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  • Penn State study examines how a person’s telomeres are affected by caloric restriction

    Penn State study examines how a person’s telomeres are affected by caloric restriction

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    Penn State researchers may have uncovered another layer of complexity in the mystery of how diet impacts aging. A new study led by researchers in the Penn State College of Health and Human Development examined how a person’s telomeres -; sections of genetic bases that function like protective caps at the ends of chromosomes -; were affected by caloric restriction.

    The team published their results in Aging Cell. Analyzing data from a two-year study of caloric restriction in humans, the researchers found that people who restricted their calories lost telomeres at different rates than the control group -; even though both groups ended the study with telomeres of roughly the same length. Restricting calories by 20% to 60% has been shown to promote longer life in many animals, according to previous research.

    Over the course of human life, every time a person’s cells replicate, some telomeres are lost when chromosomes are copied to the new cell. When this happens, the overall length of the cell’s telomeres becomes shorter. After cells replicate enough times, the protective cap of telomeres completely dissipates. Then, the genetic information in the chromosome can become damaged, preventing future reproduction or proper function of the cell. A cell with longer telomeres is functionally younger than a cell with short telomeres, meaning that two people with the same chronological age could have different biological ages depending on the length of their telomeres. 

    Typical aging, stress, illness, genetics, diet and more can all influence how often cells replicate and how much length the telomeres retain, according to Idan Shalev, associate professor of biobehavioral health at Penn State. Shalev led the researchers who analyzed genetic samples from the national CALERIE study -; the first randomized clinical trial of calorie restriction in humans. Shalev and his team sought to understand the effect of caloric restriction on telomere length in people. Because telomere length reflects how quickly or slowly a person’s cells are aging, examining telomere length could allow scientists to identify one way in which caloric restriction may slow aging in humans.

    “There are many reasons why caloric restriction may extend human lifespans, and the topic is still being studied,” said Waylon Hastings, who earned his doctorate in biobehavioral health at Penn State in 2020 and was lead author of this study. “One primary mechanism through which life is extended relates to metabolism in a cell. When energy is consumed within a cell, waste products from that process cause oxidative stress that can damage DNA and otherwise break down the cell. When a person’s cells consume less energy due to caloric restriction, however, there are fewer waste products, and the cell does not break down as quickly.” 

    The researchers tested the telomere length of 175 research participants using data from the start of the CALERIE study, one year into the study and the end of the study after 24 months of caloric restriction. Approximately two-thirds of study participants participated in caloric restriction, while one-third served as a control group.

    During the study, results showed that telomere loss changed trajectories. Over the first year, participants who were restricting caloric intake lost weight, and they lost telomeres more rapidly than the control group. After a year, the weight of participants on caloric restriction was stabilized, and caloric restriction continued for another year. During the second year of the study, participants on caloric restriction lost telomeres more slowly than the control group. At the end of two years, the two groups had converged, and the telomere lengths of the two groups was not statistically different.

    This research shows the complexity of how caloric restriction affects telomere loss. We hypothesized that telomere loss would be slower among people on caloric restriction. Instead, we found that people on caloric restriction lost telomeres more rapidly at first and then more slowly after their weight stabilized.”


    Idan Shalev, associate professor of biobehavioral health at Penn State

    Shalev said the results raised a lot of important questions. For example, what would have happened to telomere length if data had been collected for another year? Study participants are scheduled for data collection at a 10-year follow-up, and Shalev said that he was eager to analyze those data when they become available.

    Despite the ambiguity of the results, Shalev said there is promise for the potential health benefits of caloric restriction in humans. Previous research on the CALERIE data has demonstrated that caloric restriction may help reduce harmful cholesterol and lower blood pressure. For telomeres, the two-year timeline was not sufficient to show benefits, but those may still be revealed, according to Shalev and Hastings.

    Three of Shalev’s trainees, Hastings, current graduate student Qiaofeng Ye and former postdoctoral scholar Sarah Wolf, led the research under Shalev’s guidance.

    Hastings said the opportunity to lead this study was critical to his career.

    “I was recently hired as an assistant professor in the Department of Nutrition at Texas A&M University, and I will begin that work in the fall semester,” Hastings said. “Prior to this project, I had limited experience in nutrition. This project literally set the course of my career, and I am grateful to Dr. Shalev for trusting me with that responsibility.”

    Calen Ryan and Daniel Belsky of Columbia University Mailman School of Public Health, Sai Krupa Das of Tufts University, Kim Huffman and William Kraus of Duke University School of Medicine, Michael Kobor and Julia MacIsaac of University of British Columbia, Corby Martin and Leanne Redman of Pennington Biomedical Research Center and Susan Racette of Arizona State University College of Health Solutions all contributed to this research.

    The National Institute on Aging funded this research.

    Source:

    Journal reference:

    Hastings, W. J., et al. (2024). Effect of long‐term caloric restriction on telomere length in healthy adults: CALERIETM 2 trial analysis. Aging Cell. doi.org/10.1111/acel.14149.

