Geroprotectors are drugs that decrease the rate of aging and therefore extend life span. Metformin has been described as a geroprotector, and several studies have shown that metformin can slow down the rate of aging. The mechanisms behind the geroprotective effect of metformin are less established. The goal of this review is to investigate the evidence for the geroprotective effect of metformin and to describe the possible mechanisms behind it.
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References
1.
LopezAD, MathersCD, EzzatiM, JamisonDT, MurrayCJ. Global and regional burden of disease and risk factors, 2001: Systematic analysis of population heath data. Lancet, 2006; 367:1747–1757.
CollinsJJ, EvasonK, PickettCL, SchneiderDL, KornfeldK. The anticonvulsant ethoxysuximide disrupts sensory function to extend C. elegans lifespan. PLOS Genet, 2008; 4:e1000230.
4.
McCollG, KillileaDW, HubbardAE, VantipalliMC, MelovS, LithgowGJ. Pharmacological analysis of lithium-induced delayed aging in Caenorhabditis elegans. J Biol Chem, 2008; 283:350–357.
5.
HarrisonDE, StrongR, SharpZD, NelsonJF, AstleCM, FlurkeyK, NadonNL, WilkinsonJE, FrenkelK, CarterCS, PahorM, JavorsMA, FernandezE, MillerRA. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature, 2009; 60:392–395.
6.
MillerRA, HarrisonDE, AstleCM, BaurJA, BoydAR, de CaboR, FernandezE, FlurkeyK, JavorsMA, NelsonJF, OrihuelaCJ, PletcherS, ScharpZD, SinclairD, StarnesJW, WilkinsonJE, NadonNL, StrongR. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci, 2011; 66:191–201.
7.
BjedovI, ToivonenJM, KerrF, SlackC, JacobsonJ, FoleyA, PartridgeL. Mechanisms of life span extension by rapamycin in the fruit fly Drosophilia melanogaster. Cell Metab, 2010; 11:35–46.
WoodJG, RoginaB, LavuS, HowitzK, HelfandSL, TatarM, SinclairDA. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 2004; 430:686–689.
10.
ValenzanoDR, TerzibasiE, GenadeT, CattaneoA, DomeniciL, CellerinoA. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol, 2006; 16:296–300.
11.
StrongR, MillerRA, AstleCM, FloydRA, FlurkeyK, HensleyKL, JavorsMA, LeeuwenburghC, NelsonJF, OnginiE, NadonNL, WarnerHR, HarrisonDE. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell, 2008; 7:641–650.
12.
SpindlerSR. Caloric restriction: From soup to nuts. Ageing Res Rev, 2010; 9:324–353.
13.
WeindruchR, WalfordRL. The Retardation of Aging and Disease by Dietary Restriction. Thomas Springfield: Illinois, 1988.
14.
MairW, DillinA. Aging and survival: The genetics of life span extension by dietary restriction. Ann Rev Biochem, 2008; 77:727–754.
HolloszyJO, FontanaL. Caloric restriction in humans. Exp Gerontol, 2007; 42:709–712.
17.
KirpichnikovD, McFarlaneSI, SowersJR. Metformin: An update. Ann Intern Med, 2002; 137:25–33.
18.
HundalRS, InzucchiSE. Metformin. New understandings, new uses. Drugs, 2003; 63:1879–1894.
19.
DhahbiJM, MotePL, FahyGM, SpindlerSR. Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics, 2005; 23:343–350.
20.
IngramDK, ZhuM, MamczarzJ, ZouS, LaneMA, RothGS, deCaboR. Calorie restriction mimetics: An emerging research field. Aging Cell, 2006; 5:97–108.
21.
DykensJA, JamiesonJ, MarroquinL, NadanacivaS, BillisPA, WillY. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxic Appl Pharmacol, 2008; 233:203–210.
22.
DilmanVN, AnisimovVN. Effect of treatment with phenofromin, dyphenyl-hydantoin or l-DOPA on life span and tumor incidence in C3H/Sn mice. Gerontology, 1980; 26:241–245.
23.
AnisimovVN, SemenchenkoAV, YashinAI. Insulin and longevity: Antidiabetic biguanides as geroprotectors. Biogerontology, 2003; 4:297–307.
