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University of Warwick Researchers Identity Blood Protein Biomarkers That Can Predict Dementia Onset Years in Advance

With further study, this research may provide clinical laboratories with a new proteomic biomarker for dementia screenings that identifies risk more than 10 years before symptoms appear

Researchers at the University of Warwick in the UK and Fudan University in Shanghai, China, identified four protein biomarkers in blood that they say can predict dementia up to 15 years before diagnosis. They say these biomarkers may lead to clinical laboratory blood tests that offer alternatives to costly brain scans and lumbar punctures for diagnosis of dementia.

The scientists “used the largest cohort of blood proteomics and dementia to date,” according to a University of Warwick news release. This included taking blood from 52,645 “healthy” people without dementia who participated in the UK Biobank—a population-based study cohort, the new release noted.

“The proteomic biomarkers are [easy] to access and non-invasive, and they can substantially facilitate the application of large-scale population screening,” said neurovegetative disease specialist Jin-tai Yu, MD, PhD, a professor at Fudan University and co-author of the study, in the news release.

The scientists published their findings in the journal Nature Aging titled, “Plasma Proteomic Profiles Predict Future Dementia in Healthy Adults.”

“The advent of proteomics offers an unprecedented opportunity to predict dementia onset,” the researchers wrote.

“This is a well-conducted study that adds to what we know about changes in blood that occur very early in diseases that cause dementia, which will be important for early diagnosis in the future,” said Tara Spires-Jones, PhD, in a post from the Science Media Center in the UK. “However,” she added, “it is important to note that these are still scientific research studies and that there are currently no blood tests available for routine use that can diagnose dementia with certainty.

Jones, who was not involved in the study, is President of the British Neuroscience Association (BNA) and group leader of the UK Dementia Research Institute at the University of Edinburgh.

“Based on this study, it does seem likely that blood tests will be developed that can predict risk for developing dementia over the next 10 years, although individuals at higher risk often have difficulty knowing how to respond,” Suzanne Schindler, MD, PhD (above), told Reuters. Schindler, an Associate Professor of Neurology at Washington University in St. Louis, was not involved in the research. Clinical laboratories may soon have a new blood test for dementia. (Photo copyright: VJDementia.)

Predicting Onset of Dementia with 90% Accuracy

The researchers analyzed 52,645 blood samples from the UK Biobank (UKBB). The samples were collected between 2006 and 2010 from healthy individuals who at that time were without dementia.

By March 2023, 1,417 of the study participants had developed Alzheimer’s disease or some other form of dementia. The researchers looked at 1,463 proteins and identified four that were present in high levels among those people:

“Individuals with higher GFAP levels were 2.32 times more likely to develop dementia,” the researchers wrote in Nature Aging. “Notably, GFAP and LTBP2 were highly specific for dementia prediction. GFAP and NEFL began to change at least 10 years before dementia diagnosis.”

When adding known risk factors such as age, sex, and genetics, the researchers said they could predict onset of dementia with 90% accuracy, according to the University of Warwick news release.

“Our findings strongly highlight GFAP as an optimal biomarker for dementia prediction, even more than 10 years before the diagnosis, with implications for screening people at high risk for dementia and for early intervention,” the researchers wrote.

The news release also noted that smaller studies had already identified some of the proteins as potential biomarkers, “but this new research was much larger and conducted over several years.”

Further Validation Needed

Amanda Heslegrave, PhD, of the UK Dementia Research Institute, University College London described the UKBB as “an excellent resource” in the Science Media Center (SMC) post. However, she noted, it’s “a highly curated biobank and may not capture all populations that we need to know the risk for. The new biomarkers identified will need further validation before being used as screening tools.”

Another expert raised additional questions about the University of Warwick/Fudan University study in the SMC post.

“These results may help researchers understand the biological systems involved in the development of dementia,” said David Curtis, MD, PhD, of the UCL Genetics Institute at University College London. “However in my view the strengths of the reported associations are not really strong enough to say that these would form a useful test for predicting who will get dementia in the future.”

Conversely, Curtis pointed to other studies suggesting that phosphorylated tau (p-tau) proteins are better candidates for developing a simple blood test.

