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

It is possible oxidative stress, glycation, telomere shortening and chronological age -along with various genes- all work together to cause aging?

Introduction

http://learn.genetics.utah.edu/content/begin/traits/telomeres/ J Pathol 2007; 211: 114–123

< Telomere >

< Senescence theory >

Free radical theoryOxidative stress theoryMoleculer Inflammation theoryCross-lin-king theoryImmunological theoryTelomere theory

★ End of replication problem ★

< Telomerase >

End of replication problem

End of replication problem

http://atlasgeneticsoncology.org/Deep/SubTelomereID20025.html

Cardiovasc Res. 2009 Feb 1;81(2):244-52. Epub 2008 Dec 1.

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.

< Telomere dysfunction >

Nature Reviews Cancer 1, 203-213 (December 2001)

End of replication problem

http://www.barshop.uthscsa.edu/main/research/u38

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.

★ Setting the Numver of Doublings ★

EMBO reports 7, 5, 479–483 (2006)

★ Senescence ★

Nature Medicine, Vol. 11, No. 9, pp. 920–922

< Senescence is a barrier to cancer >

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 activation as a target of age-associated disease>

Telomerase Therapy for Age-associated Disease

J Pathol 2007; 211: 114–123

- hTERT treat - keratinocytes, dermal fibroblasts, muscle satellite cells, endothelial cells, retinal-pigmented 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 telomere-based replicative senescence.

★ 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

< 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

Targeting Telomerase for Cancer Therapeutics

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