Mechanism of Telomere Induced Senescence

Despite these exceptions to the telomere hypothesis of cell aging and immortalization, the fact that numerous studies have now shown, in many different types of human primary cell cultures, that ectopic expression of Tert is sufficient to restore telomerase activity, prevent telomere shortening, and endow the cells with replica-tive immortality (Harley 2001) clearly shows that telomere shortening is the primary mechanism accounting for the finite replicative life span of normal human cells, at...

Telomere Shortening and Organismal Aging

Genomic instability has long been recognized as a common characteristic of both aging and cancer cells. Accumulation of genomic changes such as random point mutations has been proposed as a cause of aging (Dolle et al. 1997). In support of this hypothesis, increasing evidence links human premature aging syndromes and mouse models of premature aging with DNA damage-induced genome dysfunction. Mutant mice unable to repair accumulated DNA damages exhibit symptoms of premature aging and die early...

Consequences of Telomerase Loss In Vivo The Telomerase Knockout Mouse

Telomeric repeats in human cells are typically between 10 and 15 kb in length. Furthermore, telomerase activity is stringently regulated in human tissues, i.e., unde-tectable in many somatic tissues but present in germ cells, activated leukocytes, and stem cells from a variety of organs (Harley et al. 1994, Wright et al. 1996, Newbold 1997, Weng et al. 1997). This regulation is achieved almost entirely through stringent downregulation of hTert (Meyerson et al. 1997). In contrast to humans, the...

Role of Telomere Length and Telomerase in Human Disease

Short telomeres are characteristic of human diseases of various origins that are associated with ageing, such as cardiovascular disease (Oh et al. 2003, O'Sullivan et al. 2002, Wiemann et al. 2002, Samani et al. 2001). In addition, a correlation between telomere length and risk of death from heart disease or infections has been recently observed (Cawthon et al. 2003), further indicating that telomere length may directly contribute to such diseases. Finally, factors considered to accelerate...

References

Baird DM, Davis T, Rowson J, Jones CJ, Kipling D (2004) Normal telomere erosion rates at the single cell level in Werner syndrome fibroblast cells. Hum Mol Genet 13 1515-24 Blackburn EH, Greider CW, Szostak JW (2006) Telomeres and telomerase the path from maize, Tetrahymena and yeast to human cancer and aging. Nat Med 12 1133-38 Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91...

Heterogeneity The Hallmark of Ageing

Ageing is characterized by random accumulation of unrepaired cellular and molecular damage. The mechanisms involved are inherently stochastic, i.e., driven by chance (Kirkwood 2005). In fact, several studies have demonstrated stochastic heterogeneity as an important feature of the ageing process Examining the effect of ageing on cell integrity in different tissues of Caenorhabditis elegans by electron microscopy (Herndon et al. 2002), it was found that stochastic factors are clearly involved in...

Preclinical Studies

Several studies have investigated the use of unmodified DNA oligomers or phosphorothioate backbone-modified oligodeoxynucleotides (PS-ODN) directed against hTERT or, more commonly, the hTERC template to achieve conventional antisense gene silencing by RNAseH-mediated target degradation (Glukhov et al. 1998, Ji et al. 2006, Kraemer et al. 2003, Norton et al. 1996). PS-ODN directed against the hTERC template region demonstrated potent telomerase inhibition in vitro. However, whereas end-protected...

Age Dependent Lineage Skewing of HSCs

It is well documented that a decline in immune function accompanies the natural ageing process in both mice and humans Morrison et al. 1996, Marley et al. 1999, Liang et al. 2005 . This finding has far-reaching implications given the success of stem cell transplantation using stem cells from older individuals and the etiology of age-associated hematopoietic conditions. It has been hypothesized that age-related hematological defects have their origin in cell intrinsic changes in the functional...