Twenty-five years after the disclosure of the telomeric DNA sequence and 22 years after the discovery of telomerase, it has become clear that telomeres and telomerase influence disease of human ageing including cancer. This book summarizes our current knowledge on the role of telomeres and telomerase in ageing, regeneration, and cancer with a special focus on ageing stem cells. Moreover, the book reviews current efforts to target telomeres and telomerase for anticancer treatment or regenerative therapies.

1.1 Ageing

The molecular analysis of ageing is an emerging research field that will have great impact on patients care, lifestyle, and on disease prevention in the human population worldwide. Major molecular mechanisms that influence the ageing process include (1) the accumulation of molecular damage affecting DNA and proteins, (2) alterations in gene expression, including alterations in checkpoint responses, metabolic pathways, and developmental pathways, and (3) the decline in adult stem cell function. All these mechanisms lead to a decrease in organ maintenance and function, thus representing a major factor limiting the quality of life during ageing. Moreover, the accumulation of molecular damage increases genetic alterations and the cancer risk during ageing. Indeed, increased age is the leading cause of cancer. Understanding the molecular basis of ageing will ultimately point to targets for novel therapies aiming to improve the function of cells and organs in the ageing organism, thus allowing increased vitality or what we think of as "healthy ageing."

In this book, Andrew Dillin and Jan Karlseder provide an overview on different model organisms that are currently used to study ageing on the cellular and organismal levels. The authors discuss how different molecular mechanisms (telomere shortening, insulin signaling, caloric restriction, mitochondrial function) may differentially impact ageing of mitotically active versus postmitotic cells. Richard Allsopp summarizes the influence of progressive telomere shortening and checkpoints induced by dysfunctional telomeres on cellular ageing. When telomeres lose capping function, a DNA damage response is induced, and the resultant telomere shortening is one of the factors that leads to an accumulation of unrepaired DNA damage during ageing, which causes cellular growth arrest. Similarly, DNA damage checkpoints have been demonstrated for telomere-based replicative ageing as well. There is now convincing evidence for progressive telomere shortening in various human tissues during ageing, including stem cell compartments. It remains an open debate as to what extent replicative senescence occurs during human ageing in vivo. Sandy Chang summarizes the consequences of telomere dysfunction on ageing in mouse models. He describes evidence that telomere shortening can cooperate with other pathways that are involved in DNA damage accumulation and premature ageing (Werner Syndrome).

Oxidative damage is another factor that is responsible for the accumulation of DNA damage during ageing. Joao F. Passos and colleagues summarize experimental data indicating that oxidative damage and telomere dysfunction are interconnected and cooperate to induce cellular ageing. It will be interesting to see whether similar cooperation occurs during human ageing, which could then explain the exponential accumulation of DNA damage in late life, when telomeres get short. Hong-Yan Du, Monica Bessler, and Philip Mason conclude the first part of the book on telomeres and ageing by summarizing disease states associated with telomerase mutations and telomere shortening in humans. There is a growing number of human disease syndromes that are associated with organ failure and that are caused by mutations in one allele of genes encoding for telomerase (hTERT or hTR). It is notable that mutation in only one allele of human telomerase leads to impaired organ homeostasis and premature death of these patients, sometimes at an age of 30-50 years. These findings demonstrate that telomere reserves in humans are rather limited and that a reduction in telomerase gene dosage has severe consequences that affect the ability to live a "full" human lifespan. These findings provide strong evidence that telomere shortening can also influence normal ageing in humans without telomerase mutations.

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