24.
AnisimovVN. Effect of phenformin on life span, estrus function and spontaneous tumor incidence in rats. Farmakol Toksikol, 1982; 45:127.
25.
AnisimovVN. Effect of butformin and diphenin on life span, estrus function and spontaneous tumor incidence in female rats. Vopr Onkol, 1980; 6:42–48.
26.
AnisimovVN. Metformin for aging and cancer prevention. Aging, 2010; 11:1–15.
27.
AnisimovVN, BersteinLM, EgorminPA, PiskunovaTS, PopovichIG, ZaberzhinskiMA, PoroshinaTE, SemenchenkoAV, ProvincialiM, ReF, FranceschiC. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol, 2005; 40:685–693.
28.
AnisimovVN, EgorminPA, BershteinLM, ZabezhinskiiMA, PiskunovaTS, PopovichIG, SemenchenkoAV. Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med, 2005; 139:721–723.
29.
JalvingM, GietemaJA, LefrandtJD, de JongS, REynersAKL, GansROB, de VriesEGE. Metformin: Taking away the Candy for cancer?Eur J Cancer, 2010; 46:2369–2380.
30.
AnisimovVN, EgorminPA, PiskunovaTS, PopovichIG, TyndykML, YurovaMN, ZabezhinskiMA, AnikinIV, KarkachAS, RomanyukhaAA. Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo. Cell Cycle, 2010; 1:188–197.
31.
AnisimovVN, BersteinLM, EgorminPA, PiskunovaTS, PopovichIG, ZaberzhinskiMA, TyndykML, YurovaMV, KovalenkoIG, PoroshinaTE, SemenchenkoAV. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle, 2008; 7:2769–2773.
32.
AnisimovVN, BersteinLM, PopovichIG, ZabezhinskiMA, EgorminPA, PiskunovaTS, SemenchenkoAV, TyndykML, YurovaMN, KovalenkoIG, PoroshinaTE. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging, 2011; 3:148–157.
33.
ViauA, El KarouiK, LaouariD, BurtinM, NguyenC, MoriK, PilleboutE, BergerT, MakTW, KnebelmannB, FriedlanderG, BaraschJ, TerziF. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest, 2010; 120:4065–4076.
34.
SmithDLJr, ElamCFJr, MattisonJA, LaneMA, RothGS, IngramDK, AllisonDB. Metformin supplementation and life span in Fischer-344 rats. J Gerontol Biol Sci Med Sci, 2010; 65A:468–474.
35.
YuBP, MasoroEJ, McMahanCA. Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics. J Gerontol, 1985; 40:657–670.
36.
SprottRL, AustadSN. Animal models for aging research. SchneiderE, RoweJW. Handbook of the Biology of Aging, 4th. Academic Press: Orlando, 1996; 2–23.
37.
AnisimovVN, PiskunovaTS, PopovichIG, ZabezhinskiMA, TyndykML, EgorminPA, YurovaMN, RosenfeldSV, SemenchenkoAV, KovalenkoIG, PoroshinaTE, BersteinLM. Gender differences in metformin effects on aging, life span and spontaneous tumorigenesis in 129/Sv mice. Aging (Albany NY), 2010; 2:1–14.
38.
MaTC, BuescherJL, OatisB, FunkJA, NashAJ, CarrierRL, HoytKR. Metformin therapy in a transgenic mouse model of Huntington's disease. Neurosci Lett, 2007; 411:98–103.
39.
OnkenB, DriscollM. 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, 2010; 5:e8758.
40.
SpindlerSR. Use of microarray biomarkers to identify longevity therapeutics. Aging Cell, 2006; 5:39–50.
41.
LaneMA, BaerDJ, RumplerWV, WeindruchR, IngramDK, TilmontEM, CutlerRG, RothGS. Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents. Proc Natl Acad Sci USA, 1996; 93:4159–4164.
42.
HeilbronnLK, de JongeL, FrisardMI, DeLanyJP, Larson-MeyerE, RoodJ, NguyenT, MartinCK, VolaufovaJ, MostMM, GreenwayFL, SmithSR, DeutschWA, WilliamsonDA, RavussinE. Pennington CALERIE Team. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals. J Am Med Assoc, 2006; 295:1539–1548.
