Previously

1
Previously
Cells need external signals to promote cell
proliferation Cells have internal controls to
limit of divisions
2
Telomere length as hypothesis for aging

• What evidence supports this kind of hypothesis?
• Correlation between biological age, cellular age
  and appearance?
• Elissa Epel et al. 2004 telomere length of blood
  cells from mothers of healthy children and
  mothers caring for chronically ill children.

3
First Chromosomes, Replication, Telomeres and
Aging (vs Immortality)

• What is a chromosome?
• Why copy chromosomes?
• What happens when a cell doesnt have the correct
  number? (total number -- not talking about single
  mutations)
• Largest pause in cell cycle-- G1/S transition.
  Hmm, why?

4
Process of copying DNA DNA replication

• http//www.youtube.com/watch?vgL3aigv7w4A
• http//www.youtube.com/watch?v-mtLXpgjHL0feature
  related
• Semi-conservative process requiring DNA helicase,
  primase, DNA polymerase, ligase, ssbinding
  proteins..
• Because both strands must be copied at same
  time-- leading and lagging strand.
• http//www.youtube.com/watch?vdIZpb93NYlwfeature
  related

5
So what about the ends?

• Telomeres TTAGGG repeats
• uses in protection and attachment
• Why is their replication a problem?
• (How do gametes get around this?)

6
http//bcs.whfreeman.com/lodish6e/ Ch6
Animation Telomere replication
7
Hayflick meets End Replication Problem

• Carol Greider and Calvin Harley
• Is this the clock? (early 1990s and now
• Nobel prize)
• What is the consequence of high telomerase
  activity according to this hypothesis?
• Of having low telomerase activity?

8

• Greider and Haley In adult humans only cells
  with high telomerase expression are germline
  cells and cancer cells Consistent?

9

• Looked at 1000 human primary cancers and saw 90
  had increased telomerase activity
• BUT HAVING high activity wasnt enough to
  predict outcome (acute myelocytic leukemia
  cases)
• so perhaps contributes but not sufficient?
• What if you could get rid of all telomerase
• Predict the phenotype

10
Greiders Telomerase free mice

• Chromosomes stick together or lost during
  division
• Mouse version of symptoms similar to Werners
  syndrome
• BUT mice could still form tumors Getting rid of
  telomerase not enough to get rid of cancer.

11
Aging vs Immortality

• If short telomeres lead to cell death do long
  telomeres lead to immortal cell lines? What if
  you could turn telomerase back on? (Harley and
  Shay)
• 1998 Tom Brokaw announced
• they have found a way to reverse the aging
  process
• (perhaps a bit overstated..but)

12

• In Epels work telomeres of stress group 9-17
  years shorter, appearance more aged than that of
  less stress group
• Consistent with hypothesis?
• Lieberman et al. 9/09 telomere repeat-encoding
  RNA (TERRA) mediates and partially stabilizes
  interactions between telomeric proteins that play
  essential roles in DNA Replication

13
What happens when you manipulate telomere length?

• Austriaco and Guarente paper
• Big picture?
• Why yeast?
• What are they doing? (physically
  manipulating)