What is a telomere?
Long strands of DNA are folded into chromosomes within each of our cells, telomeres are the protective end caps that help to keep all of this important information with the chromosomes. However, telomeres shorten with age and eventually become so thin that our chromosomes become exposed, and our cells die. The specifics of when and how this happens or if certain chromosomes are more affected than others is a hot topic within the space of anti-aging, regenerative medicine, and longevity.
Revolutionizing telomere sequencing
Recently Salk Institute collaborated closely with experts at Oxford Nanopore Technologies to develop a groundbreaking tool called Telo-seq. It is designed to revolutionize telomere science, the study of telomeres in aging and disease. Current methods have difficulty in sequencing whole telomeres, and only measure their average length across all chromosomes. This method enables researchers to determine the entire sequences and the precise length of each individual telomere length on each chromosome.
“Previous methods for measuring telomere length were low resolution and rather inaccurate,” says the study’s senior author Jan Karlseder, professor, chief science officer, and Donald and Darlene Shiley Chair for Research on Aging at Salk. “We could hypothesize about how individual telomeres might play a role in aging and cancer, but it was simply impossible to test those hypotheses. Now we can.”
Telomere Science
The collaborative research combines aspects of their long-read sequencing technique with novel biochemistry and bioinformatics approaches, the resulting method starts at the end of each telomere and sequences well into the subtelomere region. This allows the scientists to identify which chromosome they are looking at and examine its telomere structure and composition in unprecedented detail.
What they have observed so far
Numerous features of telomere biology that had not been accessible to scientists before have been described using this new method. For example, within individual human samples, each chromosome arm can have different telomere lengths, and these telomeres can vary significantly in their shortening rates.
These dynamics can also vary in different tissues and cell types within the same person. This is likely for many reasons such as the amount of stress and inflammation affecting the different parts of the body. When taken together, this suggests that there are potential chromosome arm-specific factors influencing telomere dynamics in aging and disease.
“Aging is an incredibly heterogeneous process that affects everyone differently,” says Karlseder. “We are very interested in whether differences in aging are related to different telomere shortening rates between people or chromosomes, and how we might be able to slow this down to promote healthy aging.”
Telomere shortening
Many telomeropathies involve stem cells that run out of telomere length which causes the cells to lose their ability to divide into new cells. When this happens, it can lead to certain cancers, hair loss, and immune disorders. This telomere tech will enable researchers to investigate if these diseases are inherited or associated with individual chromosomes in order to develop targeted interventions.
Overactive repair mechanisms
Shortening of telomeres can affect a cell’s lifespan, but overactive repair mechanisms can be equally damaging. When this occurs cells can enter an immortal state and divide indefinitely which leads to cancer.
Cells can use telomerase enzymes or the alternative lengthening of telomeres (ALT) mechanisms to repair a damaged telomere. However, the length and composition of the telomere will differ depending on the mechanism used. There was no efficient way for researchers to measure this, until now.
“With Telo-seq, we can quickly determine whether a cancer is telomerase-positive or ALT-positive,” says first author Tobias Schmidt, a postdoctoral researcher in Karlseder’s lab. “This is critical because ALT-positive cancers are often more aggressive and require different treatment approaches than telomerase-positive cancers. In this sense, Telo-seq could be used as a quick and reliable diagnostic tool to identify cancer types and guide more personalized treatment plans.”
Just the tip of the iceberg
The researchers believe that aside from the immediate clinical applications, the greatest impact this telomere tech will have is in igniting a new area of more precise telomere research. The possibilities unlocked by this innovative technique are truly vast, from discovering missing puzzle pieces to fundamental mechanisms of aging to developing therapies for telomere-related cancers and disorders.
“Telo-seq will allow us to answer questions about development, aging, stem cells, and cancer that we simply couldn’t address with previous tools,” says Karsleder. “We don’t even know what we’ve been missing, and I think the things we’re starting to learn now are really just the tip of the iceberg. It’s a very exciting time for telomere science.”
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Image: Microscopy image showing (green) telomeres, the protective caps at the ends of (blue) chromosomes, which play a crucial role in cellular aging. Credit: Salk Institute
