Blog: Study points to a key feature of health and wellness at any age: immune resilience

Sunil Ahuja, Muthu Manoharan et al. describe immune resilience, a collection of traits that promote longevity and reduce severity of viral infections. The blue-clad spheres are T-cells. The lower sphere is COVID-19 featuring red spike proteins. Illustration courtesy the research team.

Contributed by the research team that led this study.

Have you ever boasted about having a strong immune system? Or, alternatively, wondered why you seem to get extra sick extra often? Common sense suggests that people respond differently to sickness and stress. But so far, there has not been an easy way to verify this hunch or to consistently measure what may be a core, underlying aspect of health.

This week, National Institutes of Health-supported researchers proposed a new framework for understanding what they call immune resilience: the capacity of some people to avoid illness and/or bounce back more quickly when they do get sick with viral infections or other inflammatory stressors. They found that people who maintain good immune resilience even in the face of immune system stressors tend to live longer and to stay healthier.

Additional reading on this research:

Importantly, the researchers also developed accessible tools for measuring immune resilience in both healthcare settings and clinical research. Now, instead of turning to an online quiz to try to discover your “real age,” you may be able to gauge the strength of your immune system by taking a simple lab test.

Those tests could help doctors factor in immune resilience before surgeries or during checkups to predict patient risks and outcomes. Another measurement is based on the expression of certain genes. These tests could help researchers control for immune resilience in clinical trials, uncover connections between immune resilience and aging, and learn more about how and why immune resilience is eroded in some persons but not others facing the same inflammatory stressor.

Findings from 48,500 people

The paper, published June 13 in the journal Nature Communications, combines findings from around 48,500 people in different studies conducted in Africa, Europe and North America. The research involved a global team led by Sunil Ahuja, MD, a professor of medicine at The University of Texas Health Science Center at San Antonio and director of the Veterans Administration Center for Personalized Medicine.

The research team found that, as in other facets of life, resilience at an immune level is related to both what you are up against and how you respond. According to the researchers, low levels of inflammatory stress combined with highly competent immune responses were most protective for health. Still, some people managed to maintain high immune function even in the face of lots of inflammatory stress, a finding that raises new opportunities for research into longevity and health.

Like people’s emotional responses, immune systems can essentially overreact, under-react or respond gracefully when they sense an attack. The ability to respond effectively is called immunocompetence, which the researchers assessed by two different metrics.

The first metric involves measuring the proportional mix of two different types of T-cells, which are the white blood cells that activate when the body responds to threats. These two types, CD8+ and CD4+, are already frequently measured for patients with HIV and AIDS. Researchers identified a specific mix that predicted the best immunocompetence. They created an immune health grade (IHG) to capture how well people align with this mix on a scale of one to four, with IHG-I being the most protective and IHG-IV being the least. A simple lab test can measure that mix for individuals.

In clinical studies, though, researchers can’t always order T-cell labs. So, the authors found a different metric researchers can look at instead, using a person’s RNA samples to look at clusters of genes. Some of our genes change their expression in response to infections or other inflammatory stressors. The researchers found one pattern of gene expression that was associated with survival, which they called survival-associated signature or SAS-1. SAS-1 comprised genes related to immune competence and higher expression of these genes correlated with survival.

They also found another cluster of genes and gene expression associated with lower resilience and premature death. That mortality-associated cluster they termed MAS-1.  MAS-1 comprised genes related to inflammation and higher expression of these genes correlated with mortality. When the body kicks into gear — whether in response to the flu or simply to allergy season — that response is known as inflammation.

The researchers found that, like the T-cell metric, these patterns of gene expression can be used as a proxy for overall immune resilience. A mix of high SAS-1 gene expression and low MAS-1 gene expression, which the researchers labeled optimal immune resilience, correlated with general longevity, as well as a wide variety of specific positive health outcomes, like survival from sepsis and COVID-19, resistance to acquiring HIV infection, a slower rate of progression to AIDS, avoiding recurring cancer after a kidney transplant, and avoiding flu symptoms.

Levels of immune stressors

To tease apart the roles of immunocompetence and inflammation in immune resilience, the researchers looked at people likely to face high, medium and low levels of immune stressors in their daily lives. For low levels, they looked at thousands of people participating in studies on aging. For medium levels, they looked at people with autoimmune disorders, kidney transplants or COVID-19 infections, along with sex workers exposed to sexually transmitted infections. For high levels of immune system activation, they looked at people living with HIV, who experience consistent inflammatory stress because their immune systems misread lots of things as threats.

