Deep Aging Clocks: The Emergence of AI-based Biomarkers of Aging and Longevity

There are two kinds of age: chronological age, which is the number of years one has lived, and biological age, which is influenced by our genes, lifestyle, behaviour, the environment and other factors. Biological age is the superior measure of true age and is the most biologically relevant feature, as it closely correlates with mortality and health status. The search for reliable predictors of biological age has been ongoing for several decades, and until recently, largely without success.

Since 2016 the use of deep learning techniques to find predictors of chronological and biological age has been gaining popularity in the aging research community. Advances in artificial intelligence, combined with the availability of large datasets, have led to a boom in the field, increasing the variety of biomarkers that could be considered candidates as potential age predictors. One promising development that considers multiple combinations of these different predictors could shed light on the aging process and provide further understanding of what contributes to healthy aging.

In the paper titled “Deep Aging Clocks: The Emergence of AI-Based Biomarkers of Aging and Longevity” in Cell Trends in Pharmacological Sciences, Polina Mamoshina, Senior Scientist at Insilico Medicine, and Alex Zhavoronkov, the Founder of Insilico Medicine, summarise current findings on the main types of deep aging clocks and their broad range of applications in pharmaceutical industry.

“Humans are very good at guessing each other’s age using images, videos, voice, and even smell. Deep neural networks can do it better and we can now interpret what factors are most important. Very often when someone looks older than their chronological age, they are sick. A trained doctor can guess the health status of a patient just by looking at him or her. At Insilico we developed a broad range of deep biomarkers of aging that can be used by the pharmaceutical and insurance companies, as well as by the longevity biotechnology community. In this paper we describe the recent progress in this emerging field and outline a range of non-obvious applications,” said Alex Zhavoronkov, Ph.D, Founder and CEO of Insilico Medicine.

Deep biological aging clocks can be used for data quality control, biological target identification and even the evaluation of the biological relevance and value of various data types and combinations. The recent perspective on the value of human data recently appeared in Cell Trends in Molecular Medicine.

“Deep biomarkers of aging developed utilizing a variety of data types of aging are rapidly advancing the longevity biotechnology industry. Using biomarkers of aging to improve human health, prevent age-associated diseases and extend healthy life span is now facilitated by the fast-growing capacity of data acquisition, and recent advances in AI. They hold a great potential for changing not only aging research, but healthcare in general,” said Polina Mamoshina, Senior Scientist at Insilico Medicine.

Source : EurekAlert!

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Simple Test Can Tell If You’re Stressed Out

Stress is often called “the silent killer” because of its stealthy and mysterious effects on everything from heart disease to mental health.

Now researchers at the University of Cincinnati have developed a new test that can easily and simply measure common stress hormones using sweat, blood, urine or saliva. Eventually, they hope to turn their ideas into a simple device that patients can use at home to monitor their health.

The results were published this month in the journal American Chemical Society Sensors.

“I wanted something that’s simple and easy to interpret,” said Andrew Steckl, an Ohio Eminent Scholar and professor of electrical engineering in UC’s College of Engineering and Applied Science.

“This may not give you all the information, but it tells you whether you need a professional who can take over,” Steckl said.

UC researchers developed a device that uses ultraviolet light to measure stress hormones in a drop of blood, sweat, urine or saliva. These stress biomarkers are found in all of these fluids, albeit in different quantities, Steckl said.

“It measures not just one biomarker but multiple biomarkers. And it can be applied to different bodily fluids. That’s what’s unique,” he said.

Steckl has been studying biosensors for years in his Nanoelectronics Laboratory. The latest journal article is part of a series of research papers his group has written on biosensors, including one that provides a review of methods for point-of-care diagnostics of stress biomarkers.

Personal experience helping his father with a health crisis informed his research and opinion that a home test for various health concerns would be incredibly helpful.

“I had to take him quite often to the lab or doctor to have tests done to adjust his medication. I thought it would be great if he could just do the tests himself to see if he was in trouble or just imagining things,” Steckl said. “This doesn’t replace laboratory tests, but it could tell patients more or less where they are.”

UC received grant funding for the project from the National Science Foundation and the U.S. Air Force Research Lab. Steckl said the military studies acute stress in its pilots and others who are pushing the edges of human performance.

