Abstract
One of the factors affecting chronological life span (CLS) in budding yeast is nutrient, especially carbon limitation. Aside from metabolites in the growth medium such as glucose, amino acids, and acetic acid, many pharmaceuticals have also been proven to alter CLS. Besides their impact on life span, these drugs are also prospective chemicals to treat the age-associated diseases, so the identification of their action mechanism and their potential side effects is of crucial importance. In this study, the effects of caloric restriction and metformin, a dietary mimetic pharmaceutical, on yeast CLS are compared. Saccharomyces cerevisiae cells grown in synthetic dextrose complete (SDC) up to mid-exponential phase were either treated with metformin or were subjected to glucose limitation. The impacts of these perturbations were analyzed via transcriptomics, and the common (stimulation of glucose uptake, induction of mitochondrial maintenance, and reduction of protein translation) and divergent (stimulation of aerobic respiration and reprogramming of respiratory electron transport chain (ETC)) cellular responses specific to each treatment were determined. These results revealed that both glucose limitation and metformin treatment stimulate CLS extension and involve the mitochondrial function, probably by creating an efficient mitochondria-to-nucleus signaling of either aerobic respiration or ETC signaling stimulation, respectively.
Similar content being viewed by others
References
Alexander MA, Jeffries TW (1990) Respiratory efficiency and metabolite partitioning as regulatory phenomena in yeasts. Enzym Microb Technol 12(1):2–19
Algire C, Moiseeva O, Deschênes-Simard X, Amrein L, Petruccelli L, Birman E, Viollet B, Ferbeyre G, Pollak MN (2012) Metformin reduces endogenous reactive oxygen species and associated DNA damage. Cancer Prev Res 5:536–543
Andzejewski S, Gravel SP, Pollak M, St-Pierre J (2014) Metformin directly acts on mitochondria to alter cellular bioenergetics. Cancer Metab 2:12
Aris JP, Fishwick LK, Marraffini ML, Seo AY, Leeuwenburgh C, Dunn WA (2012) Amino acid homeostasis and chronological longevity in Saccharomyces cerevisiae. Subcell Biochem 57:161–186
Avila MA, Carretero MV, Rodriguez EN, Mato JM (1998) Regulation by hypoxia of methionine adenosyltransferase activity and gene expression in rat hepatocytes. Gastroenterology 114(2):364–371
Bailey C, Day C (2004) Metformin: its botanical background. Pract Diab Int 21(3):115–117
Bandhakavi S, Xie H, O’Callaghan B, Sakurai H, Kim D-H, Griffin TJ (2008) Hsf1 activation inhibits rapamycin resistance and TOR signaling in yeast revealed by combined proteomic and genetic analysis. PLoS One 3(2): e1598
Barger JL, Kayo T, Vann JM, Arias EB, Wang J, Hacker TA, Wang Y, Raederstorff D, Morrow JD, Leeuwenburgh C, Allison DB, Saupe KW, Cartee GD, Weindruch R, Prolla TA (2008) A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One 3(6):10
Barros MH, Bandy B, Tahara EB, Kowaltowski AJ (2004) Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem 279(48):49883–49888
Batada NN, Hurst LD, Tyers M (2006) Evolutionary and physiological importance of hub proteins. PLoS Comput Biol 2(7):e88
Ben Sahra I, Le Marchand-Brustel Y, Tanti J-F, Bost F (2010) Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Mol Cancer Ther 9(5):1092–1099
Ben Sahra I, Regazzetti C, Robert G, Laurent K, Le Marchand-Brustel Y, Auberger P, Tanti J-F, Giorgetti-Peraldi S, Bost F (2011) Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1. Cancer Res 71(13):4366–4372
Blackburn AS, Avery SV (2003) Genome-wide screening of Saccharomyces cerevisiae to identify genes required for antibiotic insusceptibility of eukaryotes. Antimicrob Agents Chemother 47(2):676–681