P-tau “provides a very good indicator of whether the pathological processes leading to Alzheimer’s disease are present in the brain,” he said. “When effective treatments for Alzheimer’s disease are developed it will be very helpful indeed to have simple blood tests—such as measuring phosphorylated tau—available in order to identify who could benefit.”

At least two blood tests based on the p-tau217 variant—from ALZpath and C2N—are currently available to US clinicians as laboratory developed tests (LDT).

In “University of Gothenburg Study Findings Affirm Accuracy of Clinical Laboratory Blood Test to Diagnose Alzheimer’s Disease,” Dark Daily reported on a study from the University of Gothenburg in Sweden which found that the ALZpath test was as good or better than lumbar punctures and brain scans as a diagnostic tool for Alzheimer’s.

UK Biobank

The UK Biobank continues to be used by researchers both in the UK and abroad because of the full sets of data on large numbers of patients over many years. There are few other sources of such data elsewhere in the world. The UK Biobank is a large-scale biomedical database and research resource. It contains de-identified genetic, lifestyle and health information, and biological samples from 500,000 UK participants.

On its website, the UK Biobank states, “It is the most comprehensive and widely-used dataset of its kind and is globally accessible to approved researchers who are undertaking health-related research that is in the public interest, whether they are from academic, commercial, government or charitable settings.”

Thus, clinical laboratory managers and pathologists can expect a continuing stream of published studies that identify biomarkers associated with different health conditions and to see where the data used in these analyses came from the UK’s biobank.

—Stephen Beale

Related Information:

Protein Biomarkers Predict Dementia 15 Years Before Diagnosis, According to New Study

Plasma Proteomic Profiles Predict Future Dementia in Healthy Adults

Proteins May Predict Who Will Get Dementia 10 Years Later, Study Finds

Expert Reaction to Study of Potential Protein Biomarkers for Dementia Risk

Two New p-Tau217 Blood Tests Join a Crowded Field

Plasma p-Tau-217 Assays Work Well, But No Home Run for Diagnosis

Dementia Can Be Predicted More than a Decade Before Diagnosis with These Blood Proteins

Dementia Predicted 10 Years Before Diagnosis

Early Blood Test to Predict Dementia Is Step Closer as Biological Markers Identified

Validating Blood Tests as A Possible Routine Diagnostic Assay of Alzheimer’s Disease

Scientists Close in on Elusive Goal of Adapting Nanopore Technology for Protein Sequencing

Technology could enable medical laboratories to deploy inexpensive protein sequencing with a handheld device at point of care and remote locations

Clinical laboratories engaged in protein testing will be interested in several recent studies that suggest scientists may be close to adapting nanopore-sensing technology for use in protein identification and sequencing. The new proteomics techniques could lead to new handheld devices capable of genetic sequencing of proteins at low cost and with a high degree of sensitivity, in contrast to current approaches based on mass spectrometry.

But there are challenges to overcome, not the least of which is getting the proteins to cooperate. Compact devices based on nanopore technology already exist that can sequence DNA and RNA. But “there are lots of challenges with proteins” that have made it difficult to adapt the technology, Aleksei Aksimentiev, PhD, Professor of Biological Physics at the University of Illinois at Urbana-Champaign, told ASBMB Today, a publication of the American Society for Biochemistry and Molecular Biology. “In particular, they’re not uniformly charged; they’re not linear, most of the time they’re folded; and there are 20 amino acids, plus a zoo of post-translational modifications,” he added.

The ASBMB story notes that nanopore technology depends on differences in charges on either side of the membrane to force DNA or RNA through the hole. This is one reason why proteins pose such a challenge.

Giovanni Maglia, PhD, a Full Professor at the University of Groningen in the Netherlands and researcher into the fundamental properties of membrane proteins and their applications in nanobiotechnology, says he has developed a technique that overcomes these challenges.

“Think of a cell as a miniature city, with proteins as its inhabitants. Each protein-resident has a unique identity, its own characteristics, and function. If there was a database cataloging the fingerprints, job profiles, and talents of the city’s inhabitants, such a database would undoubtedly be invaluable!” said Behzad Mehrafrooz, PhD (above), Graduate Research Assistant at University of Illinois at Urbana-Champaign in an article he penned for the university website. This research should be of interest to the many clinical laboratories that do protein testing. (Photo copyright: University of Illinois.)

