Telomeres and aging
Telomere
10 trillion (1013) cells
Telomeres
Telomere
A telomere is a region of repetitive DNA at the end of a
chromosome which protects the end of the chromosome
chromosome,
from deterioration.
If cells divided without telomeres,
telomeres they would lose the
ends of their chromosomes, and the necessary information
theyy contain.
The Nobel Prize in Physiology or Medicine 2009
Eli b h H
Elizabeth
H. Bl
Blackburn,
kb
C
Caroll W
W. G
Greider,
id Jack
J kW
W. S
Szostak
k
"how chromosomes are protected by
t l
telomeres
and
d th
the enzyme ttelomerase"
l
"
Telomeres are the ends of chromosomes
DNA St
Structure
t
Nucleotides
DNA
Adenine
Histones
Guanine
Nucleosome
Chromatin
Metaphase
p
chromosome
DNA Double
Thymine
y
Cytosine
y
helix
Adenine always pairs with
Thymine by 2 hydrogen bonds,
while Guanine pairs with
Cytosine through 3 hydrogen
bonds
Why telomeres is shorten during cell division
DNA St
Structure
t
Sugarphosphate
backbone
Sugarphosphate
b kb
backbone
100 200
million
b
base
pair
i
Base pair
10 trillion
(1013)
cells
Hydrogen
bond
DNA Double
helix
Fertilized egg (Zygote)
Telomere structure
Telomeres
T
l
are repetitive
titi DNA sequences
located at the termini of linear chromosomes
of most eukaryotic organisms
Group organism Telomeric repeat
(5 to 3 toward the end)
Vertebrates Human
Mouse
Xenopus
Long
Telomeres
Chromosome
Adult stem
cells
Telom
meres
Embryonic
stem cells
TTAGGG
TTAGGG
TTAGGG
Short
Telomere is a
repeating DNA
sequence
Telomeres are made of simple DNA repeats
bound by specific proteins
Telomere DNA
33
TTAG G G
Most of telomeres are double strains,
strains and small
regions are single strains.
For telomeres functions, proteins bound along
off DNA
DNA.
The end replication problem shortens telomeres
Telomere
Replication
Replication
Telomeres are shorten in cells divisions
Telomere length and Aged
15.000 base pair
Fetus
10.000 base pair
Born
5 000 base
5.000
b
pair
i
Aged
Telomere shorten with in vitro cells culture & with age
Telomere shorten during in vitro culture
Culture without
Culture with
telomerase
telomerase
Telomere shorten with age in people
16000
14000
Bp
12000
10000
8000
6000
4000
2000
0
Telomere length
20
40
60
age
Telomere length
Telomeres shorten during ageing of human fibroblasts
Calvin B. Harley et al., Nature 2000
80
100
Why did telomere get shorter?
Cell division
DNA replication
DNA replication
DNA replication
DNA stop replication
Cell death
Telomere length in Germ cell and somatic cells
The common biology of cancer and ageing
Toren Finkel et al.,, Nature 2007
How can we prevent telomere shortening?
Our Reproductive Cells
DO NOT Age
Telomere Shortening DOES NOT
Occur in Our Reproductive Cells
Telomerase Lengthens Telomeres
Telomerase
RNA primer
RNA template
DNA polymerase
Information of chromosome
is completed
p
new DNA
How do we produce telomerase in all our cells
Our Simple Strategy
Somatic cells Do not produce telomerase
Somatic cells contain the gene for telomerase
The gene is shut OFF
So, lets
let s turn it ON
Reproductive cells produce telomerase
Repressor
Regulatory
element
Telomerase gene
Telomeres in Cloned Animals
The first cloned animal, Dolly, was revealed to have short
telomeres that were comparable
p
to the age
g of the cell donor
P.G. Shiels et al., Analysis of telomere lengths in cloned sheep, Nature 399 (1999).
Normal telomere lengths
g were found in cloned cattle
X.C. Tian et al., Nat. Genet. 26 (2000)
Clones cloned over 5 generations did not have shorter
T Wakayama,
T.
Wk
et al.,
l Nature
N
407 (2000)
t l
telomeres
in
i mice
i
These reports iindicate
Th
di
that
h telomere
l
lengths
l
h
from the adult somatic cells can be reset byy
SCNT!!??
Telomerase in different cells types
The enzyme telomerase which elongates telomeres is active
in germ cells and early embryonic development.
S. Schaetzlein, et al., Telomere length is reset during early mammalian
embryogenesis, Proc. Natl. Acad. Sci. U. S. A. 101 (21) (2004).
The telomere length of donor nuclei telomere elongation
occurs at the transition from morula to blastocysts in mice
Liu, S.M. et al., Telomere lengthening early in development, Nat. Cell Biol. 9 (12) (2007)
and cattle
DNA methyltransferases and histone methyltransferases
control telomere length in mammalian cells
S Gonzalo
S.
Gonzalo, et al
al., DNA methyltransferases control telomere length and
telomere recombination in mammalian cells, Nat. Cell Biol. 8 (4) (2006)
Reduce DNA methylation and increase histone acetylation
resulted in significantly increase the full-term development
of cloned animal.
