Genetic Pathways of Postmitotic Cell and Organismal Survival

Besides the role of a potential ectopic cell cycle checkpoint pathway helping to modulate the life span of a postmitotic organism such as C. elegans, are there other WT + Reduced Insulin Signaling (IIS) WT + Reduced Insulin Signaling (IIS) WT + Reduced Insulin Signaling (IIS) WT + Reduced Insulin Signaling (IIS) Fig. 1.2 Reduced insulin IGF-1 signaling (IIS) synergizes with perturbations in other longevity pathways. Representative life span analysis of worms with combinatorial inactivation of...

Telomerase Specific Adaptive Immunotherapy 21 Rationale

Telomerase-specific adaptive immunotherapy aims to stimulate a CD8+ cytotoxic T lymphocyte (CTL) response against hTERT overexpression in cancer cells. Clinical approaches to induce CTL responses against tumor neoantigens generally make use of the professional antigen-presenting function of dendritic cells (DC) pulsed with neoantigen mRNA or, in the case of peptide vaccination approaches, with synthetic peptides capable of binding MHC class I molecules (HLA-A, HLA-B, or HLA-C). Pulsed DC prime...

Preclinical Studies

Cytotoxic gene therapy approaches tested to date can further be subdivided into strategies based on induction of apoptosis, enzyme prodrug therapy, targeted radiotherapy, immune-modulation, or inhibition of angiogenesis (Fig. 13.3). At least 20 individual therapeutic transgenes have so far been tested for their ability to selectively Fig. 13.3 Genes expressed under control of hTERC or hTERT promoters for preclinical models of cytotoxic gene therapy and their antitumor mechanisms of action....

Cellular versus Organismal Aging

Abstract Aging is an extremely complex process, affecting individual cells and organisms as a whole. Here we discuss the impact of telomeres, the natural chromosome ends, on cellular and organismal aging, and how telomere maintenance influences genome stability and tumorigenesis. Since telomeres represent only a fraction of the complexity of the aging process, we discuss how genome integrity and DNA damage response pathways affect postmitotic aging, and which genetic pathways promote survival...

The mTerc Wrn Compound Mutant Mouse as a Model of Human Werner Syndrome

Although a definitive connection between telomere dynamics and normal aging in humans has yet to be established, accumulating evidence has strengthened the view that accelerated telomere attrition contributes directly to acquired and inherited degenerative conditions and premature aging syndromes such as Werner Syndrome (WS see also Davis and Kipling, this volume). WS is characterized by early onset of age-related pathologies and cancer. The protein mutated in WS, WRN, appears to play a major...

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...

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...