The researchers found that immune resilience can change during inflammatory stress. In T-cell readings before and after flu season or COVID-19, as well as after volunteer challenges with common respiratory viruses, the researchers found that immune resilience goes down while the immune system is actively inflamed and fighting a threat. For most people, once the threat had passed, the metrics of immune resilience returned to levels that preceded the threat. But for other people, metrics dropped and stayed lower for months.

The researchers found that periods of inflammatory stress can degrade immunocompetence, making our bodies less effective at responding to future risks. In other words, what doesn’t kill you may make you weaker, not stronger. But that’s not true for everyone: the researchers found that a subset of people maintained consistently good immunocompetence over their lifetimes, despite repeated threats. That finding may open new avenues for research into longevity.

Researchers couldn’t predict beforehand whose immune function would degrade or remain steady after each threat. But they did find that more competent immune systems were associated with lower mortality. COVID-19 patients, for example, were less likely to die if they presented with metrics of optimal immune resilience.

In good news for people with lower immune resilience, the researchers also found that immunocompetence may improve over time.

A break from inflammatory stress can be beneficial

For degraded immune systems, it appears that just getting a break from inflammatory stress may help immunocompetence rebound. One group of sex workers, for example, had frequent unprotected sex at the beginning of the 10-year study — meaning lots of sexually transmitted infections for their immune systems to fight off. But over the next decade, they shifted to using safer sex practices. Researchers found that when their immune systems had fewer infections to fight, their immunocompetence was able to bounce back. It is possible that reducing inflammatory stress in other contexts could also help to strengthen immune resilience over time, reducing the risk of poor health outcomes.

Looking at people from ages 9 to 103, the researchers found a mix of immune resilience levels across each age bracket. While levels of immune resilience declined with age, some younger persons had lower immune resilience levels, whereas some older persons preserved metrics of optimal immune resilience. Often, age has been used as a proxy for immune status. For example, in response to the COVID-19 pandemic, older people were advised to be more cautious. However, within each age bracket, people differ in their susceptibility to severe COVID-19 outcomes; conceivably, these differences may relate to susceptibility to preserve versus degrade immune resilience during COVID-19.

The researchers also found that women tended to have higher immune resilience than men — but at an individual level, it’s impossible to guess immune resilience just by looking at gender. Screening for immune resilience as well as factors like age and gender could allow for more individualized and accurate advice about risks.

The researchers also hope that learning more about how immune resilience works can have a wide variety of benefits for people and for society. On an individual level, screening for immune resilience may help people better understand their health risks and make choices accordingly. It may also help doctors monitor treatment responses to severe viral infections or other illnesses that erode immune resilience. From a research perspective, balancing clinical trials by immune resilience levels, as well as by factors like age, gender, race, and ethnicity, may help clarify how different people will respond to vaccines or other drugs.

Finally, from a public health perspective, understanding the importance of reducing inflammatory stress may lead to new strategies for addressing health disparities on a broader scale, so that more people have the opportunity to recover optimal immune resilience and lead longer, healthier lives.


Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Ahuja SK, Manoharan MS, Lee GC, McKinnon LR, Meunier JA, Steri M, Harper N, Fiorillo E, Smith AM, Restrepo MI, Branum AP, Bottomley MJ, Orrù V, Jimenez F, Carrillo A, Pandranki L, Winter CA, Winter LA, Gaitan AA, Moreira AG, Walter EA, Silvestri G, King CL, Zheng YT, Zheng HY, Kimani J, Blake Ball T, Plummer FA, Fowke KR, Harden PN, Wood KJ, Ferris MT, Lund JM, Heise MT, Garrett N, Canady KR, Abdool Karim SS, Little SJ, Gianella S, Smith DM, Letendre S, Richman DD, Cucca F, Trinh H, Sanchez-Reilly S, Hecht JM, Cadena Zuluaga JA, Anzueto A, Pugh JA; South Texas Veterans Health Care System COVID-19 team; Agan BK, Root-Bernstein R, Clark RA, Okulicz JF, He W. Nat Commun. 2023 Jun 13;14(1):3286. doi: 10.1038/s41467-023-38238-6. PMID: 37311745.



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