“Pilots are placed under enormous stress during missions. The ground controller would like to know when the pilot is reaching the end of his or her ability to control the mission properly and pull them out before a catastrophic ending,” Steckl said.

But the UC device has widespread applications, Steckl said. His lab is pursuing the commercial possibilities.

“You’re not going to replace a full-panel laboratory blood test. That’s not the intent,” Steckl said. “But if you’re able to do the test at home because you’re not feeling well and want to know where you stand, this will tell whether your condition has changed a little or a lot.”

UC graduate Prajokta Ray, the study’s first author, said she was excited to work on such a pressing problem for her Ph.D. studies.

“Stress harms us in so many ways. And it sneaks up on you. You don’t know how devastating a short or long duration of stress can be,” Ray said. “So many physical ailments such as diabetes, high blood pressure and neurological or psychological disorders are attributed to stress the patient has gone through. That’s what interested me.”

Ray said taking exams always gave her stress. Understanding how stress affects you individually could be extremely valuable, she said.

“Stress has been a hot topic over the past couple years. Researchers have tried very hard to develop a test that is cheap and easy and effective and detect these hormones in low concentrations,” she said. “This test has the potential to make a strong commercial device. It would be great to see the research go in that direction.”

UC is at the forefront of biosensor technology. Its labs are examining continuous sweat testing and point-of-care diagnostics for everything from traumatic brain injury to lead poisoning.

Steckl, too, has been a preeminent innovator at UC. His papers have been cited more than 13,000 times, according to Google Scholar. In 2016, he used salmon sperm, a common byproduct of the fishing industry, to replace rare earth metals used in light-emitting diodes for a new kind of organic LED.

“We’re device engineers at heart,” Steckl said. “We don’t shy away from things we don’t know much about to begin with. We look for opportunities. That’s a hallmark of electrical engineers. We’re not smart enough not to go where we shouldn’t. Sometimes that pays off!”

Source: University of Cincinnati


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Early-stage Detection of Alzheimer’s in the Blood

Two major studies with promising antibodies have recently failed – possibly because they have been administered too late. A new very early-detection test gives rise to hope.

Using current techniques, Alzheimer’s disease, the most frequent cause of dementia, can only be detected once the typical plaques have formed in the brain. At this point, therapy seems no longer possible. However, the first changes caused by Alzheimer’s take place on the protein level up to 20 years sooner. A two-tier method developed at Ruhr-Universität Bochum (RUB) can help detect the disease at a much earlier stage. The researchers from Bochum published their report in the March 2019 edition of the journal “Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring”.

“This has paved the way for early-stage therapy approaches, where the as yet inefficient drugs on which we had pinned our hopes may prove effective,” says Professor Klaus Gerwert from the Department of Biophysics at RUB.

Protein folds incorrectly

In Alzheimer’s patients, the amyloid beta protein folds incorrectly due to pathological changes long before the first symptoms occur. A team of researchers headed by Klaus Gerwert successfully diagnosed this misfolding using a simple blood test; as a result, the disease can be detected approximately eight years before the first clinical symptoms occur. The test wasn’t suitable for clinical applications however: it did detect 71 per cent of Alzheimer’s cases in symptomless stages, but at the same time provided false positive diagnoses for nine per cent of the study participants. In order to increase the number of correctly identified Alzheimer’s cases and to reduce the number of false positive diagnoses, the researchers poured a lot of time and effort into optimising the test.

Second biomarker

As a result, they have now introduced the two-tier diagnostic method. To this end, they use the original blood test to identify high-risk individuals. Subsequently, they add a dementia-specific biomarker, namely tau protein, to run further tests with those test participants whose Alzheimer’s diagnosis was positive in the first step. If both biomarkers show a positive result, there is a high likelihood of Alzheimer’s disease. “Through the combination of both analyses, 87 of 100 Alzheimer’s patients were correctly identified in our study,” summarises Klaus Gerwert. “And we reduced the number of false positive diagnoses in healthy subjects to 3 of 100. The second analysis is carried out in cerebrospinal fluid that is extracted from the spinal cord.