43.
GlombMA, MonnierVM. Mechanism of protein modification by glyoxal and glucoaldehyde, reactive intermediates of Maillard reaction. J Biol Chen, 1995; 270:10017–10026.
44.
HamadaY, ArakiN, KohN, NakamuraJ, HoriuchiS, HottaN. Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway. Biochem Biophys Res Commun, 1996; 228:539–543.
45.
SjöbergJS, BulterijsS. Characteristics, formation, and pathophysiology of glucosepane: A major protein cross-link. Rej Res, 2009; 12:137–148.
46.
BjorkstenJ. The crosslinkage theory of aging. J Am Geriatr Soc, 1968; 16:408–427.
47.
BjorstenJ, TenhuH. The cross-linking theory of aging—added evidence. Exp Gerontol, 1990; 25:91–95.
48.
MéndezJD, XieJ, Aguilar-HernándezM, Méndez-ValenzuelaV. Molecular susceptibility to glycation and its implication in diabetes mellitus and related diseases. Mol Cell Biochem, 2010; 344:185–193.
49.
SembaRD, NicklettEJ, FerrucciL. Does accumulation of advanced glycation end products contribute to the aging phenotype?J Gerontol Biol Sci Med Sci, 2010; 65:963–975.
EdelsteinK, BrownleeM. Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine. Diabetes, 1992; 41:26–29.
52.
HirischJ, PetrakovaE, FeatherMS. The reaction of some dicarbonyl sugars with aminoguanidine. Carbohydr Res, 1992; 232:125–130.
53.
Ruggiero-LopezD, LecompteM, MoinetG, PatereauG, LagardeM, WiernspergerN. Reaction of metformin with dicarbonyl compounds. Possible implications in the inhibition of advanced glycation end product formation. Biochem Pharacol, 1999; 58:1765–1773.
54.
OuP, WolffSP. Aminoguanidine: A drug proposed for prophylaxis in diabetes inhibits catalase and generates hydrogen peroxide in vitro. Biochem Pharmacol, 1993; 46:1139–1144.
55.
BrooksBA, HeffernanS, ThomsonS, McLennanSV, TwiggSM, YueDK. The effects of diabetes and aminoguanidine treatment on endothelial function in a primate model of type 1 diabetes. Am J Primatol, 2008; 70:796–802.
56.
OturaiPS, RaschR, HasselagerE, JohansenPB, YokoymaH, ThomsenMK, MyrupB, Kofoed-EnevoldsenA, DeckertT. Effects of heparin and aminoguanidine on globular basement membrane thickening in diabetic rats. APMIS, 2009; 104:259–264.
57.
KihoT, KatoM, UsuiS, HiranoK. Effect of butformin and metformin on formation of advanced glycation end products by methylglyoxal. Clin Chim Acta, 2005; 358:139–145.
58.
TakanaY, IwamotoH, OnumaT, KawamoriR. Inhibitory effect of metformin on formulation of advanced glycation end products. Curr Ther Res, 1997; 58:693–697.
59.
http://www.sanofi-aventis.ca/products/en/glucophage.pdf. 2011 February 27.
60.
BaileyCJ, PathMRC, TurnerRC. Drug therapy: metformin. N Engl J Med, 1996; 334:574–579.
61.
BeisswengerPJ, HowellSK, TouchetteAD, LalS, SzwergoldBS. Metformin reduces systemic methylglyoxal levels in type 2 diabetes. Diabetes, 1999; 48:198–202.
62.
Diamanti-KandarakisE, AlexandrakiK, PiperiC, AessoposA, PaterakisT, KatsikisI, PanidisD. Effect of metformin administration on plasma advanced glycation end product levels in women with polycystic ovary syndrome. Metabolism, 2007; 56:129–134.
63.
OuslimaniN, MahroufM, PeynetJ, Bonnefont-RousselotD, CossonC, LegrandA, BeaudeuxJ-L. Metformin reduces endothelial cell expression of both the receptor for advanced glycation end products and lectin-like oxidized receptor 1. Metabolism, 2007; 56:308–313.