How the Maglia Process Works

In a Groningen University news story, Maglia said protein is “like cooked spaghetti. These long strands want to be disorganized. They do not want to be pushed through this tiny hole.”

His technique, developed in collaboration with researchers at the University of Rome Tor Vergata, uses electrically charged ions to drag the protein through the hole.

“We didn’t know whether the flow would be strong enough,” Maglia stated in the news story. “Furthermore, these ions want to move both ways, but by attaching a lot of charge on the nanopore itself, we were able to make it directional.”

The researchers tested the technology on what Maglia described as a “difficult protein” with many negative charges that would tend to make it resistant to flow.

“Previously, only easy-to-thread proteins were analyzed,” he said in the news story. “But we gave ourselves one of the most difficult proteins as a test. And it worked!”

Maglia now says that he intends to commercialize the technology through a new startup called Portal Biotech.

The Groningen University scientists published their findings in the journal Nature Biotechnology, titled “Translocation of Linearized Full-Length Proteins through an Engineered Nanopore under Opposing Electrophoretic Force.”

Detecting Post-Translational Modifications in the UK

In another recent study, researchers at the University of Oxford reported that they have adapted nanopore technology to detect post-translational modifications (PTMs) in protein chains. The term refers to changes made to proteins after they have been transcribed from DNA, explained an Oxford news story.

“The ability to pinpoint and identify post-translational modifications and other protein variations at the single-molecule level holds immense promise for advancing our understanding of cellular functions and molecular interactions,” said contributing author Hagan Bayley, PhD, Professor of Chemical Biology at University of Oxford, in the news story. “It may also open new avenues for personalized medicine, diagnostics, and therapeutic interventions.”

Bayley is the founder of Oxford Nanopore Technologies, a genetic sequencing company in the UK that develops and markets nanopore sequencing products.

The news story notes that the new technique could be integrated into existing nanopore sequencing devices. “This could facilitate point-of-care diagnostics, enabling the personalized detection of specific protein variants associated with diseases including cancer and neurodegenerative disorders,” the story states.

The Oxford researchers published their study’s findings in the journal Nature Nanotechnology titled, “Enzyme-less Nanopore Detection of Post-Translational Modifications within Long Polypeptides.”

Promise of Nanopore Protein Sequencing Technology

In another recent study, researchers at the University of Washington reported that they have developed their own method for protein sequencing with nanopore technology.

“We hacked the [Oxford Nanopore] sequencer to read amino acids and PTMs along protein strands,” wrote Keisuke Motone, PhD, one of the study authors in a post on X (formerly Twitter) following the study’s publication on the preprint server bioRxiv titled, “Multi-Pass, Single-Molecule Nanopore Reading of Long Protein Strands with Single-Amino Acid Sensitivity.”

“This opens up the possibility for barcode sequencing at the protein level for highly multiplexed assays, PTM monitoring, and protein identification!” Motone wrote.

In a commentary they penned for Nature Methods titled, “Not If But When Nanopore Protein Sequencing Meets Single-Cell Proteomics,” Motone and colleague Jeff Nivala, PhD, Principal Investigator at University of Washington, pointed to the promise of the technology.

Single-cell proteomics, enabled by nanopore protein sequencing technology, “could provide higher sensitivity and wider throughput, digital quantification, and novel data modalities compared to the current gold standard of protein MS [mass spectrometry],” they wrote. “The accessibility of these tools to a broader range of researchers and clinicians is also expected to increase with simpler instrumentation, less expertise needed, and lower costs.”

There are approximately 20,000 human genes. However, there are many more proteins. Thus, there is strong interest in understanding the human proteome and the role it plays in health and disease.

Technology that makes protein testing faster, more accurate, and less costly—especially with a handheld analyzer—would be a boon to the study of proteomics. And it would give clinical laboratories new diagnostic tools and bring some of that testing to point-of-care settings like doctor’s offices.

