They say you’re only as old as you feel, but in reality, you’re only as old as your immune cells. Even though the calendar reminds us that we’re another year older, not all people’s immune systems age at the same rate. Aging is associated with a decline in immune response, leaving a person more susceptible to disease.
However, immune system dysfunction isn’t just an issue for older adults. It’s also something that affects people with chronic illnesses, such as cytomegalovirus (CMV). Like its relative, herpes zoster (the virus that causes chickenpox), CMV is incredibly common. However, unlike the chickenpox virus, most people don’t realize they have CMV because their immune system keeps it in check. According to the Centers for Disease Control and Prevention, one in every three children has come in contact with CMV by age five, and more than half the adult population has been infected with it at some point in their lives. The virus, like its relatives, never goes away but stays dormant in the body, waiting to reactivate, and most people who are infected never know it because they don’t have symptoms.
That’s due to a healthy immune system, which is the first line of defense against invaders like bacteria and viruses. This protective system is made up of an army of cells that stop potential sickness in its tracks through a nifty trick called immunological memory. Your immune system remembers diseases and pathogens it battled in the past and helps fight subsequent infections through antibodies, which are generated by a type of white blood cell called lymphocytes. These cells come in two varieties, each with its own task: B-cells, which make antibodies that your body uses to fight off disease, and T-cells that target and kill infected cells. Like generals in an army, T-cells help lead the immune system’s fight against disease. But for people with a latent viral infection like CMV, the army is always in attack mode.
“When we have a viral infection where the virus stays in the body for a long period of time, the immune system is constantly activated,” said Sonja Schrepfer, a professor of surgery from the University of California, San Francisco. “This eventually exhausts the immune system, leading to what we call an ‘aged immune system.’” Age-related immune system decline, known as immunosenescence, is often the driving force behind the increased risk of severe outcomes from diseases like COVID-19. It also makes it harder for the body to heal wounds.
To better understand the relationship between immune aging and how the body heals itself, a team of researchers led by Schrepfer leveraged the International Space Station (ISS) National Laboratory to study the human immune system in microgravity. Using tissue chips, which are small devices engineered to model the function of human tissue, the team studied how key immune cells behave in microgravity and how that behavior affects immune cell aging.
“By sending immune cells into space, we were able to simulate the aging process of the immune system and better understand how it affects our body’s ability to repair itself as we grow older,” Schrepfer said. “We were able to use space conditions to imitate real health problems on Earth, and without a research platform like the ISS, our understanding of the human body, especially in the area of the immune system, would be limited.”
Turning to Space to Understand Immune Aging
Schrepfer became interested in the immune system during her extensive career as a surgeon specializing in organ transplants. “If a patient has an aged immune system, that can have a negative impact on the overall outcome of many different surgeries and procedures,” she said. “For instance, if you have an aged immune system in patients with bone fractures, they would heal more slowly or incompletely.”
This is what led Schrepfer to begin studying the immune system. But the idea to take her studies to space was inspired by another researcher at UCSF. Millie Hughes-Fulford was a molecular biologist at UCSF and the first female scientist to fly to space as a NASA payload specialist. In 1991, onboard the Space Shuttle Columbia, she carried out the first mission fully devoted to life sciences. Over the course of the nine-day mission, she worked on more than 18 experiments that provided a treasure trove of medical data.
Hughes-Fulford returned to Earth with a new passion for studying what happens to the human body in space, particularly how microgravity affects the immune system. Following her flight, she returned to UCSF, where she opened her research laboratory focused on studying immunosuppression in space.
Over the next two decades, Hughes-Fulford carried out multiple spaceflight experiments. In 2011, she conducted her first ISS National Lab-sponsored investigation and launched a second in 2015. These experiments focused on T-cell function and compared the natural reduction in immune function that occurs over time in the elderly with the immune suppression in astronauts during spaceflight. Her research revealed that microgravity inhibits the activation of T-cells, which was an important clue to understanding immune system dysfunction in healthy astronauts. These findings piqued Schrepfer’s interest, and she decided to send her own immune function experiments to the orbiting laboratory.
Sending Tissue Chips to Space
Research has shown that the same types of immune changes in patients with aged immune systems on Earth are seen in healthy astronauts during spaceflight, only on a much faster time scale. This makes the conditions on the space station ideal for developing an accelerated model of immune aging.
Schrepfer and her team took advantage of this unique research platform to conduct a space-based tissue chip investigation funded by the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS). BioServe Technologies, a Colorado-based organization that focuses on supporting space life science research, provided the tissue chip hardware and support for the project.
By using tissue chips, Schrepfer and her team could study immune system aging in a model that mimics human tissue function much better than rodent models. “You can compare human and rodent data on a really high level, but you can’t go into more detail because the two immune systems are so different,” Schrepfer said. “The tissue chips really give us better, more accurate data.”