“Now, new clinical studies with test participants in very early stages of the disease can be launched,” points out Gerwert. He is hoping that the existing therapeutic antibodies will still have an effect. “Recently, two major promising studies have failed, especially Crenezumab and Aducanumab – not least because it had probably already been too late by the time therapy was taken up. The new test opens up a new therapy window.”

“Once amyloid plaques have formed, it seems that the disease can no longer be treated,” says Dr. Andreas Nabers, head of the research group and co-developer of the Alzheimer’s sensor. “If our attempts to arrest the progression of Alzheimer’s fail, it will put a lot of strain on our society.”

Sensor test is simple and robust

The blood test has been upgraded to a fully automated process at the RUB Department of Biophysics. “The sensor is easy to use, robust when it comes to fluctuation in concentration of biomarkers, and standardised,” explains Andreas Nabers. “We are now conducting in-depth research to detect the second biomarker, namely tau protein, in the blood, in order to supply a solely blood-based test in future,” concludes Klaus Gerwert.

Source : Ruhr-Universität Bochum


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Biomarker for Chronic Fatigue Syndrome Identified

Hanae Armitage wrote . . . . . . . . .

Stanford scientists devised a blood-based test that accurately identified people with chronic fatigue syndrome, a new study reports.

People suffering from a debilitating and often discounted disease known as chronic fatigue syndrome may soon have something they’ve been seeking for decades: scientific proof of their ailment.

Researchers at the Stanford University School of Medicine have created a blood test that can flag the disease, which currently lacks a standard, reliable diagnostic test.

“Too often, this disease is categorized as imaginary,” said Ron Davis, PhD, professor of biochemistry and of genetics. When individuals with chronic fatigue syndrome seek help from a doctor, they may undergo a series of tests that check liver, kidney and heart function, as well as blood and immune cell counts, Davis said. “All these different tests would normally guide the doctor toward one illness or another, but for chronic fatigue syndrome patients, the results all come back normal,” he said.

The problem, he said, is that they’re not looking deep enough. Now, Davis; Rahim Esfandyarpour, PhD, a former Stanford research associate; and their colleagues have devised a blood-based test that successfully identified participants in a study with chronic fatigue syndrome. The test, which is still in a pilot phase, is based on how a person’s immune cells respond to stress. With blood samples from 40 people — 20 with chronic fatigue syndrome and 20 without — the test yielded precise results, accurately flagging all chronic fatigue syndrome patients and none of the healthy individuals.

The diagnostic platform could even help identify possible drugs to treat chronic fatigue syndrome. By exposing the participants’ blood samples to drug candidates and rerunning the diagnostic test, the scientists could potentially see whether the drug improved the immune cells’ response. Already, the team is using the platform to screen for potential drugs they hope can help people with chronic fatigue syndrome down the line.

A paper describing the research findings was published online April 29 in the Proceedings of the National Academy of Sciences. Davis is the senior author. Esfandyarpour, who is now on the faculty of the University of California-Irvine, is the lead author.

Providing the proof

The diagnosis of chronic fatigue syndrome, when it actually is diagnosed, is based on symptoms — exhaustion, sensitivity to light and unexplained pain, among other things — and it comes only after other disease possibilities have been eliminated. It is also known as myalgic encephalomyelitis and designated by the acronym ME/CFS. It’s estimated that 2 million people in the United States have chronic fatigue syndrome, but that’s a rough guess, Davis said, and it’s likely much higher.

For Davis, the quest to find scientific evidence of the malady is personal. It comes from a desire to help his son, who has suffered from ME/CFS for about a decade. In fact, it was a biological clue that Davis first spotted in his son that led him and Esfandyarpour to develop the new diagnostic tool.

The approach, of which Esfandyarpour led the development, employs a “nanoelectronic assay,” which is a test that measures changes in miniscule amounts of energy as a proxy for the health of immune cells and blood plasma. The diagnostic technology contains thousands of electrodes that create an electrical current, as well as chambers to hold simplified blood samples composed of immune cells and plasma. Inside the chambers, the immune cells and plasma interfere with the current, changing its flow from one end to another. The change in electrical activity is directly correlated with the health of the sample.