—Stephen Beale

Related Information:

Nanopores as the Missing Link to Next Generation Protein Sequencing

Nanopore Technology Achieves Breakthrough in Protein Variant Detection

The Scramble for Protein Nanopore Sequencing

The Emerging Landscape of Single-Molecule Protein Sequencing Technologies

ASU Researcher Advances the Science of Protein Sequencing with NIH Innovator Award          

The Missing Link to Make Easy Protein Sequencing Possible?

Engineered Nanopore Translocates Full Length Proteins

Not If But When Nanopore Protein Sequencing Meets Single-Cell Proteomics

Enzyme-Less Nanopore Detection of Post-Translational Modifications within Long Polypeptides

Unidirectional Single-File Transport of Full-Length Proteins through a Nanopore

Translocation of Linearized Full-Length Proteins through an Engineered Nanopore under Opposing Electrophoretic Force

Interpreting and Modeling Nanopore Ionic Current Signals During Unfoldase-Mediated Translocation of Single Protein Molecules

Multi-Pass, Single-Molecule Nanopore Reading of Long Protein Strands with Single-Amino Acid Sensitivity

Experimental Low-Cost Blood Test Can Detect Multiple Cancers, Researchers Say

Test uses a new ultrasensitive immunoassay to detect a known clinical laboratory diagnostic protein biomarker for many common cancers

Researchers from Mass General Brigham, the Dana-Farber Cancer Institute, Harvard University’s Wyss Institute and other institutions around the world have reportedly developed a simple clinical laboratory blood test that can detect a common protein biomarker associated with multiple types of cancer, including colorectal, gastroesophageal, and ovarian cancers.

Best of all, the researchers say the test could provide an inexpensive means of early diagnosis. This assay could also be used to monitor how well patients respond to cancer therapy, according to a news release.

The test, which is still in experimental stages, detects the presence of LINE-1 ORF1p, a protein expressed in many common cancers, as well as high-risk precursors, while having “negligible expression in normal tissues,” the researchers wrote in a paper they published in Cancer Discovery titled, “Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker.”

The protein had previously been identified as a promising biomarker and is readily detectable in tumor tissue, they wrote. However, it is found in extremely low concentrations in blood plasma and is “well below detection limits of conventional clinical laboratory methods,” they noted.

To overcome that obstacle, they employed an ultra-sensitive immunoassay known as a Simoa (Single-Molecule Array), an immunoassay platform for measuring fluid biomarkers.

“We were shocked by how well this test worked in detecting the biomarker’s expression across cancer types,” said lead study author gastroenterologist Martin Taylor, MD, PhD, Instructor in Pathology, Massachusetts General Hospital and Harvard Medical School, in the press release. “It’s created more questions for us to explore and sparked interest among collaborators across many institutions.”

Kathleen Burns, MD, PhD

“We’ve known since the 1980s that transposable elements were active in some cancers, and nearly 10 years ago we reported that ORF1p was a pervasive cancer biomarker, but, until now, we haven’t had the ability to detect it in blood tests,” said pathologist and study co-author Kathleen Burns, MD, PhD (above), Chair of the Department of Pathology at Dana-Farber Cancer Institute and a Professor of Pathology at Harvard Medical School, in a press release. “Having a technology capable of detecting ORF1p in blood opens so many possibilities for clinical applications.” Clinical laboratories may soon have a new blood test to detect multiple types of cancer. (Photo copyright: Dana-Farber Cancer Institute.)

Simoa’s Advantages

In their press release, the researchers described ORF1p as “a hallmark of many cancers, particularly p53-deficient epithelial cancers,” a category that includes lung, breast, prostate, uterine, pancreatic, and head and neck cancers in addition to the cancers noted above.

“Pervasive expression of ORF1p in carcinomas, and the lack of expression in normal tissues, makes ORF1p unlike other protein biomarkers which have normal expression levels,” Taylor said in the press release. “This unique biology makes it highly specific.”

Simoa was developed at the laboratory of study co-author David R. Walt, PhD, the Hansjörg Wyss Professor of Bioinspired Engineering at Harvard Medical School, and Professor of Pathology at Harvard Medical School and Brigham and Women’s Hospital.

The Simoa technology “enables 100- to 1,000-fold improvements in sensitivity over conventional enzyme-linked immunosorbent assay (ELISA) techniques, thus opening the window to measuring proteins at concentrations that have never been detected before in various biological fluids such as plasma or saliva,” according to the Walt Lab website.

