Telomeres and Aging:

Is there a connection?
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)
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.
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.
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)
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.
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.
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.
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.
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).
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
What next?
 So, scientists have determined that there is a
direct connection between telomere length
and aging. What was their next step?
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)!
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.
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.
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.
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.
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.
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.
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
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.
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
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.
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.
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
This info brought to you by:

 Elizabeth Jordan
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. 272:No. 18 pp11678-
11681
 Scientific American “Turning Back the
Strands of Time”
Sources (2 of 4)
 McElligott R, and Wellinger R J. 1997 "The
Terminal DNA Structure of Mammalian
Chromosomes." EMBO Journal Vol. 16:no.
12 pp 3705-3714. (www.emboj.org/)
 “Mapping and Cloning of a Human
Telomerase Repressor Gene on
Chromosome 3" CS Cooper et. all
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 )
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/st
10bg.html)