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A Poisoned Fountain of Youth? Long Telomeres May Significantly Increase Cancer Risk

A section of DNA
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In a new study from Johns Hopkins Medicine, researchers have produced data that suggests ultra-long telomeres, previously thought to bestow longevity, do not offer such protection. Instead, individuals with long telomeres are at risk of a range of benign and cancerous tumors and an age-linked blood condition called clonal hematopoiesis. The study, published in The New England Journal of Medicine, changes the perspective on the complex relationship between telomeres and human health.

The findings contradict the prevailing belief that long telomeres are a defense against aging. According to Mary Armanios, MD, professor of oncology at the Johns Hopkins Kimmel Cancer Center, long telomeres allow cells with age-related mutations to be more durable, increasing the risk of tumors and other growths that would normally be curtailed by standard telomere shortening processes. This revelation challenges the scientific community's understanding of cellular aging and could potentially reshape the way scientists approach age-related diseases and therapies.

Unwanted side effects

Though long telomeres in lab-grown cells have been shown to predict cellular longevity. This study suggests that there can be unwanted side effects from this longer cellular lifespan, highlighting the need for further investigation into the role telomeres play in disease development and aging. “Cells with very long telomeres accumulate mutations and appear to promote tumors and other types of growths that would otherwise be put in check by normal telomere shortening processes,” says Armanios.

Out of the 17 participants in the two-year study, tumors were identified in 12. The subjects, who were aged between 7 and 83, experienced various types of cancer, including melanoma, lymphomas and uterine fibroids. Some patients had multiple conditions at once, including enlarged thyroid glands, known as goiters. Four patients died during the study from lymphoma, colon cancer, leukemia and a brain tumor, respectively.

All 17 participants carried mutations in the POT1 gene, which is linked to telomere length. Mutant POT1 allows telomeres to be longer than normal, potentially contributing to the development of health problems observed in the study participants. Telomere length was measured for 13 participants, all of whom had telomeres 90% longer than the general population. In 9 participants, telomeres were longer than in 99% of most people.

Delayed aging

As for the “fountain of youth” theory of long telomeres, there were some signs of delayed aging in the cohort. Six participants showed some indication of delayed aging, such as an absence of gray hair into their 70s.

This was counterbalanced, however, by evidence from the participants’ blood samples. About 20% of people over 70 have aging-related mutations in blood cells. These mutations can give a survival boost to affected cells, leading them to proliferate rapidly, a process called clonal hematopoiesis. This condition has been linked to blood cancer and other cancers.

Of the 12 participants with POT1 gene mutations, eight (67%) had clonal hematopoiesis-related mutations, a rate much higher than expected in older adults. In 21 relatives with normal-length telomeres, only two had clonal hematopoiesis-related mutations, aligning with the expected rate in the general population.

Some participants with long telomeres and POT1 mutations had as many as 1,000 mutations per blood cell type. Phylogenetic analysis showed that the clonal hematopoiesis mutations in these participants' blood cells likely began when they were pre-school age.

The research team plans to examine mutation rates in other cell types in these long-telomere populations.

Reference: DeBoy EA, Tassia MG, Schratz KE, et al. Familial clonal hematopoiesis in a long telomere syndrome. NEJM. 2023. doi: 10.1056/NEJMoa2300503

This article is a rework of a press release issued by Johns Hopkins Medicine. Material has been edited for length and content.