YaSF, D'AgatiV, SchmidtAM, RamasamyR. Receptor for advanced glycation endproducts (RAGE): A formidable force in the pathogenesis of cardiovascular complications of diabetes & aging. Curr Mol Med, 2007; 7:699–710.
66.
MedvedikO, LammingDW, KimKD, SinclairDA. MSN2 and MSN4 link calorie restriction and TOR to sirtuin-mediated lifespan extension in Saccharomyces cerevisiae. PLoS Biol, 2007; 5:e261.
67.
TestaR, BonfigliAR, MarraM, TestaI. In the light of the metabolic memory theory, should not all aged people with dysglycemia be treated?Rejuvenation Res, 2010; 13:599–605.
68.
HardieDG, ScottJW, PanDA, HudsonER. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett, 2003; 546:113–120.
69.
ScholzR, SuterM, WeimannT, PolgeC, KonarevPV, ThaliRF, TuerkRD, ViolletB, WallimannT, SchlatterU, NeumannD. Homo-oligomerization and activation of AMP-activated protein kinase are mediated by the kinase domein αG-helix. J Biol Chem, 2009; 284:27425–27437.
70.
TowerMC, HardieDG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res, 2007; 100:328–341.
71.
HardieDG. New roles for the LKB1 → AMPK pathway. Curr Opin Cell Biol, 2005; 17:167–173.
72.
HardieDG, SaltIP, HawleySA, DaviesSP. AMP-activated protein kinase: An ultrasensitive system for monitoring cellular energy charge. Biochem J, 1999; 338:717–722.
73.
SandersMJ, GrondinPO, HegartyBD, SnowdenMA, CarlingD. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J, 2007; 403:139–148.
74.
MerrillGM, KurthE, HardieDG, WinderWW. AICA ribose increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol Endocrinol Metab, 1997; 273:E1107–E1112.
75.
VelascoG, GeelenMJH, GuzmanM. Control of hepatic fatty acid oxidation by 5’-AMP-activated protein kinase involves a molonyl-CoA-dependent and a molonyl-CoA-independent mechanism. Arch Biochem Biophys, 1997; 337:169–175.
76.
BergeronR, RenJM, CadmanKS, MooreIK, PerretP, PypaertM, YoungLH, SemenkovichCF, ShulmanGI. Chronic activation of AMP kinase results in NRF-1 activation and mitochondrial biogenesis. Am J Physiol Edocrinol Metab, 2001; 281:E1340–E1346.
77.
CarlingD. The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem Sci, 2004; 29:18–24.
78.
LimCT, KolaB, KorbonitsM. AMPK as a mediator of hormonal signaling. J Mol Endocrinol, 2010; 44:87–97.
79.
QiJ, GongJ, ZhaT. Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J, 2008; 25:1537–1548.
80.
ReznickRM, ZongH, LiJ, MorinoK, MooreIK, YuHJ, LiuZ-X, DongJ, MustardKJ, HawleySA, BefroyD, PypaertM, HardieDG, YoungLH, ShulmanGI. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metabolism, 2007; 5:151–156.
81.
ApfeldJ, O'ConnorG, McDonaghT, DiStefanoPS, CurtisR. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev, 2004; 18:3004–3009.
82.
ZhouG, MyersR, LiY, ShenX, Fenyk-MelodyJ. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest, 2001; 108:1167–1174.
83.
MusiN, HirshmanMF, NygrenJ, SvanfeldtM, BavenholmP, RooyachersO. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes, 2002; 51:2074–2081.
84.
ZhangL, LeH, BalschiJA. Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Physiol, 2007; 293:H457–H466.
85.
LabuzekK, LiberS, GabryelB, AdamczykJ, OkopieńB. Metformin increases phagocytosis and acidifies lysosomal/endosomal compartments in AMPK-dependent manner in rat primary microglia. Naunyn Schmiedebergs Arch Pharmacol, 2010; 381:171–86.
86.
ZouMH, KirkpatrickSS, DavisBJ, NelsonJS, WilesWG, SchlattnerU, NeumannD, BrownleeM, FreemanMB, GoldmanMH. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: Role of mitochondrial reactive nitrogen species. J Biol Chem, 2004; 279:43940–43951.
87.
