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rhLecture 17 Slides1CANCER,AGEINGandMETABOLISM2difficulties in being a long-lived MCOcancerageing3difficulties in being a long-lived MCOquantityquality4

cancer5pathogens:differencesare clearercancer cells:differencesare subtle6what are other adaptive features oftumor cells?how are they different from normal cells?cell biologygenomicsproteomicsmetabolism7fast-growing cells in midst of stationary cellsremovefront layerFF8fast-growing cells in midst of stationary cellsstarved for oxygenlack of nutrientslow O2 causes transcriptional responsehypoxia-inducible factor: HIF1-a9fast-growing cells in midst of stationary cellslow oxygenHIF1-aincreasedglycolysisangiogenicfactors10The prime cause of cancer is the replacement of the respiration of oxygen ... in normal body cells by fermentation of sugarOtto Warburg 1956

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Warburg ca 1950s12The prime cause of cancer is the replacement of the respiration of oxygen ... in normal body cells by fermentation of sugarOtto Warburg 1956

13Craig Thompson, M.D.President, Memorial Sloan-Kettering

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Science, May 200915Warburg ca 2010

16what are the special featuresof tumor cell metabolism?The prime cause of cancer is the replacement of the respiration of oxygen ... in normal body cells by fermentation of sugarOtto Warburg 1956

Tumor cells derive nearly all of their fattyacids from de novo synthesis

Sidney Weinhouse 195317Craig Thompson, M.D.President, Memorial Sloan-Kettering is glucose-dependent FA synthesisan achilles heel of tumor cells?

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fig 21-10remember citrate lyase?19fig 21-10citrate lyase as an anabolic carbon source

20FA synthesis in glycolytic tumor cells

Hatzivassiliou et al. (2005) Cancer Cell 8, 1-1121pre-developed drugs...citrateAcCoAfatty acidscitratelyasecholesterolstatins22fig 21-10Both AcCoA availability and NAD+ regeneration are blocked byinhibiting citrate lyase

23citrate lyase inhibitors

24Do citrate lyase inhibitors block tumorcell growth?25

Do citrate lyase inhibitors block tumorcell growth?26

27A new metabolic pathway in cancer?28A new metabolic pathway in cancer?~ 80% of gliomas have a mutation in IDH1 cytoplasmic version of IDH, uses NADP+mutation is always in R132, mostly R132H always heterozygous why?29A new metabolic pathway in cancer?

30A new metabolic pathway in cancer?metabolic profiling (metabolomics) revealedan abundance of 2-hydroxyglutarate ???could this be a product of the mutant IDH?31A new metabolic pathway in cancer?

mutant32A new metabolic pathway in cancer!How does production of 2OH-glutarate benefit the glioma cancer cell?33programmed cell death: apoptosisa dedicated signaling pathway for killing cells in MCOsapoptotic death has clear characteristicsemployed in development and in both intra-and inter cellular surveillancemain player...34The mitochondrion!

one way that apoptosisis activated is by theregulated release ofcytochrome c!35The mitochondrion!

one way that apoptosisis activated is by theregulated release ofcytochrome c!

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37difficulties in being a long-lived MCOquantityquality38difficulties in being a long-lived MCOcanceraging39difficulties in being a long-lived MCOin adult organisms (like us)many cells must live for theentire lifetime withoutreplacementall organisms have finite lifespans40old and young yeast

41old and young C. elegans1 day old13 days old

42old and young people

43The Search for The Fountain of Youth

Ponce de Leon44the only known mammalian longevity enhancer...45caloric restriction (CR)30-40% balanced decrease30% or more increase in longevityyeast, rotifers, flies, worms, fish, spiders mice, rats, birdsthe only known mammalian longevity enhancer...46Okinawan centenarians analysishow about in CR in humans or primates?47how about in CR in humans or primates?One controlled human studyOkinawan centenarians analysis48Biosphere 2how about in CR in humans or primates?One controlled human studyOkinawan centenarians analysis49

Biosphere 250Biosphere IINIH rhesus monkey studyhow about in CR in humans or primates?One controlled human studyOkinawan centenarians analysis51how does CR make things live longer?oxidative stress hypothesis

O2O2respiratory leak of electrons to oxygenproduces damage-causing ROS52ROS: reactive oxygen specieshighly reactive molecules produced fromcapture of electrons by O2 O2 O2-+ e- superoxideanionothers:H2O2HO(NO)53ROS: reactive oxygen specieshighly reactive molecules produced fromcapture of electrons by O2 cause damage toDNAproteinlipidsmitoROSpossible amplification loop54Possible effects of CR on ROS levelsDecreased production of ROSaltered rate of e flowmetabolic adaptations of mitosIncreased removal of ROS55how does CR make things live longer?correlated with decreased insulin levels andincreased insulin sensitivitypossible effects of insulin signaling onlongevity-associated processes?BUT: many other relevant effects of CR!!56are there master aging genes?it is easy to imagine that organismshave multiple systems that are eachrequired for maintained lifemeaningthat the genes that determine each systems function could each be aginggenesnevertheless...57progeria: an accelerated aging syndrome

Francis Collinsof HGP and NIH13 year oldJohn Tacket58progeria: an accelerated aging syndrome

59search for genes involved in aging

S. cerevisiaeC. elegans

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61aging mutants in C. elegans13 day oldmutant13 day oldwild-type

62aging mutants in C. eleganswhat genes emerged from this study?DAF2 insulin receptor homologue!.5Days

01020406080wild typedaf-263aging mutants in C. eleganswhat genes emerged from this study?DAF2 insulin receptor homologue!recall that insulin signals increasedabundance: the opposite of CR64aging mutants in C. eleganswhat genes emerged from this study?Complex I-V respiratory chain!consistent with the idea that mitochondrial activity contributes to aging65aging mutants in C. eleganswhat genes emerged from this study?EAT gens control food intakea genetic version of CR!66A model of CR(in worms)FoodinsulinsignalnutrientmetabolismETC activityAGINGA genetictest of thisidea67In fact, all three aging pathways appearseparate (in worms)Is this true in mammals?Fooddaf2(insulin)mitoactivityAGINGAGINGAGING

68geneHow about positive actinggenes in longevity?geneAGEINGAGEING

69ageing mutants in yeast

w.t.twodifferentmutantsextracopiesof UTH470a longevity gene in yeastSIR2a novel enzyme: NAD+ dependent protein deacetylaseNH-AcproteinSIR2NH2proteinNAD+71SIR2 is broadly involved in longevityincreasing SIR2 activity increases lifespan inyeastC. elegansmammalian cells (??)Drosophila72IS Sir2 broadly involved in longevity?73A molecular fountain of youth?the search is on for STACs: Sir TwoActivating Compounds

resveratrol: a naturalactivator of SIR2...increases lifespan in yeast, flies, C.elegansor does it?74Resveratrolimitates thegeneticeffects ofcaloric restriction

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