Bonawitz ND, Chatenay-Lapointe M, Pan Y, Shadel GS (2007) Reduced TOR signaling extends chronological life span via increased respiration and upregulation of mitochondrial gene expression. Cell Metab 5(4):265–277
Brazma A, Hingamp P, Quackenbush J, Sherlock G, Spellman P, Stoeckert C, Aach J, Ansorge W, Ball CA, Causton HC, Gaasterland T, Glenisson P, Holstege FC, Kim IF, Markowitz V, Matese JC, Parkinson H, Robinson A, Sarkans U, Schulze-Kremer S, Stewart J, Taylor R, Vilo J, Vingron M (2001) Minimum information about a microarray experiment (MIAME)-toward standards for microarray data. Nat Genet 29(4):365–371
Cabreiro F, Au C, Leung K-Y, Vergara-Irigaray N, Cocheme HM, Noori T, Weinkove D, Schuster E, Greene NDE, Gems D (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153(1):228–239
Cankorur-Cetinkaya A, Eraslan S, Kirdar B (2013) Transcriptional remodelling in response to changing copper levels in the Wilson and Menkes disease model of Saccharomyces cerevisiae. Mol BioSyst 9(11):2889–2908
Chillappagari S, Seubert A, Trip H, Kuipers OP, Marahiel MA, Miethke M (2010) Copper stress affects iron homeostasis by destabilizing iron-sulfur cluster formation in in Bacillus subtilis. J Bacteriol 192(10):2512–2524
Collier CA, Bruce CR, Smith AC, Lopaschuk G, Dyck DJ (2006) Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol Endocrinol Metab 291(1):E182–E189
Cusi K, Consoli A, DeFronzo RA (1996) Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 81(11):4059–4067
De Virgilio C, Loewith R (2006) The TOR signalling network from yeast to man. Int J Biochem Cell Biol 38(9):1476–1481
Dhahbi JM, Mote PL, Fahy GM, Spindler SR (2005) Identification of potential caloric restriction mimetics by microarray profiling. Physiol Genomics 23(3):343–350
Dong K, Addinall SG, Lydall D, Rutherford JC (2013) The yeast copper response is regulated by DNA damage. Mol Cell Biol 33(20):4041–4050
Dowling RJO, Zakikhani M, Fantus IG, Pollak M, Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67(22):10804–10812
Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ (Clin Res ed) 330(7503):1304–1305
Fischer Y, Thomas J, Rösen P, Kammermeier H (1995) Action of metformin on glucose transport and glucose transporter GLUT1 and GLUT4 in heart muscle cells from healthy and diabetic rats. Endocrinology 136(2):412–420
Fischer M, Timper K, Radimerski T, Dembinski K, Frey DM, Zulewski H, Keller U, Müller B, Christ-Crain M, Grisouard J (2010) Metformin induces glucose uptake in human preadipocyte-derived adipocytes from various fat depots. Diabetes Obes Metab 12(4):356–359
Garofalo C, Capristo M, Manara MC, Mancarella C, Landuzzi L, Belfiore A, Lollini PL, Picci P, Scotlandi K (2013) Metformin as an adjuvant drug against pediatric sarcomas: hypoxia limits therapeutic effects of the drug. PLoS One 8(12): e83832
Gautier L, Cope L, Bolstad BM, Irizarry RA (2004) Affy—analysis of Affymetrix GeneChip Data at the probe level. Bioinformatics 20(3):307–315
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M, Dudoit S, Ellis B, Gautier L, Ge Y, Gentry J, Hornik K, Hothorn T, Huber W, Iacus S, Irizarry R, Leisch F, Li C, Maechler M, Rossini AJ, Sawitzki G, Smith C, Smyth G, Tierney L, Yang JY, Zhang J (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5(10):R80
Gleason JE, Corrigan DJ, Cox JE, Reddi AR, McGinnis LA, Culotta VC (2011) Analysis of hypoxia and hypoxia-like states through metabolite profiling. PLoS One 6(9): e24741
González Siso MI, Becerra M, Lamas Maceiras M, Vizoso Vázquez A, Cerdán ME (2012) The yeast hypoxic responses, resources for new biotechnological opportunities. Biotechnol Lett 34(12):2161–2173
Guigas B, Detaille D, Chauvin C, Batandier C, De Oliveira F, Fontaine E, Leverve X (2004) Metformin inhibits mitochondrial permeability transition and cell death: a pharmacological in vitro study. Biochem J 382(3):877–884