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  • Nanopore sequencing unveils novel telomere length patterns

    Nanopore sequencing unveils novel telomere length patterns

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    We depend on our cells being able to divide and multiply, whether it’s to replace sunburnt skin or replenish our blood supply and recover from injury. Chromosomes, which carry all of our genetic instructions, must be copied in a complete way during cell division. Telomeres, which cap the ends of chromosomes, play a critical role in this cell-renewal process-;with a direct bearing on health and disease.

    The enzyme telomerase plays a key role in maintaining the length of telomeres as chromosomes replicate during cell division. UC Santa Cruz professor Carol Greider has been studying telomeres and telomerase for over 30 years. The impact of the discoveries she has made over that time are why she, along with two colleagues, won the Nobel Prize in Physiology or Medicine in 2009.

    So, the findings of Greider’s latest study on telomeres shouldn’t have surprised her. And yet, they did.

    Published online today in Science, a new study finds that telomere lengths follow a different pattern than has thus far been understood. Instead of telomere lengths falling under one general range of shortest to longest across all chromosomes, this study finds that different chromosomes have separate end-specific telomere-length distributions.

    According to Greider, this discovery means we don’t fully understand the molecular process that regulates telomere lengths. And that’s important because of how telomere lengths affect human health: “When telomeres get to be too short, you have age-related degenerative diseases like pulmonary fibrosis, bone-marrow failure, and immunosuppression,” Greider said. “On the other hand, if telomeres are too long, it predisposes you to certain types of cancer.”

    Kayarash Karimian, the lead author on the paper, is a former Ph.D. student in Greider’s lab at the Johns Hopkins University School of Medicine. Other co-authors of this study include researchers at the Dana-Farber Cancer Institute, Harvard Medical School, and University of Pittsburgh. Greider, a distinguished professor of molecular, cell, and developmental biology at UC Santa Cruz, and a University Professor at Johns Hopkins, was the senior author on the paper and led the work.

    Why length matters

    Without telomerase, telomeres would get shorter and shorter as a cell divides over and over again. Over the past 30 years, research by Greider and others have confirmed that short telomeres lead to degenerative disease-;as well as shown that telomere lengths fall within a certain range.

    But this paper challenges scientific consensus by showing that a singular telomere-length range is too broad. Measuring the telomeres of 147 people for this study, the researchers found in one individual that the average telomere length across all chromosomes was 4,300 bases of DNA. Then when they isolated specific chromosomes, they found most telomere lengths differed significantly from this average. In one case, lengths differed as much as 6,000 bases, which Greider describes as “jaw dropping.”

    Further, they found across all 147 individuals the same telomeres were most often the shortest or longest, implying telomeres on specific chromosome ends may be the first to trigger stem-cell failure.

    Innovating on nanopore sequencing

    To make such precise measurements at the molecular level, Greider’s team used a technique invented at UC Santa Cruz called “nanopore sequencing,” a revolutionary method for reading DNA and RNA that has had an immense impact on genomics research since its 2014 debut on the market as the commercial product MinION.

    Nanopore technology has enabled some of the most significant advances in the genomics field, such as the completion of a gapless human genome, and sequencing of COVID-19 genomes-;making it crucial in the fight to end the pandemic. UC Santa Cruz licensed the concept for nanopore-sequencing technology to the UK-based company Oxford Nanopore Technologies, which made MinION, the first hand-held DNA sequencer.

    Notably, in the eyes of nanopore sequencing’s inventors, Greider’s study proves that the technique’s ability to advance scientific research continues to unfold. Mark Akeson, emeritus professor of biomolecular engineering at UC Santa Cruz, notes that two preprint studies that corroborate the basic findings of Greider’s paper have also been posted online.

    In my opinion, this is the most important nanopore-based paper focused on human biology since the MinION was introduced. It is easy to envision broad use of their telomere-length assay in the clinic.”


    Mark Akeson, emeritus professor of biomolecular engineering at UC Santa Cruz

    Akeson and David Deamer, also an emeritus professor of biomolecular engineering at the Baskin School of Engineering, were honored at the Library of Congress last year for inventing nanopore sequencing. Their colleague and friend Daniel Branton, a Havard biologist and co-inventor of the technology, was honored as well.

    Implications for disease prevention

    Such precise DNA reads allowed Greider’s team to pinpoint the sequences adjacent to telomeres and hypothesize that those areas are where telomerase is regulating length. And if that’s true, Greider said those regions, and the proteins that bind there, could serve as potential targets for new drugs for preventing disease.

    In addition, their process of “telomere profiling” via nanopore sequencing could serve as a model for the development of additional MinION-based assays for high-throughput drug screening.

    “This accessible technique has widespread potential for use in research, diagnostics, and drug development,” Greider said. “This work indicates that there are yet undiscovered mechanisms for telomere length regulation; probing these mechanisms will inform new approaches to cancer and certain degenerative diseases.”

    The study, “Human telomere length is chromosome end-specific and conserved across individuals,” was funded by grants from the National Institutes of Health (R35CA209974 to Greider and R01HL166265), the Johns Hopkins Bloomberg Distinguished Professorship, and the National Science Foundation Graduate Research Fellowship Program.

    Source:

    University of California Santa Cruz 

    Journal reference:

    Karimian, K., et al. (2024) Human telomere length is chromosome end–specific and conserved across individuals. Science. doi.org/10.1126/science.ado0431.

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