Telomeres and
Telomerase
in Aging and Cancer
Contents
★ Telomere & Telomerase & End of replication problem
★ Setting the Numver of Doublings
★ Senescence
★ Telomere Length Changes in Human Aging
★ Telomerase Therapy for Age-associated Disease
★ Targeting Telomerase for Cancer Therapeutics
Introduction
It is possible oxidative stress, glycation,
telomere shortening and chronological age
-along with various genesall work together to cause aging?
http://learn.genetics.utah.edu/content/begin/traits/telomeres/
J Pathol 2007; 211: 114–123
★ End of replication problem ★
< Telomere >
< Senescence theory >
Free radical theory
Oxidative stress theory
Moleculer Inflammation theory
Cross-lin-king theory
Immunological theory
Telomere theory
End of replication problem
< Telomerase >
End of replication problem
http://atlasgeneticsoncology.org/Deep/SubTelomereID20025.html
End of replication problem
< Telomere dysfunction >
POT1, protection of telomeres 1; ATR, ataxia-telangiectasia mutated;
TRF2, telomere binding factor 2; ATR, ataxia-telangiectasia- and
Rad3-related; Cdc25, cell division cycle 25; Cdk4/6, cyclin-dependent
kinases 4 and 6; RB, retinoblastoma protein.
Cardiovasc Res. 2009 Feb 1;81(2):244-52. Epub 2008 Dec 1.
Nature Reviews Cancer 1, 203-213 (December 2001)
★ Setting the Numver of Doublings ★
The two anticancer mechanisms of cellular
senescence/crisis.
(Right) If an oncogenic mutation triggers
senescence, a potential cancer is prevented.
(Left) If senescence becomes impossible
because of inactivated checkpoints,
telomere-based crisis and cell death may
ensue.
If telomerase or alternative lengthening of
telomeres (ALT) becomes activated before
or during crisis, an immortal clone arises
that has already acquired malignant
properties or is on its way to full
malignancy.
http://www.barshop.uthscsa.edu/main/research/u38
★ Senescence ★
< Senescence is a barrier to cancer >
EMBO reports 7, 5, 479–483 (2006)
Nature Medicine, Vol. 11, No. 9, pp. 920–922
Senescence
Frontiers in Bioscience 14, 4044-4057, January 1, 2009
Telomere Length Changes in Human Aging
In newborn humans,
telomeres are approximately 15-20kb in length and shorten gradually throught life,
suggesting that telomere length may serve as a surrogate marker for aging.
Diseases Caused by Short Telomeres
A number of recent reports examining telomere length in peripheral blood
monomuclear cells (PBMCs) have reported correlations such as early myocardial
infarction, vascular dementia, atherosclerosis, Alzheimer's disease.
liver cirrhosis, Barrett's esophagus, ulcerative colitis, myeloproliferative disorders
ductal carcinoma in situ, prostatic & cervical intraepithelial eoplasias
★
Telomerase Therapy for Age-associated Disease ★
A dual role of telomere shortening and telomerase activation in tumor initiation and progression.
Mol. Cells, Vol. 15, No. 2, pp. 164-175
Telomerase Therapy for Age-associated Disease
Telomerase Therapy for Age-associated Disease
<Telomerase activation as a target of age-associated disease>
- hTERT treat keratinocytes, dermal fibroblasts, muscle
satellite cells, endothelial cells, retinalpigmented epithelial cells, breast epithelial cells,
corneal fibroblasts, corneal endothelial cells
-hTERT preferentially elongates the shortest
telomeres, the transient expression of
telomerase could have profound effects on cell
life span.
-A variety of chronic diseases and agedrelated
medical conditions that are due to telomerebased replicative senescence.
J Pathol 2007; 211: 114–123
★ Targeting Telomerase for Cancer Therapeutics ★
A dual role of telomere shortening and telomerase activation in tumor initiation and progression.
Mol. Cells, Vol. 15, No. 2, pp. 164-175
Targeting Telomerase for Cancer Therapeutics
< Role of Telomerase in Normal and Cancer Cells >
The telomere hypothesis for cellular mortality.
Telomere length is maintained in germ cells
by active telomerase.
In contrast, somatic cells shut telomerase
OFF and lose telomere length until they
become growth arrested during senescence.
Oncogenically transformed cells that lack
telomerase activity can bypass senescence
but then die during crisis.
Immortal cells, with telomerase ON,
can continue to proliferate and do not stop
growing either in senescence or crisis.
Journal of clinical oncology, Vol 18, Issue 13(Huly), 2000: 2626-2634
Thank You