XieZ, DongY, ScholzR, NeumannD, ZouM-H. Phosphorylation of LKB-1 at serine 428 by protein kinase C-ζ is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circ, 2008; 117:952–962.
88.
HinkeSA, MartensGA, CaiY, FinsiJ, HeimergH, PipeleersD, Van de CasteeleM. Methyl succinate antagonizes biguanide-induced AMPK-activation and death of pancreatic beta-cells through restoration of mitochondrial electron transfer. Br J Pharmacol, 2007; 105:1031–1043.
89.
ChenY, ZhouK, WangR, LiuY, KwakY-D, MaT, ThompsonRC, ZhaoY, SmithL, GaspariniL, LuoZ, XuZ. Liao F-F Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci USA, 2009; 106:3907–3912.
Chau-VanC, GambaM, SalviR, GailardRC, PralongFP. Metformin inhibits adenosine 5′-monphosphate-activated protein kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology, 2006; 148:507–511.
92.
Coyral-CastelS, ToscaL, FerreiraG, JeanpierreE, RameC, LometD, CaratyA, MongetP, ChabrolleC, DupontJ. The effect of AMPK activation on GnRH secretion in GT1-7 cells and its potential role in hypothalamic regulation of the oestrous cyclicity in rats. J Neuroendocrinol, 2008; 20:335–346.
93.
ParkM, SongK, KimHK, ParkYJ, KimHS, BaeMI, LeeJ. 2-deoxy-d-glucose protects neural progenitor cells against oxidative stress through the activation of AMP-activated protein kinase. Neurosci Lett, 2009; 449:201–206.
GonzalezAA, KumarR, MulliganJD, DavisAJ, WeindruchR, SaupeKW. Metablic adaptations to fasting and chronic caloric restriction in heart, muscle, and liver do not include changes in AMPK activity. Am J Physiol Endocrinol Metab, 2004; 287:E1032–E1037.
96.
de LangeP, FarinaP, MorenoM, RagniM, LombardiA, SilvestriE, BurroneL, LanniA, GogliaF. Sequential changes in the signal transduction responses of skeletal muscle following food deprivation. FASEB J, 2006; 20:2579–2581.
97.
ToK, YamazaH, KomatsuT, HayashidiH, oyamaH, ChibaT, HigamiY, ShimokawaI. Down-regulation of AMP-activated protein kinase by calorie restriction in rat liver. Exp Gerontol, 2007; 42:1063–1071.
98.
DagonY, AvrahamY, MagenI, GertlerA, Ben-hurT, BerryEM. Nutritional status, cognition, and survival: A new role for leptin and AMP kinase. J Biol Chem, 2005; 280:42142–42148.
PichardC, VaughanC, StrukR, ArmstrongRL, JeejeebhoyKN. Effect of dietary manipulations (fasting, hypocaloric feeding, and subsequent refeeding) on rat muscle energetic as assessed by nuclear magnetic resonance spectroscopy. J Clin Invest, 1988; 82:895–901.
101.
López-LluchG, HuntN, JonesB, ZhuM, JamiesonH, HilmerS, CascajoMV, AllardJ, IngramDK, NavasP, de CaboR. Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci USA, 2006; 103:1768–1773.
102.
MundayMR, MilicMR, TakharS, HolnessMJ, SugdenMC. The short-term regulation of hepatic acetyl-CoA carboxylase during starvation and re-feeding in the rat. Biochem J, 1999; 280:733–737.
103.
BlüherM, KahnBB, KahnCR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science, 2003; 299:572–574.
104.
KenyonCJ. The genetics of ageing. Nature, 2010; 464:504–512.
105.
OwenMR, DoranE, HalestrapAP. Evidence that metformin exerts its anti-diabetic effects though inhibition inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J, 2000; 348:607–614.
106.
El-MirMY, NogueiraV, FontaineE, AveretN, RigouletM, LeverveX. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem, 2000; 25:223–228.
107.
ForetzM, HébrardS, LeclercJ, ZarrinpashnehE, SotyM, MithieuxG, SakamotoK, AndreelliF, ViolletB. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest, 2010; 120:2355–2369.
108.
HawleySA, GadallaAE, OlsenGS, HardieDG. The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes, 2002; 51:2420–2425.
109.
