Researchers are discovering it’s possible to determine a person’s age based on the amount of protein in the blood, but the technology isn’t always correct
Mass spectrometry is increasingly finding its way into clinical laboratories and with it—proteomics—the study of proteins in the human body. And like the human genome, scientists are discovering that protein plays an integral part in the aging process.
This is a most interesting research finding. Might medical laboratories someday use proteomic biomarkers to help physicians gauge the aging progression in patients? Might this diagnostic capability give pathologists and laboratory leaders a new product line for direct-to-consumer testing that would be a cash-paying, fast-growing, profitable clinical laboratory testing service? If so, proteomics could be a boon to clinical laboratories worldwide.
When research into genomics was brand-new, virtually no one imagined that someday the direct-to-consumer lab testing model would offer genetic testing to the public and create a huge stream of revenue for clinical laboratories that process genetic tests. Now, research into protein and aging might point to a similar possibility for proteomics.
For example, through proteomics, researchers led by Benoit Lehallier, PhD, Biostatistician, Instructor of Neurology and Neurological Sciences, and senior author Tony Wyss-Coray, PhD, Professor of Neurology and Neurological Sciences and co-director of the Stanford Alzheimer’s Disease Research Center at Stanford University in California, gained an understanding of aging that suggest intriguing possibilities for clinical laboratories.
In their study, published in Nature, titled, “Undulating Changes in Human Plasma Proteome Profiles Across the Lifespan,” the scientists stated that aging doesn’t happen in a consistent process over time, reported Science Alert.
The Stanford researchers also found that they can accurately
determine a person’s age based on the levels of certain proteins in his or her
blood.
Additionally, the study of proteomics may finally explain why blood from young people can have a rejuvenating effect on elderly people’s brains, noted Scientific American.
Each of these findings is important on its own, but taken
together, they may have interesting implications for pathologists who follow
the research. And medical laboratory leaders may find opportunities in mass
spectrometry in the near future, rather than decades from now.
Three Distinct Stages in Aging and Other Findings
The Stanford study found that aging appears to happen at
three distinct points in a person’s life—around the ages 34, 60, and 78—rather
than being a slow, steady process.
The researchers measured and compared levels of nearly 3,000
specific proteins in blood plasma taken from healthy people between the ages of
18 and 95 years. In the published study, the authors wrote, “This new approach
to the study of aging led to the identification of unexpected signatures and
pathways that might offer potential targets for age-related diseases.”
Along with the findings regarding the timeline for aging, the researchers found that about two-thirds of the proteins that change with age differ significantly between men and women. “This supports the idea that men and women age differently and highlights the need to include both sexes in clinical studies for a wide range of diseases,” noted a National Institutes of Health (NIH) report.
“We’ve known for a long time that measuring certain proteins in the blood can give you information about a person’s health status—lipoproteins for cardiovascular health, for example,” stated Wyss-Coray in the NIH report. “But it hasn’t been appreciated that so many different proteins’ levels—roughly a third of all the ones we looked at—change markedly with advancing age.”
Tony Wyss-Coray, PhD (above), Professor of Neurology and Neurological Sciences at Stanford University, was senior author of the proteomics study that analyzed blood plasma from 4,263 people between the ages 18-95. “Proteins are the workhorses of the body’s constituent cells, and when their relative levels undergo substantial changes, it means you’ve changed, too,” he said in a Stanford Medicine news article. “Looking at thousands of them in plasma gives you a snapshot of what’s going on throughout the body.” (Photo copyright: Stanford University.)
Differentiating Aging from Disease
Previous research studies also found it is indeed possible
to measure a person’s age from his or her “proteomic signature.”
The researchers published their findings in Aging Cell, a peer-reviewed open-access journal of the Anatomical Society in the UK, titled, “Plasma Proteomic Signature of Age in Healthy Humans.” In it, the authors wrote, “Our results suggest that there are stereotypical biological changes that occur with aging that are reflected by circulating proteins.”
The fact that chronological age can be determined through a
person’s proteomic signature suggests researchers could separate aging from
various diseases. “Older age is the main risk factor for a myriad of chronic
diseases, and it is invariably associated with progressive loss of function in
multiple physiological systems,” wrote the researchers, adding, “A challenge in
the field is the need to differentiate between aging and diseases.”
Can Proteins Cause Aging?
Additionally, the Stanford study found that changes in protein levels might not simply be a characteristic of aging, but may actually cause it, a Stanford Medicine news article notes.
