Long Telomeres: Do They Extend Lifespan or Pose Higher Disease Risks?

Highlights:

POT1 gene mutation increases risk of cancer and familial clonal hematopoiesis syndrome
Longer telomeres in POT1 mutation carriers contribute to increased disease risk
Successive generations of POT1 mutation carriers show genetic anticipation with earlier disease onset

Telomeres are repetitive DNA sequences found at the ends of chromosomes. They play a critical role in protecting our genetic material from damage and ensuring the stability of our cells. Over time, telomeres naturally shorten, contributing to cellular aging and the development of age-related diseases ().

However, the opposite end of the spectrum - long telomeres - have been poorly understood until recently. Long telomeres may be also associated with the risk of cancer in individuals according to a new research finding.

Telomere Shortening And Ageing
Telomeres are cap- like structures at chromosome ends that play an important role in ageing and in the initiation and progression of various diseases.

‘People with a genetic mutation in the POT1 gene are more likely to develop a condition called familial clonal hematopoiesis syndrome (FCHS), as well as different types of cancers. These people have longer telomeres than usual, which can contribute to their increased risk of disease.’

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A recent study examined individuals who carry a specific mutation in a gene called POT1, which is involved in telomere maintenance. The researchers found that individuals with this mutation had longer telomeres than their non-mutation-carrying relatives. The study also found that these individuals had a higher risk of developing certain types of cancers, as well as a familial clonal hematopoiesis syndrome, a condition characterized by abnormal blood cells.

How was the study designed and conducted ?

The study design was a case-control study. They have investigated 17 people from five families who had an inherited mutation in the POT1 gene, which results in longer telomeres than usual. The study discovered various types of tumors, such as skin, thyroid, and brain tumors, in addition to the incidence of CHIP (Clonal Hematopoiesis of Indeterminate Potential) in eight out of 12 people examined. In contrast, only two out of 21 relatives without the mutation had CHIP. CHIP is a process that leads to the production of a large number of mutated blood cells, which can be linked to blood cancer.

The researchers recruited individuals with heterozygous loss-of-function mutations in the telomere-related gene POT1 (cases) and their non-mutation-carrying relatives (controls) to compare the clinical and molecular features of aging and cancer between the two groups. They also recruited a validation cohort of additional mutation carriers to confirm their findings. The researchers then evaluated the telomere length and genetic mutations in the participants and followed them over time to assess the development of age-related diseases and cancers.

POT 1 Gene Mutation and Cancer Associations

The study found that the POT1 mutation carriers had a range of benign and malignant tumors involving different tissues, including epithelial, mesenchymal, and neuronal tissues, in addition to lymphomas and myeloid cancers. The researchers also found that a majority of POT1 mutation carriers had long telomeres. While shorter telomeres are associated with aging and disease, it is not clear if longer telomeres are advantageous or if they have any associated health risks ().

The study also found that POT1 mutation carriers had a predisposition to clonal hematopoiesis of indeterminate potential, a condition characterized by the abnormal growth of blood cells. This predisposition had an autosomal dominant pattern of inheritance, meaning it is more likely to be passed down from one generation to the next. The researchers found that the risk of clonal hematopoiesis increased with age, and that it was associated with specific genetic mutations that are common in this condition.

Is Telomere Shortening a Sign of Cellular Aging?
Link between chromosome length and biological aging marker discovered. The finding helps explain why people with longer telomeres have a lower dementia risk.

The researchers also observed genetic anticipation, which is the phenomenon where the age of onset of a disease decreases in successive generations. This suggests that the risk of developing clonal hematopoiesis and related cancers may increase in future generations of POT1 mutation carriers.

In contrast to non-mutation-carrying relatives, POT1 mutation carriers maintained their telomere length over the course of two years, suggesting that their cells have an extended cellular longevity and the capacity to maintain telomeres over time. This may contribute to the development of the familial clonal hematopoiesis syndrome and associated cancers.

Link Between Short Telomeres and Osteoarthritis
Cells from osteoarthritic knees have abnormally shortened telomeres, reveal findings from a recent study.

In summary, the study found that individuals with a specific mutation in the POT1 gene have a higher risk of developing certain types of cancers and a familial clonal hematopoiesis syndrome (). This risk is associated with extended cellular longevity and the capacity to maintain telomeres over time. The findings suggest that telomere length plays a critical role in cancer development and aging and that future research may help us better understand the health risks associated with long telomeres.

It is important to note that these findings are based on a small sample size and may not apply to the general population. The study was also conducted in a specific population and may not be representative of other populations or ethnicities. However, the findings contribute to our understanding of telomere biology and may have implications for the development of future therapies for age-related diseases and cancers.

Long Telomeres Linked With an Increased Risk for Lung Adenocarcinoma
The association between that telomere length and any other cancer type or subtype was not significant. It was relevant only in the case of lung cancer.

Overall, this study highlights the importance of ongoing research in telomere biology and the need for personalized medicine approaches that take into account individual genetic factors and predispositions to disease. While we still have much to learn about the role of telomeres in health and disease, this study provides important insights into the potential risks associated with long telomeres and underscores the need for continued research in this area.

References:

Telomere Length and Clonal Hematopoiesis - (https://www.nejm.org/doi/full/10.1056/NEJMe2303022)
Telomeres, lifestyle, cancer, and aging - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370421/)

Source-Medindia