FreyerLG, Parbu-PatelA, CarlingD. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem, 2002; 277:25226–25232.
110.
ShawRJ, KosmatkaM, BardeesyN, HurleyRL, WittersLA, DePinhoRA, CantleyLC. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA, 2004; 101:3329–3335.
111.
ShawRJ, LamiaKA, VasquezD, KooS-H, BardeesyN, DePinhoRA, MontminyM, CantleyLC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science, 2005; 310:1642–1646.
112.
HurleyRL, AndersonKA, FranzoneJM, KempBE, MeansAR, WittersLA. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem, 2005; 280:29060–29066.
113.
MomcilovicM, HongSP, CarlsonM. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem, 2006; 281:25336–25343.
114.
ZeqirajE, FilippiBM, DeakM, AlessiDR, van AaltenDMF. Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science, 2009; 326:1707–1711.
115.
XieZ, DongY, ZhangJ, ScholzR, NeumannD, ZouM-H. Identification of the serine 307 of LKB1 as a novel phosphorylation site essential for its nucleocytoplasmic transport and endothelial cell angiogenesis. Mol Cell Biol, 2009; 29:3582–3596.
116.
XieZ, DongY, ScholzR, NeumannD, ZouM-H. Phosphorylation of LKB1 at serine 428 by protein kinase C-zeta is required for metformin-enhanced activation of the AMP-activated protein kinase in endothelial cells. Circulation, 2008; 117:952–962.
117.
CantóC, Gerhart-HinesZ, FeigeJN, LagougeM, NoriegaL, MilneJC, ElliottPJ, PuigserverP, AuwerxJ. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature, 2009; 458:1056–1060.
118.
KaeberleinM, PowersRWIII. Sir2 and calorie restriction in yeast: A skeptical perspective. Ageing Res Rev, 2007; 6:128–140.
119.
GreerEL, DowlatshahiD, BankoMR, VillenJ, HoangK, BlanchardD, GygiSP, BrunetA. An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol, 2007; 17:1646–1656.
120.
CaryJR, RobineJ-M, MichelJP, ChristenY. Murphy CT. A review of genes that act downstream of the DAF-16 FOXO transcription factor to influence the life span of C. elegans. Longevity and Frailty. Springer, 2005.
HendersonST, BonafeM, JohnsonTE. daf-16 protects the nematode Caenorhabditis elegans during food deprivation. J Gerontol A Biol Sci Med, 2006; 61:444–460.
123.
PacholecM, BleasdaleJE, ChrunykB, CunninghamD, FlynnD, GarofaloRS, GriffithD, GrifforM, LoulakisP, PabstB, QiuX, StockmanB, ThanabalV, VargheseA, WardJ, WithkaJ, AhnK. SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1. J Biol Chem, 2010; 285:8340–8351Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009;122:3589–3594.
124.
LiaoX-H, MajithiaA, HuangX, KimmelAR. Growth control via TOR kinase signalling, an intracellular sensor of amino acid and energy availability, with crosstalk potential to proline metabolism. Amino Acids, 2008; 35:761–770.
125.
LaplanteM, SabatiniDM. An emerging role for mTOR in lipid biosynthesis. Curr Biol, 2009; 19:R1046–R1052.
126.
WangX, ProudCG. Nutrient control of TORC1, a cell-cycle regulator. Trends Cell Biol, 2009; 19:260–267.
127.
EvansDS, KapahiP, HsuehW-C, KockelL. TOR signaling never gets old: Aging, longevity and TORC1 activity. Ageing Res Rev, 2010; 10:225–237.
128.
McCormickMA, TsaiS-Y, KennedyBK. TOR and ageing: A complex pathway for a complex process. Phil Trans R Soc B, 2011; 366:17–27.
129.
GanB. mTORC1-dependent and -independent regulation of stem cell renewal, differentiation, and mobilization. Proc Natl Acad Sci USA, 2008; 105:19384–19389.
130.
TóthML, SigmondT, BorsosÉ, BarnaJ, ErdélyiP, Takács-VellaiK, OroszL, KovácsAL, CsikósG, SassM, VellaiT. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy, 2008; 4:330–338.
131.
VellaiT, Takacs-VellaiK, ZhangY, KovacsAL, OroszL, MullerF. Genetics: influences of TOR kinase on lifespan in C. elegans. Nature, 2003; 426:620.