Halicka HD, Zhao H, Li J, Traganos F, Zhang S, Lee M, Darzynkiewicz Z (2011) Genome protective effect of metformin as revealed by reduced level of constitutive DNA damage signaling. Aging (Albany NY) 3(10):1028–1038
Hansen SH, McCormack JG (2002) Application of 13C-filtered 1H NMR to evaluate drug action on gluconeogenesis and glycogenolysis simultaneously in isolated rat hepatocytes. NMR Biomed 15(5):313–319
Hart RW, Turturro A (1997) Dietary restrictions and cancer. Environ Health Perspect 105:989–992
He L, Sabet A, Djedjos S, Miller R, Sun X, Hussain MA, Radovick S, Wondisford FE (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137(4):635–646
Johnson JE, Johnson FB (2014) Methionine restriction activates the retrograde response and confers both stress tolerance and lifespan extension to yeast, mouse and human cells. PLoS One 9(5): e97729
Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, Marette A, Kozma SC, Thomas G (2010) Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab 11(5):390–401
Kim J, Guan KL (2011) Amino acid signaling in TOR activation. Annu Rev Biochem 80:1001–1032
Kim MH, Jung YS, Moon CH, Lee SH, Baik EJ, Moon CK (2003) High-glucose induced protective effect against hypoxic injury is associated with maintenance of mitochondrial membrane potential. Jpn J Physiol 53(6):451–459
Kumar N, Dey CS (2002) Metformin enhances insulin signalling in insulin-dependent and-independent pathways in insulin resistant muscle cells. Br J Pharmacol 137(3):329–336
Kumar A, John L, Maity S, Manchanda M, Sharma A, Saini N, Chakraborty K, Sengupta S (2011) Converging evidence of mitochondrial dysfunction in a yeast model of homocysteine metabolism imbalance. J Biol Chem 286(24):21779–21795
Kwast KE, Burke PV, Staahl BT, Poyton RO (1999) Oxygen sensing in yeast: evidence for the involvement of the respiratory chain in regulating the transcription of a subset of hypoxic genes. PNAS 96(10):5446–5451
Laschober GT, Ruli D, Hofer E, Muck C, Carmona-Gutierrez D, Ring J, Hutter E, Ruckenstuhl C, Micutkova L, Brunauer R, Jamnig A, Trimmel D, Herndler-Brandstetter D, Brunner S, Zenzmaier C, Sampson N, Breitenbach M, Fröhlich KU, Grubeck-Loebenstein B, Berger P, Wieser M, Grillari-Voglauer R, Thallinger GG, Grillari J, Trajanoski Z, Madeo F, Lepperdinger G, Jansen-Dürr P (2010) Identification of evolutionarily conserved genetic regulators of cellular aging. Aging Cell 9(6):1084–1097
Leontieva OV, Blagosklonny MV (2011) Yeast-like chronological senescence in mammalian cells: phenomenon, mechanism and pharmacological suppression. Aging 3(11):1078–1091
Li C, Wong WH (2001) Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. PNAS 98(1):31–36
Logie L, Harthill J, Patel K, Bacon S, Hamilton DL, Macrae K, McDougall G, Wang H-H, Xue L, Jiang H, Sakamoto K, Prescott AR, Rena G (2012) Cellular responses to the metal-binding properties of metformin. Diabetes 61(6):1423–1433
Longo VD (2003) The Ras and Sch9 pathways regulate stress resistance and longevity. Exp Gerontol 38(7):807–811
Lowy DR, Willumsen BM (1993) Function and regulation of Ras. Annu Rev Biochem 62:851–891
MacDonald JW (2008) Affycoretools: functions useful for those doing repetitive analyses with Affymetrix GeneChips. R package version 1.28.0
Macomber L, Imlay JA (2009) The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity. PNAS 106(20):8344–8349
Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, Simon MC (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-α activation. Cell Metab 1(6):393–399
Matecic M, Smith DL, Pan X, Maqani N, Bekiranov S, Boeke JD, Smith JS (2010) A microarray-based genetic screen for yeast chronological aging factors. PLoS Genet 6(4):e1000921
