Posted on by Dr. Francis Collins
How can you tell how old someone is? Of course, you could scan their driver’s license or look for signs of facial wrinkles and gray hair. But, as researchers just found in a new study, you also could get pretty close to the answer by doing a blood test.
That may seem surprising. But in a recent study in Nature Medicine, an NIH-funded research team was able to gauge a person’s age quite reliably by analyzing a blood sample for levels of a few hundred proteins. The results offer important new insights into what happens as we age. For example, the team suggests that the biological aging process isn’t steady and appears to accelerate periodically—with the greatest bursts coming, on average, around ages 34, 60, and 78.
These findings indicate that it may be possible one day to devise a blood test to identify individuals who are aging faster biologically than others. Such folks might be at risk earlier in life for cardiovascular problems, Alzheimer’s disease, osteoarthritis, and other age-related health issues.
What’s more, this work raises hope for interventions that may slow down the “proteomic clock” and perhaps help to keep people biologically younger than their chronological age. Such a scenario might sound like pure fantasy, but this same group of researchers showed a few years ago that it’s indeed possible to rejuvenate an older mouse by infusing blood from a much younger mouse.
Those and other earlier findings from the lab of Tony Wyss-Coray, Stanford School of Medicine, Palo Alto, CA, raised the tantalizing possibility that certain substances in young blood can revitalize the aging brain and other parts of the body. In search of additional clues in the new study, the Wyss-Coray team tracked how the protein composition of blood changes as people age.
To find those clues, they isolated plasma from more than 4,200 healthy individuals between ages 18 and 95. The researchers then used data from more than half of the participants to assemble a “proteomic clock” of aging. Within certain limits, the clock could accurately predict the chronological age of the study’s remaining 1,446 participants. The best predictions relied on just 373 of the clock’s almost 3,000 proteins.
As further validation, the clock also reliably predicted the correct chronological age of four groups of people not in the study. Interestingly, it was possible to make a decent age prediction based on just nine of the clock’s most informative proteins.
The findings show that telltale proteomic changes arise with age, and they likely have important and as-yet unknown health implications. After all, those proteins found circulating in the bloodstream come not just from blood cells but also from cells throughout the body. Intriguingly, the researchers report that people who appeared biologically younger than their actual chronological age based on their blood proteins also performed better on cognitive and physical tests.
Most of us view aging as a gradual, linear process. However, the protein evidence suggests that, biologically, aging follows a more complex pattern. Some proteins did gradually tick up or down over time in an almost linear fashion. But the levels of many other proteins rose or fell more markedly over time. For instance, one neural protein in the blood stayed constant until around age 60, when its levels spiked. Why that is so remains to be determined.
As noted, the researchers found evidence that the aging process includes a series of three bursts. Wyss-Coray said he found it especially interesting that the first burst happens in early mid-life, around age 34, well before common signs of aging and its associated health problems would manifest.
It’s also well known that men and women age differently, and this study adds to that evidence. About two-thirds of the proteins that changed with age also differed between the sexes. However, because the effect of aging on the most important proteins of the clock is much stronger than the differences in gender, the proteomic clock still could accurately predict the ages in all people.
Overall, the findings show that protein substances in blood can serve as a useful measure of a person’s chronological and biological age and—together with Wyss-Coray’s earlier studies—that substances in blood may play an active role in the aging process. Wyss-Coray reports that his team continues to dig deeper into its data, hoping to learn more about the origins of particular proteins in the bloodstream, what they mean for our health, and how to potentially turn back the proteomic clock.
 Undulating changes in human plasma proteome profiles across the lifespan. Lehallier B, Gate D, Schaum N, Nanasi T, Lee SE, Yousef H, Moran Losada P, Berdnik D, Keller A, Verghese J, Sathyan S, Franceschi C, Milman S, Barzilai N, Wyss-Coray T. Nat Med. 2019 Dec;25(12):1843-1850.
What Do We Know About Healthy Aging? (National Institute on Aging/NIH)
Cognitive Health (NIA)
Wyss-Coray Lab (Stanford University, Palo Alto, CA)
NIH Support: National Institute on Aging
Posted on by Dr. Francis Collins
It’s not every day you get to perform with one of the finest voices on the planet. What an honor it was to join renowned opera singer Renée Fleming back in May for a rendition of “How Can I Keep from Singing?” at the NIH’s J. Edward Rall Cultural Lecture. Yet our duet was so much more. Between the song’s timeless message and Renée’s matchless soprano, the music filled me with a profound sense of joy, like being briefly lifted outside myself into a place of beauty and well-being. How does that happen?
