Inflammaging is an interior perfect storm where immune system remodeling, cellular aging, or senescence, and loss of control over systemic inflammation trigger chronic overstimulation of the innate immune system. As humans age and the immune system declines, immune responses become overactive and less precise, producing pro-inflammatory cytokines that drive inflammaging and maintain a persistent low-grade inflammation that contributes to age-related diseases and functional decline.

For some humans, this is an acceptable situation, and they’ve got the rocking chairs set up on the porch, ready to fade into their declining years riddled with aches, pains, and chronic system failure. For the rest of us, science is constantly opening new doors that lead to a better understanding of inflammaging, and how to counter or even avoid it.

The Unwanted Guests

Researchers have colorful ways to describe inflammaging and its undesirable effects: a suspiciously overcrowded chat room in the blood, a work cafeteria crowed with retired employees who don’t want to leave, a dinner party where guests won’t take the hint and go home. Inflammatory signals are the aging body’s unwanted hangers on, as pro-inflammatory cytokines like interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) become collect even in otherwise perfectly healthy people. Elevated levels of cytokines like IL-6 levels have become a reliable predictor of disability and even all-cause mortality among the elderly, as the unwanted inflammatory guests in the body cause arteries thicken and harden, allow neurons to lose their finely tuned communication, let joints surrender to osteoarthritis, and stand by while spinal discs decay.

As longevity medicine has expanded, our understanding of the role chronic inflammation plays in aging has shifted considerably. Over the past decade, research has identified chronic as a bellwether of aging in the body: it increases as we age, it accelerates aging and disease in experiments, and reducing it can extend healthspan and even lifespan. By stopping the march of inflammaging, scientists believe that health and mobility can continue longer than previously expected.

Rise of the Zombie Cells

The focus on understanding and preventing inflammaging is an exciting component of longevity science. At UCLA researchers identified a rogue population of immune cells that quietly accumulates in aging tissues and in the livers of people with fatty liver disease. By clearing these cells, the researchers dramatically reduced inflammation and reversed liver damage in mice, even while the animals remained on an unhealthy diet.

The study centers on a process called cellular senescence, a stress response in which cells stop dividing but refuse to die. Aptly named “zombie cells,” these senescent cells linger in tissues, sending a toxic mix of inflammatory signals to the body and causing inflammation and tissue damage that spreads from organ to organ, and playing a role in the development of multiple disorders and diseases associated with aging.

“Senescent cells are fairly rare, but think of them like a broken-down car on the 405,” said Anthony Covarrubias, Ph.D., a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “Just one stalled car can back up traffic for miles. Now imagine five or ten of them slowly accumulating. That’s what these cells do to a tissue: even a small number causes enormous disruption.”

Mitochondrial dysfunction is another inflammaging trigger. Old mitochondria can leak their DNA and spew reactive oxygen species into the cytosol, where NLRP3 picks up the signal and assembles a protein complex that activates caspase-1, an enzyme that processes pro-inflammatory cytokines, specifically IL-1β and IL-18, potent inflammatory agents. NLRP3 can launch sterile inflammation, wherein the body starts an immune response against its own accumulating cells.

NLRP3 overactivation has been linked to atherosclerotic plaques clogging blood vessels, neurodegenerative disease in the brain, and inflammatory wear-and-tear in kidneys and hearts. It sets up a cycle of destruction in the body, producing IL-1β and IL-18 to summon more inflammatory immune cells, and kicking off an inflammatory form of cell death known as caspase-1-driven pyroptosis in the tissues that surround it.

Inflammaging in Space

Can “zombie” cells exist in space? A Cedars-Sinai Board of Governors Regenerative Medicine Institute study, supported by NASA and the National Institutes of Health (NIH), is preparing to investigate the phenomenon of inflammaging on the International Space Station.

Investigators want to understand the rapid appearance of senescent cells and accelerated aging-like changes in astronauts, and they’ll be testing senolytic drugs to see if they slow or reverse these processes.

“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.”

Astronauts in low-Earth orbit are particularly prone to inflammaging, losing bone density, muscle mass, and cognitive health faster than they do on Earth. According to a recent study, four astronauts aged on average almost two years during a nine-day stay on the International Space Station, though they seemed to regain their health quite quickly once they returned to Earth. Scientists are looking into this phenomenon, hoping to find solutions that can be applied to inflammaging on Earth.

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

Fighting Inflammaging

Regardless of where in the universe an aging body finds itself, guarding against inflammaging may be the key to living, if not “to infinity and beyond,” at least to a healthy, productive, and disease-free age. Because it can impair the body’s ability to repair tissues and respond effectively to infections, inflammaging’s role in functional decline and higher mortality in older adults is critical. Understanding its contributing factors and making lifestyle changes to intervene in its progression may be the first step to a healthier lifespan.

Inflammaging Influences:

• Genetics and epigenetic changes
• Lifestyle factors such as diet, physical activity, and stress
• Environmental exposures
• Senescent cells secreting inflammatory molecules that exacerbate systemic inflammation

Prevention and Management:

• Anti-inflammatory diet: Focus on fruits, vegetables, whole grains, fatty fish, nuts, and olive oil; limit processed foods, refined sugars, and high-fat dairy
• Regular exercise: Walking, swimming, or strength training can lower inflammation
• Stress management: Meditation, adequate sleep, and relaxation techniques help modulate inflammatory response
• Avoid smoking and other pro-inflammatory behaviors

Navigating the perfect storm of inflammaging in the human body starts with self-care, and it’s already possible to mitigate its effects and potentially slow the progression of age-related diseases. As researchers learn more about fighting inflammation and halting its progression, healthier aging for all is on the horizon.

Sources:

Inflammaging in Space: Studying Aging on Organ Chips

Chronic Inflammation

UCLA Scientists Identify Zombie Cells as a Driver of 'Inflammaging'

Exoproteome of Calorie-restricted Humans Identifies Complement Deactivation as an Immunometabolic Checkpoint Reducing Inflammaging