Matuo R, Sousa FG, Soares DG, Bonatto D, Saffi J, Escargueil AE, Larsen AK, Henriques JAP (2012) Saccharomyces cerevisiae as a model system to study the response to anticancer agents. Cancer Chemother Pharmacol 70(4):491–502
Menendez JA, Cufí S, Oliveras-Ferraros C, Martin-Castillo B, Joven J, Vellon L, Vazquez-Martin A (2011) Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer. Aging (Albany NY) 3(11):1063–1077
Meynet O, Ricci JE (2014) Caloric restriction and cancer: molecular mechanisms and clinical implications. Trends Mol Med 20(8):419–427
Moler EJ, Radisky DC, Mian IS (2000) Integrating naive Bayes models and external knowledge to examine copper and iron homeostasis in S. cerevisiae. Physiol Genomics 4(2):127–135
Murakami CJ, Burtner CR, Kennedy BK, Kaeberlein M (2008) A method for high-throughput quantitative analysis of yeast chronological life span. J Gerontol A Bio Sci Med Sci 63(2):113–121
Na HJ, Park JS, Pyo JH, Lee SH, Jeon HJ, Kim YS, Yoo MA (2013) Mechanism of metformin: inhibition of DNA damage and proliferative activity in Drosophila midgut stem cell. Mech Ageing Dev 134(9):381–390
Natali A, Ferrannini E (2006) Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 49(3):434–441
Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. Elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One 5(1):13
Ota S, Horigome K, Ishii T, Nakai M, Hayashi K, Kawamura T, Kishino A, Taiji M, Kimura T (2009) Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem Biophys Res Commun 388:311–316
Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348(3):607–614
Pan Y (2011) Mitochondria, reactive oxygen species, and chronological aging: a message from yeast. Exp Gerontol 46(11):6–11
Postmus J, Tuzun I, Bekker M, Müller WH, de Mattos MJ, Brul S, Smits GJ (2011) Dynamic regulation of mitochondrial respiratory chain efficiency in Saccharomyces cerevisiae. Microbiology 157(12):3500–3511
Powers T, Walter P (1999) Regulation of ribosome biogenesis by the rapamycin-sensitive TOR-signaling pathway in Saccharomyces cerevisiae. Mol Biol Cell 10(4):987–1000
Powers 3rd RW, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20(2):174–184
Reimand J, Arak T, Vilo J (2011) g:Profiler—a web server for functional interpretation of gene lists (2011 update). Nucleic Acids Res 39:W307–W315
Rintala E, Jouhten P, Toivari M, Wiebe MG, Maaheimo H, Penttilä M, Ruohonen L (2011) Transcriptional responses of Saccharomyces cerevisiae to shift from respiratory and respirofermentative to fully fermentative metabolism. OMICS 15(7–8):461–476
Rosilio C, Ben-Sahra I, Bost F, Peyron JF (2014) Metformin: a metabolic disruptor and anti-diabetic drug to target human leukemia. Cancer Lett 346(2):188–196
Ruckenstuhl C, Netzberger C, Entfellner I, Carmona-Gutierrez D, Kickenweiz T, Stekovic S, Gleixner C, Schmid C, Klug L, Sorgo AG, Eisenberg T, Büttner S, Marino G, Koziel R, Janser-Dürr P, Fröhlich KU, Kroemer G, Madeo F (2014) Lifespan extension by methionine restriction requires autophagy-dependent vacuolar acidification. PLoS Genet 10(5): e1004347
Rutherford JC, Ojeda L, Balk J, Mühlenhoff U, Lill R, Winge DR (2005) Activation of the iron regulon by the yeast Aft1/Aft2 transcription factors depends on mitochondrial but not cytosolic iron-sulfur protein biogenesis. J Biol Chem 280(11):10135–10140
Saeedi R, Parsons HL, Wambolt RB, Paulson K, Sharma V, Dyck JRB, Brownsey RW, Allard MF (2008) Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms. Am J Physiol Heart Circ Physiol 294(6):H2497–H2506
Sajan MP, Bandyopadhyay G, Miura A, Standaert ML, Nimal S, Longnus SL, Van Obberghen E, Hainault I, Foufelle F, Kahn R, Braun U, Leitges M, Farese RV (2010) AICAR and metformin, but not exercise, increase muscle glucose transport through AMPK-, ERK-, and PDK1-dependent activation of atypical PKC. Am J Physiol Endocrinol Metab 298(2):E179–E192