The idea is to stress the samples from both healthy and ill patients using salt, and then compare how each sample affects the flow of the electrical current. Changes in the current indicate changes in the cell: the bigger the change in current, the bigger the change on a cellular level. A big change is not a good thing; it’s a sign that the cells and plasma are flailing under stress and incapable of processing it properly. All of the blood samples from ME/CFS patients created a clear spike in the test, whereas those from healthy controls returned data that was on a relatively even keel.

“We don’t know exactly why the cells and plasma are acting this way, or even what they’re doing,” Davis said. “But there is scientific evidence that this disease is not a fabrication of a patient’s mind. We clearly see a difference in the way healthy and chronic fatigue syndrome immune cells process stress.” Now, Esfandyarpour and Davis are expanding their work to confirm the findings in a larger cohort of participants. Recruitment for the larger project, which aims to further confirm the success of the diagnostic test, is being done on a rolling basis. Those who are interested in participating should contact clinical research coordinator Anna Okumu.

Doubling up

In addition to diagnosing ME/CFS, the researchers are also harnessing the platform to screen for drug-based treatments, since currently the options are slim. “Using the nanoelectronics assay, we can add controlled doses of many different potentially therapeutic drugs to the patient’s blood samples and run the diagnostic test again,” Esfandyarpour said.

If the blood samples taken from those with ME/CFS still respond poorly to stress and generate a spike in electrical current, then the drug likely didn’t work. If, however, a drug seems to mitigate the jump in electrical activity, that could mean it is helping the immune cells and plasma better process stress. So far, the team has already found a candidate drug that seems to restore healthy function to immune cells and plasma when tested in the assay. The drug, while successful in the assay, is not currently being used in people with ME/CFS, but Davis and Esfandyarpour are hopeful that they can test their finding in a clinical trial in the future.

All of the drugs being tested are either already approved by the Food and Drug Administration or will soon be broadly accessible to the public, which is key to fast access and dissemination should any of these compounds pan out.

Source: Stanford School of Medicine


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New Study Finds Test of Protein Levels in the Eye a Potential Predictor of (Future) Alzheimer’s Disease

Low levels of amyloid-β and tau proteins, biomarkers of Alzheimer’s disease (AD), in eye fluid were significantly associated with low cognitive scores, according to a new study published in the Journal of Alzheimer’s Disease. Led by researchers at Boston Medical Center, the study is the first to connect these known AD protein biomarkers in the eye to mental status. These findings indicate that proteins in the eye may be a potential source for an accessible, cost-effective test to predict future Alzheimer’s disease.

Diagnosing and starting treatment for AD before symptoms begin is key to managing the disease, because by the time symptoms appear it is often too late for current treatments to have any meaningful effect. Abnormal amounts of amyloid- β and tau proteins are biomarkers of AD, and deposits of amyloid proteins in the brain begin many years prior to symptoms of the disease. Previous research has shown an association between low levels of amyloid-β and tau proteins found in the cerebrospinal fluid obtained by lumbar puncture tests and preclinical AD, when pathological changes of AD present in the brain, but before the onset of clinical symptoms. However, lumbar puncture tests are expensive and inconvenient for many patients to undergo.

In this study, researchers used samples of eye fluid from 80 patients who were previously scheduled for eye surgery. The fluid extracted during these surgeries is typically discarded. Researchers tested the eye fluid to determine the levels of amyloid-β and tau proteins, and correlated those levels to the results of a baseline cognitive test. Low levels of these biomarker proteins were significantly associated with lower cognitive scores among the patients.

“These findings could help us build an accessible, and minimally invasive test to determine Alzheimer’s disease risk, especially among patients with eye disease,” says Lauren Wright, MD, first author on the study and ophthalmology fellow at BMC. “We noted that some of the participants who had low levels of protein biomarkers in their eye fluid already had signs of mild to moderate dementia based on their cognitive scores.”

These results reaffirm previous studies suggesting that patients with eye disease are at-risk for the development of AD, and suggest that further investigation in patients with eye disease may yield results that could be generalizable to larger populations.

“This is a great step in discovering the eye’s potential role in diagnosing preclinical Alzheimer’s disease, and further study is needed comparing protein biomarkers in the eye with more in-depth neurological testing,” adds Manju Subramanian, MD, senior author, principal investigator, and ophthalmologist at BMC.

Source: Boston Medical Center


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