Short telomeres impact on age-related diseases

Short telomeres impact on age-related diseases

January 10, 2018 Cancer and telomeres

There is mounting evidence of a causal role for telomere dysfunction in a number of degenerative disorders: due to the mechanism of DNA replication, telomeres shorten with every cell division, eventually triggering senescence. Based on this observation, the appearance of age-related diseases arises from the accumulation of short telomeres.

In each human non-dividing cell nuclei there are 92 telomeres, each one having a different length. In previous studies in mice and yeast, it was observed that the presence of short telomeres (not their average length) determined cells´ responses.

In humans, telomere length (TL) is a heritable trait and in specific cases –such as intergenerational telomere loss, leads to genetic anticipation for certain genetic diseases. In the past decade, researchers identified defects in TL maintenance as the common defect present in several rare monogenic disorders occurring during childhood. More recently this has also been seen in common disorders that manifest well into adulthood. Altogether they are known as telomere syndromes. Recognizing the manifestations of the telomere syndrome spectrum is important for diagnostic and treatment decisions in clinical situations such as dyskeratosis congenital (DC), idiopathic pulmonary fibrosis (IPF) or other bone marrow failure syndromes.

Cancer patient

Patients with telomere syndromes are cancer prone. For instance, in (classic?) dyskeratosis congenita, cancer diagnoses are 11-fold greater than observed among the general population. In addition, both DC and IPF patients are prone to develop haematological malignancies. Moreover, the degree of telomere shortness determines severity in both diseases.

In prostate cancer patients, a study evaluating the appropriateness of TL as a prognostic biomarker  showed a strong correlation between degree of TL variability of in tumor cells and shorter TL from surrounding stromal cells with progression to metastasis and cancer-related death. These associations were independent of other prognostic indicators currently used in prostate cancer.

Another example of the relevance of short telomeres is described in the context of stem cells neurogenesis. This mechanism is hypothesized as relevant to the pathophysiology of mood disorders such that more severe and more chronic conditions were associated with shorter telomeres. This has been demonstrated in depression and psy­chosis.

 

Without a doubt, these findings suggest that being able to perform fine measurements of short telomeres can serve as diagnostic and prognostic biomarkers that influence decision making in the setting of personalized medicine.


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