1. Lecture 18 Slides rh

2. CANCER,
AGEING
and
METABOLISM

3. difficulties in being a long-lived MCO
cancer
ageing

4. difficulties in being a long-lived MCO
quantity
quality

5. cancer

6. cancer cells:
differences
are subtle
pathogens:
differences
are clearer

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

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

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

10. fast-growing cells in midst of stationary cells
low oxygen
HIF1-a
increased
glycolysis
angiogenic
factors

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

12. Warburg ca 1950s…

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

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

15. Science, May 2009

16. Warburg ca 2010…

17. 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?

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

19. remember citrate lyase?
fig 21-10

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

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

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

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

24. citrate lyase inhibitors

25. Do citrate lyase inhibitors block tumor
cell growth?

26. Do citrate lyase inhibitors block tumor
cell growth?

28. A new metabolic pathway in cancer?

29. 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?

30. A new metabolic pathway in cancer?

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

32. A new metabolic pathway in cancer?
mutant

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

34. 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...

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

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

38. difficulties in being a long-lived MCO
quantity
quality

39. difficulties in being a long-lived MCO
cancer
aging

40. 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

41. old and young yeast

42. old and young C. elegans
1 day old
13 days old

43. old and young people

44. The Search for The Fountain of Youth
Ponce de Leon

45. the only known mammalian longevity enhancer...

46. 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

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

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

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

50. Biosphere 2

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

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

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

54. 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

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

56. 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!!

57. 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...

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

59. progeria: an accelerated aging syndrome

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

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

63. 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

64. 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

65. 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

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

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

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

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

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

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

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

73. IS Sir2 broadly involved in longevity?

74. 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?

75. Resveratrol
imitates the
genetic
effects of
caloric
restriction