Previously by wulinqing

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									Previously

  Cells need external
  signals to promote
  cell proliferation

  Cells have internal
  controls to limit # of
  divisions
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.
First: Chromosomes, Replication,
Telomeres and Aging (vs Immortality)

 • What is a chromosome?
 • Why copy chromosomes?
 • What happens when a cell doesn‘t have
   the correct number? (total number -- not
   talking about single mutations)
 • Largest ‗pause‘ in cell cycle-- G1/S
   transition. Hmm, why?
Process of copying DNA= DNA replication
http://www.youtube.com/watch?v=gL3aigv7w4A

http://www.youtube.com/watch?v=-mtLXpgjHL0&feature=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?v=dIZpb93NYlw&feature=related
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?)
http://bcs.whfreeman.com/lodish6e/   Ch6 Animation Telomere replication
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?
• Greider and Haley: In adult humans
  only cells with high telomerase
  expression are germline cells and
  cancer cells—
                 Consistent?
• Looked at 1000 human primary cancers and
  saw 90% had increased telomerase activity

• BUT– HAVING high activity wasn‘t 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
Greider‘s Telomerase free mice

 • Chromosomes stick together or lost
   during division

 • Mouse version of symptoms similar to
   Werner‘s syndrome

 • BUT– mice could still form tumors
   Getting rid of telomerase not enough to
   get rid of cancer.
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)
In Epel‘s 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‖
What happens when you manipulate
telomere length?

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

								
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