Simoa assays take less than two hours to run and require less than $3 in consumables. They are “simple to perform, scalable, and have clinical-grade coefficients of variation,” the researchers wrote.

Study Results

Using the first generation of the ORF1p Simoa assay, the researchers tested blood samples of patients with a variety of cancers along with 406 individuals, regarded as healthy, who served as controls. The test proved to be most effective among patients with colorectal and ovarian cancer, finding detectable levels of ORF1p in 58% of former and 71% of the latter. Detectable levels were found in patients with advanced-stage as well as early-stage disease, the researchers wrote in Cancer Discovery.

Among the 406 healthy controls, the test found detectable levels of ORF1p in only five. However, the control with the highest detectable levels, regarded as healthy when donating blood, “was six months later found to have prostate cancer and 19 months later found to have lymphoma,” the researchers wrote.

They later reengineered the Simoa assay to increase its sensitivity, resulting in improved detection of the protein in blood samples from patients with colorectal, gastroesophageal, ovarian, uterine, and breast cancers.

The researchers also employed the test on samples from 19 patients with gastroesophageal cancer to gauge its utility for monitoring therapeutic response. Although this was a small sample, they found that among 13 patients who had responded to therapy, “circulating ORF1p dropped to undetectable levels at follow-up sampling.”

“More Work to Be Done”

The Simoa assay has limitations, the researchers acknowledged. It doesn’t identify the location of cancers, and it “isn’t successful in identifying all cancers and their subtypes,” the press release stated, adding that the test will likely be used in conjunction with other early-detection approaches. The researchers also said they want to gauge the test’s accuracy in larger cohorts.

“The test is very specific, but it doesn’t tell us enough information to be used in a vacuum,” Walt said in the news release. “It’s exciting to see the early success of this ultrasensitive assessment tool, but there is more work to be done.”

More studies will be needed to valid these findings. That this promising new multi-cancer immunoassay is based on a clinical laboratory blood sample means its less invasive and less painful for patients. It’s a good example of an assay that takes a proteomic approach looking for protein cancer biomarkers rather than the genetic approach looking for molecular DNA/RNA biomarkers of cancer.

—Stephen Beale

Related Information:

Ultrasensitive Blood Test Detects ‘Pan-Cancer’ Biomarker

New Blood Test Could Offer Earlier Detection of Common Deadly Cancers

Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker

Noninvasive and Multicancer Biomarkers: The Promise of LINE-1 Retrotransposons

LINE-1-ORF1p Is a Promising Biomarker for Early Cancer Detection, But More Research Is Needed

‘Pan-Cancer’ Found in Highly Sensitive Blood Test

Cambridge Researchers in UK Develop ‘Unknome Database’ That Ranks Proteins by How Little is Known about Their Functions

Scientists believe useful new clinical laboratory assays could be developed by better understanding the huge number of ‘poorly researched’ genes and the proteins they build

Researchers have added a new “-ome” to the long list of -omes. The new -ome is the “unknome.” This is significant for clinical laboratory managers because it is part of an investigative effort to better understand the substantial number of genes, and the proteins they build, that have been understudied and of which little is known about their full function.

Scientists at the Medical Research Council Laboratory of Molecular Biology (MRC-LMB) in Cambridge, England, believe these genes are important. They have created a database of thousands of unknown—or “unknome” as they cleverly dubbed them—proteins and genes that have been “poorly understood” and which are “unjustifiably neglected,” according to a paper the scientist published in the journal PLOS Biology titled, “Functional Unknomics: Systematic Screening of Conserved Genes of Unknown Function.”

The Unknome Database includes “thousands of understudied proteins encoded by genes in the human genome, whose existence is known but whose functions are mostly not,” according to a news release.

The database, which is available to the public and which can be customized by the user, “ranks proteins based on how little is known about them,” the PLOS Biology paper notes.

It should be of interest to pathologists and clinical laboratory scientists. The fruit of this research may identify additional biomarkers useful in diagnosis and for guiding decisions on how to treat patients.