“Changes in the levels of numerous proteins that migrate
from the body’s tissues into circulating blood not only characterize, but quite
possibly cause, the phenomenon of aging,” Wyss-Coray said.
Can Proteins Accurately Predict Age? Not Always
There were, however, some instances where the protein levels inaccurately predicted a person’s age. Some of the samples the Stanford researchers used were from the LonGenity research study conducted by the Albert Einstein College of Medicine, which investigated “why some people enjoy extremely long life spans, with physical health and brain function far better than expected in the 9th and 10th decades of life,” the study’s website notes.
That study included a group of exceptionally long-lived Ashkenazi Jews, who have a “genetic proclivity toward exceptionally good health in what for most of us is advanced old age,” according to the Stanford Medicine news article.
“We had data on hand-grip strength and cognitive function
for that group of people. Those with stronger hand grips and better measured
cognition were estimated by our plasma-protein clock to be younger than they
actually were,” said Wyss-Coray. So, physical condition is a factor in
proteomics’ ability to accurately prediction age.
Although understanding the connections between protein in
the blood, aging, and disease is in early stages, it is clear additional
research is warranted. Not too long ago the idea of consumers having their DNA
sequenced from a home kit for fun seemed like fantasy.
However, after multiple FDA approvals, and the success of
companies like Ancestry, 23andMe, and the clinical laboratories that serve them,
the possibility that proteomics might go the same route does not seem so
far-fetched.
Experts list the top challenges facing widespread adoption of proteomics in the medical laboratory industry
Year-by-year, clinical
laboratories find new ways to use mass spectrometry to
analyze clinical specimens, producing results that may be more precise than
test results produced by other methodologies. This is particularly true in the
field of proteomics.
However, though mass spectrometry is highly accurate and
fast, taking only minutes to convert a specimen into a result, it is not fully
automated and requires skilled technologists to operate the instruments.
Thus, although the science of proteomics is advancing
quickly, the average pathology laboratory isn’t likely to be using mass
spectrometry tools any time soon. Nevertheless, medical
laboratory scientists are keenly interested in adapting mass spectrometry
to medical lab test technology for a growing number of assays.
Molly Campbell, Science Writer and Editor in Genomics, Proteomics, Metabolomics, and Biopharma at Technology Networks, asked proteomics experts “what, in their opinion, are the greatest challenges currently existing in proteomics, and how can we look to overcome them?” Here’s a synopsis of their answers:
Lack of High Throughput Impacts Commercialization
Proteomics isn’t as efficient as it needs to be to be
adopted at the commercial level. It’s not as efficient as its cousin genomics. For it to become
sufficiently efficient, manufacturers must be involved.
John Yates
III, PhD, Professor, Department of Molecular Medicine at Scripps Research California
campus, told Technology
Networks, “One of the complaints from funding agencies is that you can
sequence literally thousands of genomes very quickly, but you can’t do the same
in proteomics. There’s a push to try to increase the throughput of proteomics
so that we are more compatible with genomics.”
For that to happen, Yates says manufacturers need to
continue advancing the technology. Much of the research is happening at
universities and in the academic realm. But with commercialization comes
standardization and quality control.
“It’s always exciting when you go to ASMS [the conference for the American Society
for Mass Spectrometry] to see what instruments or technologies are going to be
introduced by manufacturers,” Yates said.
There are signs that commercialization isn’t far off. SomaLogic, a privately-owned American protein
biomarker discovery and clinical diagnostics company located in Boulder, Colo.,
has reached the commercialization stage for a proteomics assay platform called SomaScan. “We’ll be
able to supplant, in some cases, expensive diagnostic modalities simply from a
blood test,” Roy
Smythe, MD, CEO of SomaLogic, told Techonomy.
The graphic above illustrates the progression mass spectrometry took during its development, starting with small proteins (left) to supramolecular complexes of intact virus particles (center) and bacteriophages (right). Because of these developments, today’s medical laboratories have more assays that utilize mass spectrometry. (Photo copyright: Technology Networks/Heck laboratory, Utrecht University, the Netherlands.)
Achieving the Necessary Technical Skillset
One of the main reasons mass spectrometry is not more widely
used is that it requires technical skill that not many professionals possess.