132.
KapahiP, ZidBM, HarperT, KosloverD, SapinV, BenzerS. Regulation of lifespan in drosophila by modulation of genes in the TOR signalling pathway. Curr Biol, 2004; 14:885–890.
133.
JiaK, ChenD, RiddleDL. The TOR pathway interacts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development, 2004; 131:3897–3906.
134.
MagwereT, ChapmanT, PartridgeL. Sex differences in the effect of dietary restriction on life span and mortality rates in female and male Drosophila melanogaster. J Gerontol A Biol Sci Med Sci, 2004; 59:3–9.
135.
van HeemstD, BeekmanM, MooijaartSP, HeijmansBT, BrandtBW, ZwaanBJ, SlagboomPE, WestendorpRGJ. Reduced insulin/IGF-1 signalling and human longevity. Aging Cell, 2005; 4:79–85.
136.
HansenM, TaubertS, CrawfordD, LibinaN, LeeSJ, KenyonC. Lifespan extension by conditions that inhibit translation in Caenorhabditis elegans. Aging Cell, 2007; 6:95–110.
137.
E EstepPW3rd, WarnerJB, BulykML. Short-term calorie restriction in male mice feminizes gene expression and alters key regulators of conserved aging regulatory pathways. PLoS One, 2009; 4:e5242.
138.
DrazninB. Molecular mechanisms of insulin resistance: Serine phosphorylation of insulin receptor substrate-1 and increased expression of p85α. The two sides of a coin. Diabetes, 2006; 55:2392–2397.
139.
BlagosklonnyMV. Aging and immortality. Quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle, 2006; 5:2087–2102.
140.
KennedyBK, KaeberleinM. Hot topics in aging research: protein translation, 2009. Aging Cell, 2009; 8:617–623.
141.
GilbertWV, ZouK, ButlerTK, DoudnaJA. Cap-independent translation is required for starvation-induced differentiation in yeast. Science, 2007; 317:1224–1227.
142.
BeckT, HallMN. The TOR signaling pathway controls nuclear localization of nutrient-regulated transcription factors. Nature, 1999; 402:689–692
BlagosklonnyMV. Increasing healthy lifespan by suppressing aging in our lifetime. Cell Cycle, 2010; 9:4788–4794.
145.
JimenoA, RudekMA, KuleszaP, MaWW, WeelhouseJ, HowardA. Pharmacodynamic-guided modified continuous reassessment method-based, dose-finding study of rapamycin in adult patients with solid tumors. J Clin Oncol, 2008; 26:4172–4179.
146.
BlagosklonnyMV. An anti-aging drug today: From senescence-promoting genes to anti-aging pill. Drug Disc Today, 2007; 12:218–224.
147.
HoudeVP, BrûléS, FestucciaWT, BlanchardP-G, BellmannK, DeshaiesY, MaretteA. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes, 2010; 59:1338–1348.
148.
BussiereCT, LakeyJR, ShapiroAM, KorbuttGS. The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells. Diabetologia, 2006; 49:2341–2349.
149.
CunninghamJT, RodgersJT, ArlowDH, VazquezF, MoothaVK, PuigserverP. mTOR controls mitochondrial oxidative function through a YY1-PGC-1α transcriptional complex. Nature, 2007; 450:736–740.
150.
FraenkelM, Ketzinel-GiladM, AriavY, PappoO, KaracaM, CastelJ, BerthaultMF, MagnanC, CerasiE, KaiserN, LeibowitzG. mTOR inhibition by rapmycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes, 2008; 57:945–957.
151.
SehgalSN, Molnar-KimberK, OcainTD, WeichmanBW. Rapamycin: A novel immunosuppressive macrolide. Med Res Rev, 1994; 14:1–22.
152.
DumontFJ, SuQ. Mechanism of action of the immunosuppressant rapamycin. Life Sci, 1996; 58:373–395.
153.
WeichhartT, SaemannMD. The multiple facets of mTOR in immunity. Trends Immunol, 2009; 30:218–226.
154.
JanesMR, FrumanDA. Immune regulation by rapamycin: moving beyond T cells. Sci Signal, 2009; 2,67:pe25.