Sean Munro, PhD

“These uncharacterized genes have not deserved their neglect,” said Sean Munro, PhD (above), MRC Laboratory of Molecular Biology in Cambridge, England, in a press release. “Our database provides a powerful, versatile and efficient platform to identify and select important genes of unknown function for analysis, thereby accelerating the closure of the gap in biological knowledge that the unknome represents.” Clinical laboratory scientists may find the Unknome Database intriguing and useful. (Photo copyright: Royal Society.)

Risk of Ignoring Understudied Proteins

Proteomics (the study of proteins) is a rapidly advancing area of clinical laboratory testing. As genetic scientists learn more about proteins and their functions, diagnostics companies use that information to develop new assays. But did you know that researchers tend to focus on only a small fraction of the total number of protein-coding DNA sequences contained in the human genome?

The study of proteomics is primarily interested in the part of the genome that “contains instructions for building proteins … [which] are essential for development, growth, and reproduction across the entire body,” according to Scientific American. These are all protein-coding genes.

Proteomics estimates that there are more than two million proteins in the human body, which are coded for 20,000 to 25,000 genes, according to All the Science.

To build their database, the MRC researchers ranked the “unknome” proteins by how little is known about their functions in cellular processes. When they tested the database, they found some of these less-researched proteins important to biological functions such as development and stress resistance. 

“The role of thousands of human proteins remains unclear and yet research tends to focus on those that are already well understood,” said Sean Munro, PhD, MRC Laboratory of Molecular Biology in Cambridge, England, in the news release. “To help address this we created an Unknome database that ranks proteins based on how little is known about them, and then performed functional screens on a selection of these mystery proteins to demonstrate how ignorance can drive biological discovery.”

Munro created the Unknome Database along with Matthew Freeman, PhD, Head of England’s Sir William Dunn School of Pathology, University of Oxford.

In the paper, they acknowledged the human genome encodes about 20,000 proteins, and that the application of transcriptomics and proteomics has “confirmed that most of these new proteins are expressed, and the function of many of them has been identified.

“However,” the authors added, “despite over 20 years of extensive effort, there are also many others that still have no known function.”

They also recognized limited resources for research and that a preference for “relative safety” and “well-established fields” are likely holding back discoveries.

The researchers note “significant” risks to continually ignoring unexplored proteins, which may have roles in cell processes, serve as targets for therapies, and be associated with diseases as well as being “eminently druggable,” Genetic Engineering News reported.

Setting up the Unknome Database

To develop the Unknome Database, the researchers first turned to what has already come to fruition. They gave each protein in the human genome a “knownness” score based on review of existing information about “function, conservation across species, subcellular localization, and other factors,” Interesting Engineering reported.

It turns out, 3,000 groups of proteins (805 with a human protein) scored zero, “showing there’s still much to learn within the human genome,” Science News stated, adding that the Unknome Database catalogues more than 13,000 protein groups and nearly two million proteins. 

The researchers then tested the database by using it to determine what could be learned about 260 “mystery” genes in humans that are also present in Drosophila (small fruit flies).

“We used the Unknome Database to select 260 genes that appeared both highly conserved and particularly poorly understood, and then applied functional assays in whole animals that would be impractical at genome-wide scale,” the researchers wrote in PLOS Biology.

“We initially selected all genes that had a knownness score of ≤1.0 and are conserved in both humans and flies, as well as being present in at least 80% of available metazoan genome sequences. … After testing for viability, the nonessential genes were then screened with a panel of quantitative assays designed to reveal potential roles in a wide range of biological functions,” they added.

“Our screen in whole organisms reveals that, despite several decades of extensive genetic screens in Drosophila, there are many genes with essential roles that have eluded characterization,” the researchers conclude.

Clinical Laboratory Testing Using the Unknome Database

Future use of the Unknome Database may involve CRISPR technology to explore functions of unknown genes, according to the PLOS Biology paper.

Munro told Science News the research team may work with other research efforts aimed at understanding “mysterious proteins,” such as the Understudied Proteins Initiative.

The Unknome Database’s ability to be customized by others means researchers can create their own “knownness” scores as it applies to their studies. Thus, the database could be a resource in studies of treatments or medications to fight diseases, Chemistry World noted.

