Telomeres and Aging: Is there a connection?

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Telomeres and AgingIs there a connection?
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What are telomeres?

• Telomeres are
• Repetitive DNA sequences at the ends of all human
  chromosomes
• They contain thousands of repeats of the
  six-nucleotide sequence, TTAGGG
• In humans there are 46 chromosomes and thus 92
  telomeres (one at each end)

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What do telomeres do?

• They protect the chromosomes.
• They separate one chromosome from another in the
  DNA sequence
• Without telomeres, the ends of the chromosomes
  would be "repaired", leading to chromosome fusion
  and massive genomic instability.

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Telomere function, cont.

• Telomeres are also thought to be the "clock" that
  regulates how many times an individual cell can
  divide. Telomeric sequences shorten each time the
  DNA replicates.

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Think of it like this.

• Telomeres effectively "cap" the end of a
  chromosome in a manner similar to the way the
  plastic on the ends of our shoelaces "caps" and
  protects the shoelaces from unraveling. (Geron
  corporation)

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How are telomeres linked to aging?

• Once the telomere shrinks to a certain level, the
  cell can no longer divide. Its metabolism slows
  down, it ages, and dies.

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Telomeres Aging

• Healthy human cells are mortal because they can
  divide only a finite number of times, growing
  older each time they divide. Thus cells in an
  elderly person are much older than cells in an
  infant.

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Telomeres Aging

• It has been proposed that telomere shortening may
  be a molecular clock mechanism that counts the
  number of times a cell has divided and when
  telomeres are short, cellular senescence (growth
  arrest) occurs.

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Telomeres Aging

• It is believed that shortened telomeres in
  mitotic (dividing) cells may be responsible for
  some of the changes we associate with normal
  aging.

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Think of it like this

• Geron Corporation likens the telomere and aging
  condition to this
• For the cell, having a long telomere can be
  compared to having a full tank of gas in your
  automobile having a short telomere is like
  running on empty. Each time a cell divides, its
  telomeres become a little shorter until the cells
  simply can no longer divide (e.g., it runs out of
  fuel).

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Telomeres Aging

• After a certain number of cell divisions, the
  telomeres would be so short as to somehow prevent
  the cell from further proliferation--putting it
  in a state called senescence. In other words, he
  proposed that telomere length offered a clock for
  telling a cell's longevity. - Scientific
  American

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What next?

• So, scientists have determined that there is a
  direct connection between telomere length and
  aging. What was their next step?

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What Next?

• Dr. Jerry Shay and his colleagues (The University
  of Texas Southwestern Medical Center at Dallas )
  found that cellular aging can be bypassed or put
  on hold by the introduction of the catalytic
  component of telomerase (i.e., the fuel added to
  the gas tank to keep the car running)!

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What is telomerase, anyway?

• Telomerase (TEE-LÓM-ER-ACE) is a
  ribonucleoprotein enzyme complex (a cellular
  reverse transcriptase) that has been referred to
  as a cellular immortalizing enzyme.
• It stabilizes telomere length by adding hexameric
  (TTAGGG) repeats onto the telomeric ends of the
  chromosomes, thus compensating for the erosion of
  telomeres that occurs in its absence.

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So how does this all link together?

• In the laboratory, cells in tissue culture with
  introduced telomerase have extended the length of
  their telomeres. They have already divided for
  250 generations past the time they normally would
  stop dividing, and are continuing to divide
  normally, giving rise to normal cells with the
  normal number of chromosomes.

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How Does Telomerase Work?

• Telomerase works by adding back telomeric DNA to
  the ends of chromosomes, thus compensating for
  the loss of telomeres that normally occurs as
  cells divide.
• Most normal cells do not have this enzyme and
  thus they lose telomeres with each division.

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How Does Telomerase Work?

• In humans, telomerase is active in germ cells, in
  vitro immortalized cells, the vast majority of
  cancer cells and, possibly, in some stem cells.
• High telomerase activity exists in germ cells,
  stem cells, epidermal skin cells, follicular hair
  cells, and cancer cells.

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How Does Telomerase Work?

• Research also shows that the counter that
  controls the wasting away of the telomere can be
  "turned on" and "turned off". The control button
  appears to be an enzyme called telomerase which
  can rejuvenate the telomere and allow the cell to
  divide endlessly. Most cells of the body contain
  telomerase but it is in the "off" position so
  that the cell is mortal and eventually dies.

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How Does Telomerase Work?

• Some cells are immortal because their telomerase
  is switched on
• Examples of immortal cells blood cells and
  cancer cells
• Cancer cells do not age because they produce
  telomerase, which keeps the telomere intact.

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Visual Example

• The next slide shows cells stained to visualize
  the presence of telomerase.
• The bottom dish was treated to produce active
  telomerase and is still dividing
• The top dish of normal cells of the same age has
  stopped dividing

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Telomerase and Cancer

• There is experimental evidence from hundreds of
  independent laboratories that telomerase activity
  is present in almost all human tumors but not in
  tissues adjacent to the tumors.

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Telomerase and Cancer

• Thus, clinical telomerase research is currently
  focused on the development of methods for the
  accurate diagnosis of cancer and on novel
  anti-telomerase cancer therapeutics

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Experimentation

• Many experiments have shown that there is a
  direct relationship between telomeres and aging,
  and that telomerase has the ability to prolong
  life and cell division.

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Genetic Link

• The telomerase control gene has been mapped to
  3p21 (chromosome 3, the p (short) arm, locus 21)
• Although the gene for telomerase is present in
  all cells, hTRT is present only in immortal
  cells, where it serves to fuse the repeating
  sequences of DNA to the chromosomes, thereby
  lengthening the telomeres.

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Genetic Link

• Proof that introduction of the hTRT gene into
  mortal cells would cause them to produce active
  telomerase was offered in the December 1, 1997,
  issue of Nature Genetics by Genron researchers

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This info brought to you by

• Elizabeth Jordan

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Sources (1 of 4)

• Reveal P J, Henkels K M, and Truchi J J. 1997
  "Synthesis of the Mammalian Telomere Lagging
  Strand in Vitro." Journal Of BioChemistry Vol.
  272No. 18 pp11678-11681
• Scientific American Turning Back the Strands of
  Time

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Sources (2 of 4)

• McElligott R, and Wellinger R J. 1997 "The
  Terminal DNA Structure of Mammalian Chromosomes."
  EMBO Journal Vol. 16no. 12 pp 3705-3714.
  (www.emboj.org/)
• Mapping and Cloning of a Human Telomerase
  Repressor Gene on Chromosome 3" CS Cooper et.
  all

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Sources (3 of 4)

• Geron Symposium No. 3 Telomerase and Telomere
  Dynamics in Cancer and Aging (www.geron.com/)
• Mouse model demonstrates role of telomeres and
  telomerase in aging, cancer and lifespan
  (http//www.arclab.org/ March 4, 1999 )

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Sources (4 of 4)

• Shay/Wright Laboratory The University of Texas
  Southwestern Medical Center at Dallas.
  (www.swmed.edu/)
• Aging and Cancer Are Telomeres and Telomerase
  the Connection? (http//www.accessexcellence.org/
  LC/ST/st10bg.html)