Telomeres and Telomerase in Aging and Cancer Contents

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/Sub. Telomere. ID 20025. html

End of replication problem < Telomere dysfunction > POT 1, protection of telomeres 1; ATR, ataxia-telangiectasia mutated; TRF 2, telomere binding factor 2; ATR, ataxia-telangiectasia- and Rad 3 -related; Cdc 25, cell division cycle 25; Cdk 4/6, 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/u 38

★ 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 -20 kb 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> - h. TERT treat keratinocytes, dermal fibroblasts, muscle satellite cells, endothelial cells, retinalpigmented epithelial cells, breast epithelial cells, corneal fibroblasts, corneal endothelial cells -h. TERT 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

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