rh Lecture 17 Slides

CANCER, AGEING and METABOLISM

difficulties in being a long-lived MCO cancerageing

difficulties in being a long-lived MCO quantityquality

cancer

pathogens: differences are clearer cancer cells: differences are subtle

what are other adaptive features of tumor cells? how are they different from normal cells? cell biology genomics proteomics metabolism

fast-growing cells in midst of stationary cells remove front layer F F

fast-growing cells in midst of stationary cells starved for oxygen lack of nutrients low O 2 causes transcriptional response hypoxia-inducible factor: HIF1- 

fast-growing cells in midst of stationary cells low oxygen HIF1-  increased glycolysis angiogenic factors

“The prime cause of cancer is the replacement of the respiration of oxygen... in normal body cells by fermentation of sugar” Otto Warburg 1956

Warburg ca 1950s…

“The prime cause of cancer is the replacement of the respiration of oxygen... in normal body cells by fermentation of sugar” Otto Warburg 1956

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

Science, May 2009

Warburg ca 2010…

what are the special features of tumor cell metabolism? “The prime cause of cancer is the replacement of the respiration of oxygen... in normal body cells by fermentation of sugar” Otto Warburg 1956 Tumor cells derive nearly all of their fatty acids from de novo synthesis Sidney Weinhouse 1953

Craig Thompson, M.D. President, Memorial Sloan-Kettering is glucose-dependent FA synthesis an “achilles heel” of tumor cells?

fig remember citrate lyase?

fig citrate lyase as an anabolic carbon source…

FA synthesis in glycolytic tumor cells Hatzivassiliou et al. (2005) Cancer Cell 8, 1-11

pre-developed drugs... citrate AcCoA fatty acids citrate lyase cholesterol statins

fig Both AcCoA availability and NAD+ regeneration are blocked by inhibiting citrate lyase

citrate lyase inhibitors

Do citrate lyase inhibitors block tumor cell growth?

Do citrate lyase inhibitors block tumor cell growth?

A 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?

A new metabolic pathway in cancer?

metabolic profiling (metabolomics) revealed an abundance of 2-hydroxyglutarate… ??? could this be a product of the mutant IDH?

A new metabolic pathway in cancer? mutant

A new metabolic pathway in cancer! How does production of 2OH-glutarate benefit the glioma cancer cell?

programmed cell death: apoptosis a dedicated signaling pathway for killing cells in MCOs apoptotic death has clear characteristics employed in development and in both intra- and inter cellular surveillance main player...

The mitochondrion! one way that apoptosis is activated is by the regulated release of cytochrome c!

The mitochondrion! one way that apoptosis is activated is by the regulated release of cytochrome c!

difficulties in being a long-lived MCO quantityquality

difficulties in being a long-lived MCO canceraging

difficulties in being a long-lived MCO in adult organisms (like us) many cells must live for the entire lifetime without replacement all organisms have finite lifespans

old and young yeast

old and young C. elegans 1 day old13 days old

old and young people

The Search for The Fountain of Youth Ponce de Leon

the only known mammalian longevity enhancer...

caloric restriction (CR) 30-40% balanced decrease 30% or more increase in longevity yeast, rotifers, flies, worms, fish, spiders mice, rats, birds the only known mammalian longevity enhancer...

Okinawan centenarians analysis how about in CR in humans or primates?

One controlled human study Okinawan centenarians analysis

Biosphere 2 how about in CR in humans or primates? One controlled human study Okinawan centenarians analysis

Biosphere 2

Biosphere II NIH rhesus monkey study how about in CR in humans or primates? One controlled human study Okinawan centenarians analysis

how does CR make things live longer? oxidative stress hypothesis O2O2 O2O2 respiratory leak of electrons to oxygen produces damage-causing ROS

ROS: reactive oxygen species highly reactive molecules produced from capture of electrons by O 2 O2O2 O2˙-O2˙- +e-e- superoxide anion others: H2O2H2O2 HO ˙ (NO ˙ )

ROS: reactive oxygen species highly reactive molecules produced from capture of electrons by O 2 cause damage to DNAproteinlipids mito ROS possible amplification loop

Possible effects of CR on ROS levels Decreased production of ROS altered rate of e flow metabolic adaptations of mitos Increased removal of ROS

how does CR make things live longer? correlated with decreased insulin levels and increased insulin sensitivity possible effects of insulin signaling on longevity-associated processes? BUT: many other relevant effects of CR!!

are there master “aging” genes? it is easy to imagine that organisms have multiple systems that are each required for maintained life meaning that the genes that determine each system’s function could each be “aging” genes nevertheless...

progeria: an accelerated aging syndrome Francis Collins of HGP and NIH 13 year old John Tacket

progeria: an accelerated aging syndrome

search for genes involved in aging S. cerevisiaeC. elegans

aging mutants in C. elegans 13 day old mutant 13 day old wild-type

aging mutants in C. elegans what genes emerged from this study? DAF2 insulin receptor homologue!.5 Days wild type daf-2

aging mutants in C. elegans what genes emerged from this study? DAF2 insulin receptor homologue! recall that insulin signals increased abundance: the opposite of CR

aging mutants in C. elegans what genes emerged from this study? Complex I-V respiratory chain! consistent with the idea that mitochondrial activity contributes to aging

aging mutants in C. elegans what genes emerged from this study? EAT gens control food intake a genetic version of CR!

A model of CR (in worms) Food insulin signal nutrient metabolism ETC activity AGING A genetic test of this idea

In fact, all three aging pathways appear separate (in worms) Is this true in mammals? Food daf2 (insulin) mito activity AGING

gene How about positive acting genes in longevity? gene AGEING

ageing mutants in yeast w.t. two different mutants extra copies of UTH4

a longevity gene in yeast SIR2 a novel enzyme: NAD + dependent protein deacetylase NH-Ac protein SIR2 NH 2 protein NAD +

SIR2 is broadly involved in longevity increasing SIR2 activity increases lifespan in yeast C. elegans mammalian cells (??) Drosophila

IS Sir2 broadly involved in longevity?

A molecular fountain of youth? the search is on for STACs: Sir Two Activating Compounds resveratrol: a natural activator of SIR2... increases lifespan in yeast, flies, C.elegans or does it?

Resveratrol imitates the genetic effects of caloric restriction