Indeed, the benefits of music for human health and well-being have long been recognized. But biomedical science still has a quite limited understanding of music’s mechanisms of action in the brain, as well as its potential to ease symptoms of an array of disorders including Parkinson’s disease, stroke, and post-traumatic stress disorder (PTSD). In a major step toward using rigorous science to realize music’s potential for improving human health, NIH has just awarded $20 million over five years to support the first research projects of the Sound Health initiative. Launched a couple of years ago, Sound Health is a partnership between NIH and the John F. Kennedy Center for the Performing Arts, in association with the National Endowment for the Arts.
With support from 10 NIH institutes and centers, the Sound Health awardees will, among other things, study how music might improve the motor skills of people with Parkinson’s disease. Previous research has shown that the beat of a metronome can steady the gait of someone with Parkinson’s disease, but more research is needed to determine exactly why that happens.
Other fascinating areas to be explored by the Sound Health awardees include:
• Assessing how active music interventions, often called music therapies, affect multiple biomarkers that correlate with improvement in health status. The aim is to provide a more holistic understanding of how such interventions serve to ease cancer-related stress and possibly even improve immune function.
• Investigating the effects of music on the developing brain of infants as they learn to talk. Such work may be especially helpful for youngsters at high risk for speech and language disorders.
• Studying synchronization of musical rhythm as part of social development. This research will look at how this process is disrupted in children with autism spectrum disorder, possibly suggesting ways of developing music-based interventions to improve communication.
• Examining the memory-related impacts of repeated exposures to a certain song or musical phrase, including those “earworms” that get “stuck” in our heads. This work might tell us more about how music sometimes serves as a cue for retrieving associated memories, even in people whose memory skills are impaired by Alzheimer’s disease or other cognitive disorders.
• Tracing the developmental timeline—from childhood to adulthood—of how music shapes the brain. This will include studying how musical training at different points on that timeline may influence attention span, executive function, social/emotional functioning, and language skills.
We are fortunate to live in an exceptional time of discovery in neuroscience, as well as an extraordinary era of creativity in music. These Sound Health grants represent just the beginning of what I hope will be a long and productive partnership that brings these creative fields together. I am convinced that the power of science holds tremendous promise for improving the effectiveness of music-based interventions, and expanding their reach to improve the health and well-being of people suffering from a wide variety of conditions.
The Soprano and the Scientist: A Conversation About Music and Medicine, (National Public Radio, June 2, 2017)
NIH Workshop on Music and Health, January 2017
Sound Health (NIH)
NIH Support: National Center for Complementary and Integrative Health; National Eye Institute; National Institute on Aging; National Institute on Alcohol Abuse and Alcoholism; National Institute on Deafness and Other Communication Disorders; National Institute of Mental Health; National Institute of Neurological Disorders and Stroke; National Institute of Nursing Research; Office of Behavioral and Social Sciences Research; Office of the Director
Posted on by Dr. Francis Collins
If you’ve spent time with individuals affected with Alzheimer’s disease (AD), you might have noticed that some people lose their memory and other cognitive skills more slowly than others. Why is that? New findings indicate that at least part of the answer may lie in differences in their immune responses.
Researchers have now found that slower loss of cognitive skills in people with AD correlates with higher levels of a protein that helps immune cells clear plaque-like cellular debris from the brain . The efficiency of this clean-up process in the brain can be measured via fragments of the protein that shed into the cerebrospinal fluid (CSF). This suggests that the protein, called TREM2, and the immune system as a whole, may be promising targets to help fight Alzheimer’s disease.
The findings come from an international research team led by Michael Ewers, Institute for Stroke and Dementia Research, Ludwig-Maximilians-Universität München, Germany, and Christian Haass, Ludwig-Maximilians-Universität München, Germany and German Center for Neurodegenerative Diseases. The researchers got interested in TREM2 following the discovery several years ago that people carrying rare genetic variants for the protein were two to three times more likely to develop AD late in life.
Not much was previously known about TREM2, so this finding from a genome wide association study (GWAS) was a surprise. In the brain, it turns out that TREM2 proteins are primarily made by microglia. These scavenging immune cells help to keep the brain healthy, acting as a clean-up crew that clears cellular debris, including the plaque-like amyloid-beta that is a hallmark of AD.
In subsequent studies, Haass and colleagues showed in mouse models of AD that TREM2 helps to shift microglia into high gear for clearing amyloid plaques . This animal work and that of others helped to strengthen the case that TREM2 may play an important role in AD. But what did these data mean for people with this devastating condition?
There had been some hints of a connection between TREM2 and the progression of AD in humans. In the study published in Science Translational Medicine, the researchers took a deeper look by taking advantage of the NIH-funded Alzheimer’s Disease Neuroimaging Initiative (ADNI).