According to a statement prepared for Healthcare Dive by SomaLogic, a Boulder, Colorado-based protein biomarker company, diagnostic tests that measure proteins can be applied to diseases and conditions such as:

In a study published in Science Translational Medicine, SomaLogic’s SomaScan assay was reportedly successful in predicting the likelihood within four years of myocardial infarction, heart failure, stroke, and even death.

“The 27-protein model has potential as a ‘universal’ surrogate end point for cardiovascular risk,” the researchers wrote in Science Translational Medicine.

Proteomics definitely has its place in clinical laboratory testing. The development of MRC-LMB’s Unknome Database will help researchers’ increase their knowledge about the functions of more proteins which should in turn lead to new diagnostic assays for labs.

—Donna Marie Pocius

Related Information:

Mapping the ‘Unknome’ May Reveal Critical Genes Scientists Have Ignored

How Many Proteins Exist?

Unknome: A Database of Human Genes We Know Almost Nothing About

Functional Unknomics: Systematic Screening of Conserved Genes of Unknown Function

Unknome Database Ranks Proteins Based on How Little is Known about Them

How a New Database of Human Genes Can Help Discover New Biology

The Unknome Catalogs Nearly Two Million Proteins. Many are Mysterious

Into the Unknome: Scientists at MRC LMB in Cambridge Create Database Ranking Human Proteins by How Little We know About Them

Scientists Hope to Illuminate Unknown Human Proteins with New Public Database

Proteomic Tests Empower Precision Medicine

A Proteomic Surrogate for Cardiovascular Outcomes That is Sensitive to Multiple Mechanisms of Change in Risk

Northwestern University Study Shares News Insights into Aging Guided by Transcriptome, Gene Length Imbalance

Findings could lead to deeper understanding of why we age, and to medical laboratory tests and treatments to slow or even reverse aging

Can humans control aging by keeping their genes long and balanced? Researchers at Northwestern University in Evanston, Illinois, believe it may be possible. They have unveiled a “previously unknown mechanism” behind aging that could lead to medical interventions to slow or even reverse aging, according to a Northwestern news release.

Should additional studies validate these early findings, this line of testing may become a new service clinical laboratories could offer to referring physicians and patients. It would expand the test menu with assays that deliver value in diagnosing the aging state of a patient, and which identify the parts of the transcriptome that are undergoing the most alterations that reduce lifespan.

It may also provide insights into how treatments and therapies could be implemented by physicians to address aging.

The Northwestern University scientists published their findings in the journal Nature Aging title, “Aging Is Associated with a Systemic Length-Associated Transcriptome Imbalance.”

“I find it very elegant that a single, relatively concise principle seems to account for nearly all of the changes in activity of genes that happen in animals as they change,” Thomas Stoeger, PhD, postdoctoral scholar in the Amaral Lab who led the study, told GEN. Clinical laboratories involved in omics research may soon have new anti-aging diagnostic tests to perform. (Photo copyright: Amaral Lab.)

Possible ‘New Instrument’ for Biological Testing

Researchers found clues to aging in the length of genes. A gene transcript length reveals “molecular-level changes” during aging: longer genes relate to longer lifespans and shorter genes suggest shorter lives, GEN summarized.

The phenomenon the researchers uncovered—which they dubbed transcriptome imbalance—was “near universal” in the tissues they analyzed (blood, muscle, bone, and organs) from both humans and animals, Northwestern said. 

According to the National Human Genome Research Institute fact sheet, a transcriptome is “a collection of all the gene readouts (aka, transcript) present in a cell” shedding light on gene activity or expression.

The Northwestern study suggests “systems-level” changes are responsible for aging—a different view than traditional biology’s approach to analyzing the effects of single genes.

“We have been primarily focusing on a small number of genes, thinking that a few genes would explain disease,” said Luis Amaral, PhD, Senior Author of the Study and Professor of Chemical and Biological Engineering at Northwestern, in the news release.

“So, maybe we were not focused on the right thing before. Now that we have this new understanding, it’s like having a new instrument. It’s like Galileo with a telescope, looking at space. Looking at gene activity through this new lens will enable us to see biological phenomena differently,” Amaral added.