Sequea DA, Sharma N, Arias EB, Cartee GD (2012) Calorie restriction enhances insulin-stimulated glucose uptake and Akt phosphorylation in both fast-twitch and slow-twitch skeletal muscle of 24-month-old rats. J Gerontol A Biol Sci Med Sci 67(12):1279–1285
Smith DL, McClure JM, Matecic M, Smith JS (2007) Calorie restriction extends the chronological lifespan of Saccharomyces cerevisiae independently of the sirtuins. Aging Cell 6(5):649–662
Smith DL, Elam CF, Mattison JA, Lane MA, Roth GS, Ingram DK, Allison DB (2010) Metformin supplementation and life span in Fischer-344 rats. J Gerontol A Biol Sci Med Sci 65(5):468–474
Sorrentino JA, Sanoff HK, Sharpless NA (2014) Defining the toxicology of aging. Trends Mol Med 20(7):375–384
Stipanuk MH (2004) Sulfur amino acid metabolism: pathways for production and removal of homocysteine and cysteine. Annu Rev Nutr 24:539–577
Tahara EB, Cunha FM, Basso TO, Della Bianca BE, Gombert AK, Kowaltowski AJ (2013) Calorie restriction hysteretically primes aging Saccharomyces cerevisiae toward more effective oxidative metabolism. PLoS One 8(2):e56388
Vemuri GN, Eiteman MA, McEwen JE, Olsson L, Nielsen J (2007) Increasing NADH oxidation reduces overflow metabolism in Saccharomyces cerevisiae. PNAS 104(7):2402–2407
Verduyn C, Stouthamer AH, Scheffers WA, van Dijken JP (1991) A theoretical evaluation of growth yields of yeasts. Antonie Van Leeuwenhoek 59(1):49–63
Wei M, Fabrizio P, Hu J, Ge H, Cheng C, Li L, Longo VD (2008) Life span extension by calorie restriction depends on Rim15 and transcription factors downstream of Ras/PKA, Tor, and Sch9. PLoS Genet 4(1):e13
Wei M, Fabrizio P, Madia F, Hu J, Ge H, Li LM, Longo VD (2009) Tor1/Sch9-regulated carbon source substitution is as effective as calorie restriction in life span extension. PLoS Genet 5(5):e1000467
Werner EA, Bell J (1922) The preparation of methylguanidine, and of ββ-dimethylguanidine by the interaction of dicyanodiamide, and methylammonium and dimethylammonium chlorides respectively. J Chem Soc Trans 121:1790
Wheaton WW, Chandel NS (2011) Hypoxia 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol 300(3):C385–C393
Whittington HJ, Hall AR, McLaughlin CP, Hausenloy DJ, Yellon DM, Mocanu MM (2013) Chronic metformin associated cardioprotection against infarction: not just a glucose lowering phenomenon. Cardiovasc Drugs Ther 27(1):5–16
Wile DJ, Toth C (2010) Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care 33(1):156–161
Wu N, Gu C, Gu H, Hu H, Han Y, Li Q (2011) Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD153. Neoplasma 58(6):482–490
Wu CL, Qiang L, Han W, Ming M, Viollet B, He YY (2013) Role of AMPK in UVB-induced DNA damage repair and growth control. Oncogene 32(21):2682–2689
Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174
Acknowledgments
This work was financially supported by Boğaziçi Research Fund through project 5681 and also by the Scientific and Technological Research Council of Turkey through project 110M428. We thank Prof. Stephen G. Oliver and Dr. Pınar Pir for providing the yeast strains.
Ethical statement
The manuscript does not contain experiments using animals. The manuscript also does not contain human studies.
Conflict of interest
The authors declare that they have no competing interests.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
ESM 1
(PDF 1165 kb)
Rights and permissions
About this article
Cite this article
Borklu-Yucel, E., Eraslan, S. & Ulgen, K.O. Transcriptional remodeling in response to transfer upon carbon-limited or metformin-supplemented media in S. cerevisiae and its effect on chronological life span. Appl Microbiol Biotechnol 99, 6775–6789 (2015). https://doi.org/10.1007/s00253-015-6728-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-015-6728-5