Inflammaging: Anti-Aging Research on the Space Station

Adults over age 65 represent almost 40% of all U.S. healthcare spending, and almost 80% of them report having multiple chronic conditions. Yet research into the underlying drivers of age-related disease unfolds alongside aging itself, delaying results for decades.

To expedite study of the pathologies of aging, Cedars-Sinai investigators are leveraging space, capitalizing on the rapid physical degradation observed in astronauts since the earliest days of spaceflight.

{{cta-block}}

A new study launched at the Cedars-Sinai Board of Governors Regenerative Medicine Institute is growing organ models to be flown to the International Space Station. The research, supported by NASA and the National Institutes of Health, focuses on two primary drivers of aging and age-related disease:

• “Inflammaging,” the chronic, systemic low-grade inflammation caused, in part, by increasing immune dysregulation associated with aging and linked to cardiovascular disease, Alzheimer’s disease, cancers, muscle weakness and other age-related conditions
• Senescent or “zombie” cells, which can cause inflammation and tissue damage, spread from organ to organ, and are linked to developing multiple disorders and diseases associated with aging

{{providers}}

For a disease or aging process that takes years to develop on Earth, we can see parallels in the course of days and weeks in astronauts.

“The contribution of inflammaging and senescent cells to aging and age-related disease is becoming a major area of biomedical research,” said Arun Sharma, PhD, director of Cedars-Sinai’s Center for Space Medicine Research. “By taking these organ models to the space station, we hope to improve our understanding of these processes and ultimately to identify drug therapies to combat them.”

Models of Accelerated Aging

Astronauts in low-Earth orbit lose bone density, muscle mass and cognitive health faster than they do on Earth. A recent study estimated that four astronauts aged on average almost two years during a nine-day stay on the International Space Station, though they were found to regain much of their health quite quickly once they returned to Earth.

With more astronauts spending longer periods in space, medicine must advance to protect humans from this rapid-aging problem.

Regenerative Medicine Institute investigators are at the forefront of biomedical research in microgravity—a primary driver of rapid aging in space, along with radiation. On the most recent of six missions to the space station, researchers worked with astronauts to grow cellular models of heart and brain organs in space for the first time.

Currently, using another system called organ-on-a-chip, investigators at the institute are growing heart, brain and gut cell models on Earth. Built with induced pluripotent stem cells (iPSCs), these microfluidic chip systems—about the length of an AA battery—mimic organs’ structure and function in vivo. Cells grown on the chips can receive nutrients and other media as well as discharge metabolic waste, allowing investigators to test their responses to drugs and environmental effects.

Eventually, researchers will introduce immune-system elements, such as monocytes and macrophages, into the organ-on-a-chip systems to investigate how they may accelerate the inflammaging process.

Ultimately, the organs-on-chips will travel to space, where astronauts will measure inflammaging effects against controls on Earth.

“Monocytes respond and become inflammatory when there is an insult to the system or cells become senescent,” said Clive Svendsen, PhD, executive director of the Regenerative Medicine Institute and the Kerry and Simone Vickar Family Foundation Distinguished Chair in Regenerative Medicine at Cedars-Sinai. “So, we are very interested to see how immune responses differ between the organ chips in space and those on Earth.”

The team will also work with James Kirkland, MD, director of the Cedars-Sinai Center for Advanced Gerotherapeutics, to test senolytic treatments against inflammaging in the organ models.

Inflammaging, Cellular Senescence and Senolytics

Short-term inflammation indicates that the body’s immune system is working to fight infection or repair damage. However, inflammaging—chronic inflammation—accelerates aging by damaging cells and tissues over time. Some 35% of American adults are estimated to have chronic inflammation, and according to a study in the journal Nature Medicine, more than half of all deaths can be attributed to inflammation-related diseases.

Senescent cells are cells that have been damaged but do not die. They stop replicating, which is beneficial in the case of cancerous cells, but some of these cells can spread their senescence to surrounding and distant tissues.

“Around 30% to 70% of senescent cells develop what we call a tissue-damaging form of senescence-associated secretory phenotype,” said Kirkland. “They produce factors that get into the blood, attract and activate the immune system, and can spread senescence both locally and systemically through the bloodstream.”

As the number of senescent cells increases with age, so does the body’s immune response, resulting in more inflammation and tissue damage and triggering more cells to become senescent—a self-perpetuating, vicious cycle.

Senolytics help the immune system target and kill senescent cells.

Simulated galactic cosmic radiation induces senescence in human lung fibroblasts and human endothelial cells in culture, Kirkland says. Cosmic and UV radiation is faced not only by astronauts but also pilots and crews on commercial airlines, which have increased rates of basal cell carcinoma and melanoma when compared to the general population.

In 2015, Kirkland and his team reported finding a new class of drugs—which they called senolytics—that slowed the aging process in animal models: improving heart function, reducing frailty and extending healthspan.

“Senolytics help the immune system target and kill senescent cells,” Kirkland said. “Since our first discovery in 2015, we’ve found hundreds of these senolytics.”

In preclinical studies, certain senolytics have been found to eliminate the senescent cells caused by cosmic and UV radiation.

Kirkland is now working with the investigators to identify senolytic drugs to test on the organ chips at the space station.

Implications on Earth

NASA is increasing its human space missions, with plans to send people back to the moon and on to Mars. Private space travel is also a growing industry, with two commercial space stations scheduled to launch in 2027.

“With more astronauts spending longer periods in space, medicine must advance to protect humans from this rapid-aging problem,” said Svendsen.

Regenerative Medicine Institute investigators’ primary focus, however, is to identify treatments against age-related diseases for terrestrials—without having to wait for aging to take place at a terrestrial pace.

“For a disease or aging process that takes years to develop on Earth, we can see parallels in the course of days and weeks in astronauts,” said Sharma. “So, low-Earth orbit is potentially a really useful model system for us to study aging processes.”

Cedars-Sinai, he points out, is uniquely positioned to do this work.

“We already have significant expertise in space research and biology, we are industry leaders in stem cell modeling and organ chip systems, and we have unrivaled expertise in gerontology and the study of cell senescence,” he said. “This study integrates and leverages our strengths in all these areas.”