“For a long time, MS-based proteomic analyses were technically demanding at
various levels, including sample processing, separation science, MS and the
analysis of the spectra with respect to sequence, abundance and
modification-states of peptides and proteins and false discovery rate
(FDR) considerations,” Ruedi
Aebersold, PhD, Professor of Systems Biology at the Institute of Molecular Systems Biology (IMSB) at
ETH Zurich, told Technology
Networks.
Aebersold goes on to say that he thinks this specific
challenge is nearing resolution. He says that, by removing the problem created
by the need for technical skill, those who study proteomics will be able to
“more strongly focus on creating interesting new biological or clinical
research questions and experimental design.”
Yates agrees. In a paper titled, “Recent Technical Advances in
Proteomics,” published in F1000 Research, a peer-reviewed open research
publishing platform for scientists, scholars, and clinicians, he wrote, “Mass
spectrometry is one of the key technologies of proteomics, and over the last
decade important technical advances in mass spectrometry have driven an
increased capability of proteomic discovery. In addition, new methods to
capture important biological information have been developed to take advantage
of improving proteomic tools.”
No High-Profile Projects to Stimulate Interest
Genomics had the Human Genome Project
(HGP), which sparked public interest and attracted significant funding. One of
the big challenges facing proteomics is that there are no similarly big,
imagination-stimulating projects. The work is important and will result in
advances that will be well-received, however, the field itself is complex and difficult
to explain.
Emanuel
Petricoin, PhD, is a professor and co-director of the Center for Applied
Proteomics and Molecular Medicine at George
Mason University. He told Technology
Networks, “the field itself hasn’t yet identified or grabbed onto a
specific ‘moon-shot’ project. For example, there will be no equivalent to the
human genome project, the proteomics field just doesn’t have that.”
He added, “The equipment needs to be in the background and
what you are doing with it needs to be in the foreground, as is what happened
in the genomics space. If it’s just about the machinery, then proteomics will
always be a ‘poor step-child’ to genomics.”
Democratizing Proteomics
Alexander
Makarov, PhD, is Director of Research in Life Sciences Mass Spectrometry
(MS) at Thermo Fisher
Scientific. He told Technology
Networks that as mass spectrometry grew into the industry we have today,
“each new development required larger and larger research and development teams
to match the increasing complexity of instruments and the skyrocketing
importance of software at all levels, from firmware to application. All this
extends the cycle time of each innovation and also forces [researchers] to
concentrate on solutions that address the most pressing needs of the scientific
community.”
Makarov describes this change as “the increasing democratization of MS,” and says that it “brings with it new requirements for instruments, such as far greater robustness and ease-of-use, which need to be balanced against some aspects of performance.”
One example of the increasing democratization of MS may be
several public proteomic datasets available to scientists. In European
Pharmaceutical Review, Juan
Antonio Viscaíno, PhD, Proteomics Team Leader at the European Bioinformatics Institute (EMBL-EBI)
wrote, “These datasets are increasingly reused for multiple applications, which
contribute to improving our understanding of cell biology through proteomics
data.”
Sparse Data and Difficulty Measuring It
Evangelia
Petsalaki, PhD, Group Leader EMBL-EBI, told Technology
Networks there are two related challenges in handling proteomic data.
First, the data is “very sparse” and second “[researchers] have trouble
measuring low abundance proteins.”
Petsalaki notes, “every time we take a measurement, we
sample different parts of the proteome or phosphoproteome and
we are usually missing low abundance players that are often the most important
ones, such as transcription
factors.” She added that in her group they take steps to mitigate those
problems.
“However, with the advances in MS technologies developed by
many companies and groups around the world … and other emerging technologies
that promise to allow ‘sequencing’ proteomes, analogous to genomes … I expect
that these will not be issues for very long.”
So, what does all this mean for clinical laboratories? At the
current pace of development, its likely assays based on proteomics could become
more common in the near future. And, if throughput and commercialization ever
match that of genomics, mass spectrometry and other proteomics tools could
become a standard technology for pathology laboratories.
The human proteome map provides a catalog of proteins expressed in nondiseased issues and organs to use as baseline in understanding changes that occur in disease
Given the growing importance of proteins in medical laboratory testing, pathologists will want to know about a major milestone recently achieved in this field. Researchers have announced that drafts of the complete human proteome have been released to the public.
Experts are comparing this to the first complete map of the human genome that was made public in 2000. Clinical laboratory managers and pathologists know how the availability of this information provided the foundation for rapid advances in understanding different aspects involving DNA and RNA. (more…)
