Mapping molecular markers of physical fitness

“Patterns of molecular activity in the blood may hold clues not only to how fit someone is, but also to the biological processes that support physical performance. Researchers at MIT, GE HealthCare, and the U.S. Military Academy at West Point have developed a computational model that links thousands of these molecular signals to fitness levels, revealing pathways that could inform future studies to improve fitness training and speed injury or disease recovery. To develop their model, the researchers analyzed more than 50,000 biomarkers in 86 cadets at the U.S. Military Academy who were training for a military competition. Using these data, the researchers were able to identify molecular pathways that appear to contribute to higher levels of physical fitness. “We had 50,000 measurements, and we wanted to get it down to about 100 where there’s some likelihood that the markers that we’re measuring are mechanistically linked to physical fitness. So, not just a statistical correlation, of which there will be many, but markers where there’s a likelihood that there is a causal relationship,” says Ernest Fraenkel, the Grover M. Hermann Professor in Health Sciences and Technology in MIT’s Department of Biological Engineering. These biomarkers can be measured by analyzing blood samples, which could offer a simple way to provide an athlete, for example, or perhaps someone with chronic illness or a long-term injury, with additional information about potential areas to focus their efforts to reduce risk of injury, accelerate recovery, or improve their performance ceiling beyond what conventional measures show. Azar Alizadeh, a principal scientist with GE HealthCare’s Healthcare Technology and Innovation Center, is the paper’s lead author. Fraenkel and Luca Marinelli, a senior principal scientist with GE HealthCare, are the senior authors of the new study, which appears in the journal Communications Biology . Mapping fitness To find the genetic basis of a simple trait such as height, scientists can perform large-scale studies known as genome-wide association studies (GWAS), in which genetic markers from thousands of people can be linked with height. However, the picture becomes much more complicated for traits such as physical fitness, which is determined by the interplay of many different genetic, physiological, and environmental factors. The researchers set out to try to identify some of those factors, working with a group of 86 volunteers at the U.S. Military Academy at West Point who were training for the Sandhurst Military Skills Competition. Alizadeh led the experimental study design and execution, in collaboration with GE HealthCare, GE Research, West Point, and MIT scientists. During the three-month study period, volunteers participated in up to five sessions. At each session, blood samples were taken before and after intense exercise. The researchers also measured other traits such as lean muscle mass and VO 2 max (the maximum rate of oxygen consumption during exercise). From the blood samples, the researchers were able to measure more than 50,000 biomarkers, which they obtained by analyzing DNA methylation patterns, sequencing messenger RNA transcripts, and analyzing thousands of the proteins and small molecules found in the samples. From their set of 50,000 biomarkers, the researchers hoped to identify a smaller number that could predict overall physical fitness, as measured by performance on the Army Combat Fitness Test (ACFT). This test includes a 2-mile run, maximum deadlift (the heaviest weight a person can lift for a single repetition up to 340 pounds), and sprint-drag-carry, a test that involves sprinting, dragging a sled, and carrying kettlebells. One way to do this would be to simply train a computational model to identify correlations between fitness and biomarkers. However, with only 86 subjects in the study, that approach would likely yield correlations that were random and did not actually contribute to physical fitness, Fraenkel says. To take a more targeted approach, the researchers first created a network model that represents the interactions between the markers, based on existing databases that catalog those interactions. These connections might represent proteins that interact with each other in a signaling pathway, or a transcription factor that turns on a set of genes. “We built a network that you can think of as a city map. You want to find the places in the city map that are lighting up — not just one light going on, but a whole bunch of houses or street lamps going on in the same neighborhood,” Fraenkel says. “We can find neighborhoods on this enormous molecular map that are active at the same time, in a way that correlates with the phenotype that we measure.” “We built upon the network bioinformatics from the Fraenkel lab to create an end-to-end predictive modeling framework to discover biological expression circuits that drive groups of physical characteristics predictive of ACFT scores, for example, body composition or exercise physiology metrics like VO 2 max,” Marinelli says. After feeding the measurements from the study participants into this predictive model, known as PhenoMol, the researchers were able to identify more than 100 biomarkers linked to performance on the ACFT. Fitness predictions based on these biomarkers were much more accurate than those of a model that correlated biomarkers with performance on the ACFT without taking network connections into account. Additionally, PhenoMol performed similarly to a model that predicted participants’ fitness based on measurements of their VO 2 and lean muscle mass. Cellular pathways The researchers found that the biomarkers identified by PhenoMol clustered into several different cellular pathways. Those include pathways involved in blood coagulation and the complement cascade — a part of the immune system involved in clearing damaged cells. Those systems likely help with recovery from tissue injury and stress response during exercise, Fraenkel says. Another prominent cluster involves molecules related to the urea cycle, which is responsible for eliminating the ammonia that results from the breakdown of proteins. The model also identified biomarkers that are linked with the function of mitochondria (the organelles that generate energy within cells). Fraenkel now hopes to dig deeper into which markers show someone’s current fitness, and which might reveal what their potential fitness levels could be. This could help to reveal potential strengths that might not show up in traditional fitness tests, he says. That kind of prediction could be useful not only for athletic training, but also for other people who are recovering from an injury or disease, or people experiencing the effects of aging. For example, using this approach in different populations might provide useful information for an elderly person after a stroke, since such events often require months of therapy to regain significant mobility. “This has relevance for the military and for sports teams, but also in a lot of normal life situations where maybe someone is going through rehabilitation for some injury or disease and they’ve hit a wall,” Fraenkel says. “Or during aging, you may be able to see when somebody’s losing capacity or when they have more capacity than they’ve been able to actualize.” Molecular markers of fitness could also be used in clinical trials to rigorously test the potential benefits of popular food supplements and fitness programs, he adds. To make the testing process simpler, the researchers would like to narrow down their pool of biomarkers to a handful that could be easily measured from a blood sample using a single method suitable for widespread use. The research was developed with funding from the Defense Advanced Research Projects Agency (DARPA), which states that the views, opinions, or findings expressed are those of the authors and should not be interpreted as representing the official views or policies of the U.S. government.

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