Within each of our cells, long strands of DNA are folded into chromosomes and capped with protective structures called telomeres. Telomeres shorten as we age, eventually becoming so diminished that our chromosomes are exposed, leading to cell death. The specifics of this shortening process, and whether certain chromosomes are more affected than others, have remained unclear—until now.
Scientists at the Salk Institute have developed an innovative tool called Telo-seq, poised to revolutionize the study of telomeres in aging and disease. Unlike existing methods, which struggle to sequence entire telomeres and measure only their average length across chromosomes, Telo-seq enables researchers to determine the complete sequence and precise length of telomeres on each individual chromosome.
Researchers are already employing Telo-seq to uncover novel telomere dynamics in human health and disease with unprecedented resolution. Their findings, published in Nature Communications on June 18, 2024, are expected to stimulate a surge of new studies and the development of telomere-targeting therapeutics for age-related diseases.
“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.”
Karlseder and his colleagues collaborated closely with experts at Oxford Nanopore Technologies, combining 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, enabling scientists to identify the specific chromosome and examine its telomere structure and composition in detail.
Using this technique, the researchers have uncovered numerous features of telomere biology that were previously inaccessible. They have observed that within individual human samples, each chromosome arm can have different telomere lengths, and these telomeres can vary significantly in their shortening rates. These dynamics also differ across various tissues and cell types within the same person, influenced by factors such as stress and inflammation affecting different parts of the body. This suggests the existence of potential chromosome arm-specific factors influencing telomere dynamics in aging and disease.
“Aging is an incredibly heterogeneous process that affects everyone differently,” Karlseder explains. “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.”
The advent of Telo-seq marks a significant breakthrough in understanding telomere biology. By providing precise, chromosome-specific insights into telomere dynamics, this tool opens new avenues for research into the mechanisms of aging and the development of targeted therapies to combat age-related diseases. As scientists delve deeper into the complexities of telomere shortening, the potential for enhancing human health and longevity becomes increasingly tangible.
Source: Salk Institute