In their Nature Aging paper, Amaral and his colleagues wrote, “We hypothesize that aging is associated with a phenomenon that affects the transcriptome in a subtle but global manner that goes unnoticed when focusing on the changes in expression of individual genes.

“We show that transcript length alone explains most transcriptional changes observed with aging in mice and humans,” they continued.

Researchers Turn to AI, RNA Sequencing

According to their published study, the Northwestern University scientists used large datasets, artificial intelligence (AI), and RNA (ribonucleic acid) sequencing in their analysis of tissue derived from:

  • Humans (men and women), age 30 to 49, 50 to 69, and 70 years and older. 
  • Mice, age four months to 24 months.
  • Rats, age six to 24 months.
  • Killifish, age five weeks to 39 weeks.

Scientific American reported the following study findings:

  • In tissues studied, older animals’ long transcripts were not as “abundant” as short transcripts, creating “imbalance.”
  • “Imbalance” likely prohibited the researchers’ discovery of a “specific set of genes” changing.
  • As animals aged, shorter genes “appeared to become more active” than longer genes.
  • In humans, the top 5% of genes with the shortest transcripts “included many linked to shorter life spans such as those involved in maintaining the length of telomeres.”
  • Conversely, the researchers’ review of the leading 5% of genes in humans with the longest transcripts found an association with long lives.
  • Antiaging drugs—rapamycin (aka, sirolimus) and resveratrol—were linked to an increase in long-gene transcripts.

“The changes in the activity of genes are very, very small, and these small changes involve thousands of genes. We found this change was consistent across different tissues and in different animals. We found it almost everywhere,” Thomas Stoeger, PhD, postdoctoral scholar in the Amaral Lab who led the study, told GEN.

In their paper, the Northwestern scientists noted implications for creation of healthcare interventions.

“We believe that understanding the direction of causality between other age-dependent cellular and transcriptomic changes and length-associated transcriptome imbalance could open novel research directions for antiaging interventions,” they wrote.

Other ‘Omics’ Studies

Dark Daily has previously reported on transcriptomics studies, along with research into the other “omics,” including metabolomics, proteomics, and genomics.

In “Spatial Transcriptomics Provide a New and Innovative Way to Analyze Tissue Biology, May Have Value in Surgical Pathology,” we explored how newly combined digital pathology, artificial intelligence (AI), and omics technologies are providing anatomic pathologists and medical laboratory scientists with powerful diagnostic tools.

In “Swiss Researchers Develop a Multi-omic Tumor Profiler to Inform Clinical Decision Support and Guide Precision Medicine Therapy for Cancer Patients,” we looked at how new biomarkers for cancer therapies derived from the research could usher in superior clinical laboratory diagnostics that identify a patient’s suitability for personalized drug therapies and treatments.

And in “Human Salivary Proteome Wiki Developed at University of Buffalo May Provide Biomarkers for New Diagnostic Tools and Medical Laboratory Tests,” we covered how proteins in human saliva make up its proteome and may be the key to new, precision medicine diagnostics that would give clinical pathologists new capabilities to identify disease.

Fountain of Youth

While more research is needed to validate its findings, the Northwestern study is compelling as it addresses a new area of transcriptome knowledge. This is another example of researchers cracking open human and animal genomes and gaining new insights into the processes supporting life.

For clinical laboratories and pathologists, diagnostic testing to reverse aging and guide the effectiveness of therapies may one day be possible—kind of like science’s take on the mythical Fountain of Youth.  

—Donna Marie Pocius

Related Information:

Aging Is Driven by Unbalanced Genes

Aging Linked to Gene Length Imbalance and Shift Towards Shorter Genes

NIH: Transcriptome Fact Sheet

Aging Is Associated with a Systemic Length-Associated Transcriptome Imbalance

Aging Is Linked to More Activity in Short Genes than in Long Genes

Spatial Transcriptomics Provide a New and Innovative Way to Analyze Tissue Biology, May Have Value in Surgical Pathology

Swiss Researchers Develop a Multi-omic Tumor Profiler to Inform Clinical Decision Support and Guide Precision Medicine Therapy for Cancer Patients

Human Salivary Proteome Wiki Developed at University of Buffalo May Provide Biomarkers for New Diagnostic Tools and Medical Laboratory Tests

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