Moderate stem cell telomere shortening rate postpones cancer onset in stochastic model

TL;DR

This study presents a stochastic model showing that moderate telomere shortening in stem cells can delay cancer onset and influence organism longevity, highlighting a balance between cancer risk and aging.

Contribution

The paper introduces a novel stochastic model linking telomere dynamics in stem cells to cancer risk and aging, providing insights into telomerase regulation effects.

Findings

Longer initial telomeres delay cancer onset.

Shorter initial telomeres reduce early-life cancer risk.

Evolution favors shorter cancer-free lifespan to postpone late-life cancer.

Abstract

Mammalian cells are restricted from proliferating indefinitely. Telomeres at the end of each chromosome are shortened at cell division and, when they reach a critical length, the cell will enter permanent cell cycle arrest - a state known as senescence. This mechanism is thought to be tumor suppressing, as it helps prevent precancerous cells from dividing uncontrollably. Stem cells express the enzyme telomerase, which elongates the telomeres, thereby postponing senescence. However, unlike germ cells and most types of cancer cells, stem cells only express telomerase at levels insufficient to fully maintain the length of their telomeres leading to a slow decline in proliferation potential. It is not yet fully understood how this decline influences the risk of cancer and the longevity of the organism. We here develop a stochastic model to explore the role of telomere dynamics in relation to both senescence and cancer. The model describes the accumulation of cancerous mutations in a multicellular organism and creates a coherent theoretical framework for interpreting the results of several recent experiments on telomerase regulation. We demonstrate that the longest average cancer free life span before cancer onset is obtained when stem cells start with relatively long telomeres that are shortened at a steady rate at cell division. Furthermore, the risk of cancer early in life can be reduced by having a short initial telomere length. Finally, our model suggests that evolution will favour a shorter than optimal average cancer free life span in order to postpone cancer onset until late in life.