155.
SharpZD, StrongR. The role of mTOR signaling in controlling mammalian life span: What a fungicide teaches us about longevity. J Gerontol Biol Sci Med Sci, 2010; 65:580–589.
156.
DowlingRJO, ZakikhaniM, FantusIG, PollakM, SonenbergN. Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer Cells. Cancer Res, 2007; 67:10804–10812.
KimuraN, TokunagaC, DalalS, RichardsonC, YoshinoK, HaraK, KempBE, WittersLA, MimuraO, YonezawaK. A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signaling pathway. Genes Cells, 2003; 8:65–79.
161.
KrauseU, BertrandL, HueL. Contol of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes. Eur J Biochem, 2002; 269:3751–3759.
162.
BolsterDR, CrozierSJ, KimballRS, JeffersonLS. AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through downregulated mTOR signaling. J Biol Chem, 2002; 277:23977–23980.
163.
KalenderA, SelvarajA, KimSY, GulatiP, BrûléS, ViolletB, KempBE, BardeesyN, DennisP, SchlagerJJ, MaretteA, KozmaSC, ThomasG. Metformin, independent of AMPK, inhibits mTORC1 in a Rag GTPase-dependent manner. Cell Metabolism, 2010; 11:390–401.
164.
SancakY, Bar-PeledL, ZoncuR, MarkhardAL, NadaS, SabatiniDM. Ragulator-Rag complex targes mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell, 2010; 141:290–303.
165.
GhoshHS, McBurneyM, RobbinsPD. SIRT1 negatively regulates the mammalian target of rapamycin. PLoS One, 2010; 5:e9199.
166.
JonesRG, PlasDR, KubekS, BuzzaiM, MuJ, XuY, BirnbaumMJ, ThompsonCB. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell, 2005; 18:283–293.
167.
Fruehwald-SchultesB, OltmannsKM, ToschekB, SopkeS, KernW, BornJ. Short-term treatment with metformin decreases serum leptin concentration without affecting body weight and body fat content in normal-weight healthy men. Metabolism, 2002; 51:531–356.
168.
LeoVD, La MarcaA, OrvietoR, MorganteG. Effect of metormin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome. J Clin Endocrinol Metabol, 2000; 85:1598–1600.
169.
PawelczykL, SpaczynskiRZ, BanaszewskaB, BulebaAJ. Metformin therapy increases insulin-like growth factor binding protein-1 in hyperinsulinemic women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol, 2004; 113:209–213.
170.
GuarenteL. Mitochondria—a nexus for aging, calorie restriction, and sirtuins?Cell, 2008; 132:171–176.
171.
PiwkowskaA, RogackaD, JankowskiM, DominiczakMH, StepińskiJK, AngielskiS. Metformin induces suppression of NA(P)H oxidase activity in podocytes. Biochem Biophys Res Commun, 2010; 393:268–273.
172.
PavlovićD, KocićR, KocićG, JevtovićS, MikićS, StojanovićM, DjordjevićPB. Effect of four-week metformin treatment on plasma and erythrocyte antioxidative defense enzymes in newly diagnosed obese patients with type 2 diabetes. Diabetes Obes Metab, 2000; 2:251–256.
173.
GargiuloP, CacceseD, PignatelliP. Metformin decreases platelet superoxide anion production in diabetic patients. Diabetes Metab Res Rev, 2002; 18:156–159.
174.
WeindruchR, KayoT, LeeC-K, ProllaTA. Microarray profiling of gene expression in aging and its alteration by caloric restriction in mice. J Nutr, 2001; 131:918S–923S.
175.
KicksteinE, KarussS, ThornhillP, RutschowD, ZellerR, SharkeyJ, WilliamsomR, FuchsM, KöhlerA, GlossmannA, SchneiderR, SutherlandC, SchweigerS. Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling. Proc Natl Acad Sci USA, 2010; 107:21830–21835.
176.
WilliamsT, CourchetJ, ViolletB, BrenmanJE, PolleuxF. AMP-activated protein kinase (AMPK) activity is not required for neuronal development but regulates axogenesis during metabolic stress. Proc Natl Acad Sci USA, 2011; 108:5849–5854.