures of the rat suprachiasmatic nucleus. Neuroscience96:591–596

[122] SoltLA, WangY, BanerjeeS, HughesT, KojetinDJ, LundasenT, ShinY, LiuJ, CameronMD, NoelR (2012) Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists. Nature485:62–68

[123] StashiE, LanzRB, MaoJ, MichailidisG, ZhuB, KettnerNM, PutluriN, ReinekeEL, ReinekeLC, DasguptaS (2014) SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm. Cell reports6:633–645

[124] SterniczukR, AntleMC, LaferlaFM, DyckRH (2010a) Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: part 2. Behavioral and cognitive changes. Brain Res1348:149–155

[125] SterniczukR, DyckRH, LaferlaFM, AntleMC (2010b) Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: part 1. Circadian changes. Brain Res1348:139–148

[126] SwaabDF, FliersE, PartimanTS (1985) The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res342:37–44

[127] TorraIP, TsibulskyV, DelaunayF, SaladinR, LaudetV, FruchartJC, KosykhV, StaelsB (2000) Circadian and glucocorticoid regulation of Rev-erbalpha expression in liver. Endocrinology141:3799–3806

[128] TurekFW, JoshuC, KohsakaA, LinE, IvanovaG, McDearmonE, LaposkyA, Losee-OlsonS, EastonA, JensenDR (2005) Obesity and metabolic syndrome in circadian Clock mutant mice. Science308:1043–1045

[129] UmJH, YangS, YamazakiS, KangH, ViolletB, ForetzM, ChungJH (2007) Activation of 5’-AMP-activated kinase with diabetes drug metformin induces casein kinase Iepsilon (CKIepsilon)-dependent degradation of clock protein mPer2. J Biol Chem282:20794–20798

[130] ValentinuzziVS, ScarbroughK, TakahashiJS, TurekFW (1997) Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. Am J Physiol273:R1957–R1964

[131] van SomerenEJ, HagebeukEE, LijzengaC, ScheltensP, de RooijSE, JonkerC, PotAM, MirmiranM, SwaabDF (1996) Circadian rest-activity rhythm disturbances in Alzheimer’s disease. Biol Psychiatry40:259–270

[132] VidenovicA, LazarAS, BarkerRA, OvereemS (2014) ‘The clocks that time us’–circadian rhythms in neurodegenerative disorders. Nat Rev Neurol10:683–693

[133] WeinertD (2000) Age-dependent changes of the circadian system. Chronobiol Int17:261–283

[134] WelshDK, TakahashiJS, KaySA (2010) Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol72:551–577

[135] WoodJG, RoginaB, LavuS, HowitzK, HelfandSL, TatarM, SinclairD (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature430:686–689

[136] WuY, TangD, LiuN, XiongW, HuangH, LiY, MaZ, ZhaoH, ChenP, QiX (2017) Reciprocal regulation between the circadian clock and hypoxia signaling at the genome level in mammals. Cell Metab. doi:10.1016/j.cmet.2016.09.009

[137] WyseCA, CooganAN (2010) Impact of aging on diurnal expression patterns of CLOCK and BMAL1 in the mouse brain. Brain Res1337:21–31

[138] YamazakiS, StraumeM, TeiH, SakakiY, MenakerM, BlockGD (2002) Effects of aging on central and peripheral mammalian clocks. Proc Natl Acad Sci USA99:10801–10806

[139] YanL, OkamuraH (2002) Gradients in the circadian expression of Per1 and Per2 genes in the rat suprachiasmatic nucleus. Eur J Neurosci15:1153–1162

[140] YanL, KaratsoreosI, LesauterJ, WelshDK, KayS, FoleyD, SilverR (2007) Exploring spatiotemporal organization of SCN circuits. Cold Spring Harb Symp Quant Biol72:527–541

[141] YoonIY, KripkeDF, ElliottJA, YoungstedtSD, RexKM, HaugerRL (2003) Age-related changes of circadian rhythms and sleep-wake cycles. J Am Geriatr Soc51:1085–1091

[142] ZhangEE, LiuY, DentinR, PongsawakulPY, LiuAC, HirotaT, NusinowDA, SunX, LandaisS, KodamaY (2010) Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med16:1152–1156

[143] ZhouJN, HofmanMA, SwaabDF (1995) VIP neurons in the human SCN in relation to sex, age, and Alzheimer’s disease. Neurobiol Aging16:571–576

RIGHTS & PERMISSIONS

2017 The Author(s) 2017. This article is published with open access at Springerlink.com and journal.hep.com.cn