Lecture 18 Slides rh

CANCER, AGEING and METABOLISM

difficulties in being a long-lived MCO cancer ageing

difficulties in being a long-lived MCO quantity quality

cancer

cancer cells: differences are subtle pathogens: differences are clearer

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

fast-growing cells in midst of stationary cells starved for oxygen lack of nutrients low O2 causes transcriptional response hypoxia-inducible factor: HIF1-a

fast-growing cells in midst of stationary cells low oxygen HIF1-a 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

President, Memorial Sloan-Kettering 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 what are the special features of tumor cell metabolism?

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

remember citrate lyase? fig 21-10

citrate lyase as an anabolic carbon source… fig 21-10

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

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

Both AcCoA availability and NAD+ regeneration are blocked by inhibiting citrate lyase fig 21-10

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?

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?

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 quantity quality

difficulties in being a long-lived MCO cancer aging

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 old 13 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) 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

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

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

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

Biosphere 2

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

how does CR make things live longer? oxidative stress hypothesis respiratory leak of electrons to oxygen O2 produces damage-causing ROS

ROS: reactive oxygen species highly reactive molecules produced from capture of electrons by O2 O2˙- O2 + e- superoxide anion others: H2O2 HO˙ (NO˙)

ROS: reactive oxygen species highly reactive molecules produced from capture of electrons by O2 cause damage to DNA protein lipids 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 13 year old John Tacket Francis Collins of HGP and NIH

progeria: an accelerated aging syndrome

search for genes involved in aging S. cerevisiae C. elegans

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

aging mutants in C. elegans what genes emerged from this study? DAF2 insulin receptor homologue! .5 Days 1 20 40 60 80 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 A genetic test of this idea AGING

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

How about positive acting genes in longevity? gene gene AGEING AGEING

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

SIR2 a longevity gene in yeast a novel enzyme: NAD+ dependent protein deacetylase NH-Ac protein SIR2 NH2 NAD+

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

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