ADNI began more than a decade ago to develop methods for early AD detection, intervention, and treatment. The initiative makes all its data freely available to AD researchers all around the world. That allowed Ewers, Haass, and colleagues to focus their attention on 385 older ADNI participants, both with and without AD, who had been followed for an average of four years.
Their primary hypothesis was that individuals with AD and evidence of higher TREM2 levels at the outset of the study would show over the years less change in their cognitive abilities and in the volume of their hippocampus, a portion of the brain important for learning and memory. And, indeed, that’s exactly what they found.
In individuals with comparable AD, whether mild cognitive impairment or dementia, those having higher levels of a TREM2 fragment in their CSF showed a slower decline in memory. Those with evidence of a higher ratio of TREM2 relative to the tau protein in their CSF also progressed more slowly from normal cognition to early signs of AD or from mild cognitive impairment to full-blown dementia.
While it’s important to note that correlation isn’t causation, the findings suggest that treatments designed to boost TREM2 and the activation of microglia in the brain might hold promise for slowing the progression of AD in people. The challenge will be to determine when and how to target TREM2, and a great deal of research is now underway to make these discoveries.
Since its launch more than a decade ago, ADNI has made many important contributions to AD research. This new study is yet another fine example that should come as encouraging news to people with AD and their families.
 Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M, Trojanowski JQ, Shaw LM, Weiner MW, Haass C; Alzheimer’s Disease Neuroimaging Initiative. Sci Transl Med. 2019 Aug 28;11(507).
 Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, Nuscher B, Xiong M, Ghasemigharagoz A, Katzmarski N, Krasemann S, Lichtenthaler SF, Müller SA, Colombo A, Monasor LS, Tahirovic S, Herms J, Willem M, Pettkus N, Butovsky O, Bartenstein P, Edbauer D, Rominger A, Ertürk A, Grathwohl SA, Neher JJ, Holtzman DM, Meyer-Luehmann M, Haass C. Nat Neurosci. 2019 Feb;22(2):191-204.
Alzheimer’s Disease and Related Dementias (National Institute on Aging/NIH)
Alzheimer’s Disease Neuroimaging Initiative (University of Southern California, Los Angeles)
Ewers Lab (University Hospital Munich, Germany)
Haass Lab (Ludwig-Maximilians-Universität München, Germany)
Institute for Stroke and Dementia Research (Munich, Germany)
NIH Support: National Institute on Aging
Posted on by Dr. Francis Collins
August is here, and many folks have plans to enjoy a well-deserved vacation this month. I thought you might enjoy taking a closer look during August at the wonder and beauty of the brain here on my blog, even while giving your own brains a rest from some of the usual work and deadlines.
Some of the best imagery—and best science—comes from the NIH-led Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, a pioneering project aimed at revolutionizing our understanding of the human brain. Recently, the BRAIN Initiative held a “Show Us Your Brain Contest!”, which invited researchers involved in the effort to submit their coolest images. So, throughout this month, I’ve decided to showcase a few of these award-winning visuals.
Let’s start with the first-place winner in the still-image category. What you see above is an artistic rendering of deep brain stimulation (DBS), an approach now under clinical investigation to treat cognitive impairment that can arise after a traumatic brain injury and other conditions.
The vertical lines represent wire leads with a single electrode that has been inserted deep within the brain to reach a region involved in cognition, the central thalamus. The leads are connected to a pacemaker-like device that has been implanted in a patient’s chest (not shown). When prompted by the pacemaker, the leads’ electrode emits electrical impulses that stimulate a network of neuronal fibers (blue-white streaks) involved in arousal, which is an essential component of human consciousness. The hope is that DBS will improve attention and reduce fatigue in people with serious brain injuries that are not treatable by other means.
Andrew Janson, who is a graduate student in Christopher Butson’s NIH-supported lab at the Scientific Computing and Imaging Institute, University of Utah, Salt Lake City, composed this image using a software program called Blender. It’s an open-source, 3D computer graphics program often used to create animated films or video games, but not typically used in biomedical research. That didn’t stop Janson.
With the consent of a woman preparing to undergo experimental DBS treatment for a serious brain injury suffered years before in a car accident, Janson used Blender to transform her clinical brain scans into a 3D representation of her brain and the neurostimulation process. Then, he used a virtual “camera” within Blender to capture the 2D rendering you see here. Janson plans to use such imagery, along with other patient-specific modeling and bioelectric fields simulations, to develop a virtual brain stimulation surgery to predict the activation of specific fiber pathways, depending upon lead location and stimulation settings.