For the investigation, the team used tissue chips to grow three-dimensional cultures of three types of cells. These included mesenchymal stromal cells (MSCs), multipotent stem cells found in bone marrow that help make and repair a variety of skeletal tissues; endothelial progenitor cells (EPCs), stem cells that develop into vascular cells; and the immune system’s T-cells. The cells used in this investigation came from three donors—one with a healthy immune system and two with aged immune systems.
With this tissue chip model, the team was able to examine how well the immune cells in space worked to trigger stem cells to multiply and migrate for tissue repair. However, the use of the three cell types made the investigation complex. That’s because MSCs and EPCs are adherent cells, meaning they stick to surfaces like blood vessels in the body, while immune cells are floating cells. To accommodate both adherent and floating cells, the team needed specific tissue chip hardware, and BioServe was able to provide it.
“As an organization, we help researchers choose the hardware that is best suited for their experiments,” said Stefanie Countryman, director of BioServe. “For this investigation, we needed to make sure the astronauts doing the experiment could change the media without sucking out all the immune cells floating in it.”
Schrepfer said the tissue chip design was critical to the investigation because it allowed the cells to be fed and sustained for long-duration culture in space. The design also enabled the return of live tissue samples to Earth for further culture, providing the opportunity to observe immune cell function in space and the cells’ process of reacclimating to gravity back on the ground. This allowed the research team not only to study the process of immune aging in space but also to investigate whether there may be a way to reverse it.
Under a Doctor’s Care
The investigation had two parts. The first, which launched on SpaceX’s 16th Commercial Resupply Services (CRS) mission, aimed to understand how long it takes immune cells to age in space by studying them over the course of two weeks. And the second, which flew on SpaceX CRS-25, sought to determine whether the aging process could be reversed once the cells were back on the ground.
For Schrepfer’s second spaceflight experiment, the tissue chips remained on station for about a month, where they were cared for by NASA astronaut Kjell Lindgren, who is also a medical doctor. Lindgren and other crew members would feed the cells in the tissue chips by changing the nutrient media and would photograph the chips so the research team could track how the experiment was progressing.
Years before becoming an astronaut, Lindgren attended Colorado State University, where he studied the effects of weightlessness on the cardiovascular system. His interest in spaceflight and how it impacts the human body motivated him to pursue a career not just in medicine but, more specifically, in aerospace medicine. So, when Lindgren learned that he would get to work on Schrepfer’s immune cell aging experiment while in space, he was thrilled.
“We’ve seen evidence of decreased wound healing in space, which means the immune system is not functioning like it should be,” Lindgren said. “The research that we do on station correlates to disease processes in the human body on Earth, and to be able to work on an experiment that has a direct benefit for people on Earth is really exciting.”
Understanding Spaceflight-Induced Changes
Results from the team’s first spaceflight experiment confirmed that microgravity induces a decline in immune function similar to that caused by the aging process on Earth but on a much quicker time scale. “In microgravity, we learned that we could imitate the aging of immune cells, and our data from the first flight showed that it happens as fast as within three days,” Schrepfer said.
During that initial spaceflight, the team also learned that stem cells thrive in space, but once they come in contact with immune cells, that all changes. “The immune cells have a drastic effect on stem cells,” Schrepfer said. “They are not like normal stem cells we see on Earth; they’re not even functional at all.”
To probe deeper into this finding, the team designed the second spaceflight experiment to better understand what happens to stem cells in space. Results revealed that microgravity significantly increases the growth of TEMRA cells, which are terminally differentiated T-cells that help eliminate infected cells. TEMRA cells produce proteins called cytokines that kickstart the immune system and help the body regulate inflammation.
When the immune system functions normally, cytokines trigger an inflammatory response that helps fight disease and repair tissue. But in microgravity, the team observed increased growth of TEMRA cells resulting in an excessive number of cytokines. And Schrepfer’s team observed that this excessive cytokine activity has a negative impact on stem cell function, which can, in turn, hinder the body’s ability to heal wounds and get rid of invaders like viruses.
Schrepfer and her team also found that immune dysfunction in the spaceflight cells remained once the cells were back on Earth, which unfortunately meant they could not identify a way to reverse immune aging. However, results provided new insights into the mechanisms behind immune system function, which could lead to the discovery of novel targets to develop therapeutics to treat immune aging.
“We’re currently looking for ways to eliminate senescent immune cells, much like the way we use immune cells as cancer therapy—we want to teach the immune cells to look at senescent cells like they would look at tumors and help eliminate them,” Schrepfer said. “Then, we could replace the exhausted immune cells with healthy ones, restoring immune function in patients.”
Such a therapy would allow the body to better fight off disease. It could also help patients respond better to vaccines and help prevent the resurgence of latent viruses, all of which are controlled by the immune system. Although nothing can prevent aging, these types of therapies could help improve the quality of life for an ever-growing elderly population and patients with immune system dysfunction.
“Unfortunately, we learned that we cannot reverse immune cell aging, but we may be able to treat it,” Schrepfer said. “That’s something we are looking into and are excited to explore more.”