What the Immune System Does When You’re Not Sick—and Why It Matters for Aging

When most of us think of the immune system, we picture the body’s emergency response, protecting us from invading pathogens and reacting to injuries. While it’s true that the approximately 1.8 trillion immune cells in our bodies serve an important protective role, the immune system does more for us than put out physiological fires. In fact, the innate immune system, the general defense system you’re born with, is active all the time. Even in the absence of infection or injury, it performs quiet, consistent work that is essential for maintaining our overall health.

Innate immune cells play a vital role in helping the body adapt to everyday demands, reinforce barriers, and support responses to challenges like temperature shifts and mechanical stress. For Andres Hidalgo, PhD, professor of immunobiology at Yale School of Medicine, that maintenance view of immunity guides a set of questions he is striving to answer about how innate immune cells preserve tissue function and what happens as those protective roles erode across the lifespan.

This quietly supportive role may be where the immune system has its greatest impact on long-term health and longevity.

Hidalgo compares his view of the immune system to the maintenance workforce of a city: mechanics, sanitation workers, and road crews.

“Imagine a scenario where we got rid of the city’s trash and recycling service,” he says. “At first, nothing dramatic happens—you can still go about your daily life. But over time, trash accumulates, the environment deteriorates, and eventually it creates problems.”

Similarly, he explains, the body is still able to function for a time even in the absence of innate immune cells performing their regular maintenance work. But small inefficiencies begin to emerge.

“The heart contracts, the lungs breathe, but performance begins to slip,” says Hidalgo. That may not seem like a major issue, but just like garbage piling up to the point of overflowing into the street, these small effects accumulate over time.

“You get more tired. Your back hurts. You forget things. You lose hearing and vision,” he says. In other words, rather than causing immediate failure, the gradual loss of immune maintenance support accelerates the kinds of decline typically associated with aging.

Understanding this maintenance role may offer important insight into how we age and how that trajectory might be altered.

The innate immune system includes several different cell types, each with specialized roles. Hidalgo’s lab focuses primarily on two: neutrophils and macrophages.

Neutrophils, the most abundant immune cell, are produced in the bone marrow but move throughout the body, adapting to different environments. They have a lifespan of less than 24 hours, which means the body must continuously produce them, about 100 billion a day for a healthy adult.

For many years, scientists assumed neutrophils were uniform. But advances in imaging technology, as well as in flow cytometry and single-cell transcriptomics, have revealed something more complex. “It was a matter of resolution,” says Hidalgo. What once appeared to be a single cell type we now know to be multiple distinct states. “They’re coming in different flavors. They go to different places, and they do different things.”

More recently, Hidalgo, as part of an international consortium of scientists, generated a transcriptional map called NeuMap, the first comprehensive guide of neutrophil organization across tissues and disease states. Hidalgo’s lab continues to expand and refine this map to better understand how certain diseases impact the function of neutrophils, and to find ways to reprogram those cells to potentially benefit patients.

This insight into the heterogeneity of neutrophils has facilitated other discoveries from Hidalgo’s lab, including the role certain neutrophils play in building and maintaining healthy skin.

Macrophages are less abundant than neutrophils but are equally important in keeping our systems running optimally. They reside within tissues and interact closely with parenchymal cells, which are responsible for essential functions of our organs and include cardiomyocytes in the heart and hepatocytes in the liver. When macrophages are disrupted or depleted in an organ, it’s no longer able to sustain performance over time.

In a 2020 study published in Cell, Hidalgo and others found that cardiomyocytes, which allow the heart to pump in a coordinated, continuous manner, rely on macrophages to clear out mitochondria and other waste material. Depletion of those cardiac macrophages leads to the accumulation of discarded mitochondria, inflammation, organ dysfunction, and emergence of aging-like characteristics.

Taken together, these research findings suggest that aging may reflect not just wear and tear on the body, but the gradual breakdown of immune-supported maintenance.

As researchers build increasingly detailed maps of immune cells, they are also beginning to explore how that information might be applied in a clinical setting.

“Can you start discriminating what’s happening to the individual by looking at neutrophils in the blood?” Hidalgo asks. If so, we may eventually be able to diagnose a host of diseases or even pre-disease states through a simple blood draw. Early research suggests it may be possible to detect patterns associated with different conditions, pointing toward new approaches to diagnose and monitor disease.

Looking even further ahead, Hidalgo is interested in whether bolstering the immune system’s maintenance role could help preserve health. For instance, we know that macrophages become less effective at their cleanup role over time. What if we could introduce new macrophages, essentially sending in a backup crew of fresh workers?

“We’re playing with the idea that if we restore a healthy innate immune system, we can extend healthy lifespan,” Hidalgo says. However, he emphasizes that the goal is not necessarily to live longer, but to maintain optimal function for longer. “Not the absolute lifespan, but the quality.”

The maintenance role of the immune system is not dramatic or immediately visible. But it may be central to how the body sustains itself over time.

Hidalgo is focused on understanding how these processes operate across billions of cells cycling through the body each day.

“Can we use this massive army of cells to improve our quality of health?” he asks. “What these cells do to make us function better, to stay healthier and delay aging, what they do to preserve that state, that’s what we’re interested in.”