DBS has been used for many years to relieve motor symptoms of certain movement disorders, including Parkinson’s disease and essential tremor. More recent experimental applications include this one for traumatic brain injury, and others for depression, addiction, Alzheimer’s disease, and chronic pain. As the BRAIN Initiative continues to map out the brain’s complex workings in unprecedented detail, it will be exciting to see how such information can lead to even more effective applications of to DBS to help people living with a wide range of neurological conditions.
Deep Brain Stimulation for Movement Disorders (National Institute of Neurological Disorders and Stroke/NIH)
Video: Deep Brain Stimulation (University of Utah, Salt Lake City)
Butson Lab (University of Utah)
Show Us Your Brain! (BRAIN Initiative/NIH)
NIH Support: National Institute of Neurological Disorders and Stroke
Posted on by Dr. Francis Collins
Courtesy of the Chen and Macosko labs
A few years ago, I highlighted a really cool technology called Drop-seq for simultaneously analyzing the gene expression activity inside thousands of individual cells. Today, one of its creators, Evan Macosko, reports significant progress in developing even better tools for single-cell analysis—with support from an NIH Director’s New Innovator Award.
In a paper in the journal Science, Macosko, Fei Chen, and colleagues at the Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, recently unveiled another exciting creation called Slide-seq . This technology acts as a GPS-like system for mapping the exact location of each of the thousands of individual cells undergoing genomic analysis in a tissue sample.
This 3D video shows the exquisite precision of this new cellular form of GPS, which was used to generate a high-resolution map of the different cell types found in a tiny cube of mouse brain tissue. Specifically, it provides locations of the cell types and gene expression in the hippocampal regions called CA1 (green), CA2/3 (blue), and dentate gyrus (red).
Because using Slide-seq in the lab requires no specialized imaging equipment or skills, it should prove valuable to researchers across many different biomedical disciplines who want to look at cellular relationships or study gene activity in tissues, organs, or even whole organisms.
How does Slide-seq work? Macosko says one of the main innovations is an inexpensive rubber-coated glass slide nicknamed a puck. About 3 millimeters in diameter, pucks are studded with tens of thousands of 10 micron-sized beads, each one decorated with a random snippet of genetic material—an RNA barcode—that serves as its unique identifier of the bead.
The barcodes are sequenced en masse, and the exact location of each barcoded bead is indexed using innovative software developed by a team led by Chen, who is an NIH Director’s Early Independence awardee.
Then, the researchers place a sample of fresh-frozen tissue (typically, 10 micrometers, or 0.00039 inches, thick) on the puck and dissolve the tissue, lysing the cells and releasing their messenger RNA (mRNA). That leaves only the barcoded beads binding the mRNA transcripts expressed by the cells in the tissue—a biological record of the genes that were turned on at the time the sample was frozen.
The barcoded mRNA is then sequenced. The spatial position of each mRNA molecule can be inferred, using the reference index on the puck. This gives researchers a great deal of biological information about the cells in the tissue, often including their cell type and their gene expression pattern. All the data can then be mapped out in ways similar to those seen in this video, which was created using data from 66 pucks.
Slide-seq has been tested on a range of tissues from both mouse and human, replicating results from similar maps created using existing approaches, but also uncovering new biology. For example, in the mouse cerebellum, Slide-seq allowed the researchers to detect bands of variable gene activity across the tissues. This intriguing finding suggests that there may be subpopulations of cells in this part of the brain that have gene activity influenced by their physical locations.
Such results demonstrate the value of combining cell location with genomic information. In fact, Macosko now hopes to use Slide-seq to study the response of brain cells that are located near the buildup of damaged amyloid protein associated with the early-stage Alzheimer’s disease. Meanwhile, Chen is interested in pursuing cell lineage studies in a variety of tissues to see how and where changes in the molecular dynamics of tissues can lead to disease.
These are just a few examples of how Slide-seq will add to the investigative power of single-cell analysis in the years ahead. In meantime, the Macosko and Chen labs are working hard to develop even more innovative approaches to this rapidly emerging areas of biomedical research, so who knows what “seq” we will be talking about next?
 Slide-seq: A scalable technology for measuring genome-wide expression at high spatial resolution. Rodriques SG, Stickels RR, Goeva A, Martin CA, Murray E, Vanderburg CR, Welch J, Chen LM, Chen F, Macosko EZ. Science. 2019 Mar 29;363(6434):1463-1467.
Single Cell Analysis (NIH)
Macosko Lab (Broad Institute of Harvard and MIT, Cambridge)
Chen Lab (Broad Institute)
NIH Support: National Institute on Aging; Common Fund