Unleashing the Power of Immune Resilience: The Key to Defying Disease and Extending Lifespan

A revolutionary research study introduces the concept of “immune resilience,” which refers to the ability to withstand infections and inflammatory stressors and bounce back from them. Using innovative metrics, the research team measured the varying levels of immune resilience among individuals and discovered that it is not solely dependent on age, but also impacts lifespan and overall health.

In a multinational study, researchers from The University of Texas Health Science Center at San Antonio, in collaboration with partners from five countries, unveiled that the capacity to resist or recover from infections and other inflammatory stressors, known as “immune resilience,” differs greatly among individuals. The team devised a unique set of metrics to quantify the level of immune resilience, providing valuable insights for healthcare decisions and advancing our understanding of the variations in lifespan and health outcomes, even among individuals of similar ages. These findings were published in the peer-reviewed scientific journal Nature Communications on June 13.

The study received support from a MERIT award and other grants from the National Institute of Allergy and Infectious Diseases (NIAID), a part of the National Institutes of Health, as well as awards from the U.S. Veterans Health Administration and a Distinguished Clinical Scientist Award from the Doris Duke Charitable Foundation.

Sunil Ahuja, Muthu Manoharan, and their team described immune resilience as the underlying factor that explains why some individuals possess robust immune systems and experience reduced inflammation, irrespective of their age. The accompanying illustration showcases blue-clad T-cells, while the lower sphere represents COVID-19 with its distinctive red spike proteins.

Challenging the Notion of Age Dependency

Although age does influence how the body responds to infectious and inflammatory stressors, certain individuals maintain or restore optimal immune resilience regardless of their age. Sunil K. Ahuja, MD, a professor specializing in infectious diseases at UT Health Science Center San Antonio and the director of the Veterans Administration (VA) Center for Personalized Medicine, emphasized that immune resilience involves maintaining good immune function (known as immunocompetence) and minimizing inflammation during periods of inflammatory stress.

“We found that during aging and when experiencing inflammatory stress, some individuals can resist the decline of immune resilience,” explained Weijing He, MD, a co-author and senior research scientist at the VA Center for Personalized Medicine and Foundation for Advancing Veterans’ Health Research. This discovery challenges the commonly held belief that immune resilience is solely dictated by age.

Promising Results

The laboratory tests developed to assess levels of immune resilience were conducted on nearly 50,000 individuals across different age groups and with varying challenges to their immune systems. The evaluation revealed that individuals with optimal levels of immune resilience were more likely to:

• Live longer
• Resist HIV and influenza infections
• Withstand AIDS
• Prevent the recurrence of skin cancer after a kidney transplant
• Survive COVID-19 infection
• Survive sepsis

The researchers employed two methods to measure immune resilience:

1. By examining the balance between CD8+ and CD4+ T-cells, two types of white blood cells responsible for fighting infections. Many infectious and autoimmune diseases lead to an imbalance in the levels of these T-cells. The researchers divided the balance between CD8+ and CD4+ T-cells into four distinct categories, known as immune health grades, and measured them across various infection cohorts and age groups.
2. By analyzing the expression levels of genes associated with immunocompetence and higher chances of survival versus those linked with inflammation and an increased risk of death. The gene expression markers indicative of high immunocompetence and low inflammation were identified, and the immune health grade was used to track optimal immune resilience.

While many people tend to focus solely on inflammation when considering disease outcomes, Grace C. Lee, PharmD, PhD, a research investigator at the VA Center for Personalized Medicine and an assistant professor at The University of Texas at Austin College of Pharmacy, emphasized that the concept of immune resilience captures the levels of immunocompetence and inflammation together.

A Leap Forward

This study introduces the groundbreaking concept of immune resilience, which views the balance between immunocompetence and inflammation as a critical determinant of health outcomes, irrespective of age. “By looking beyond inflammation, we may uncover new prevention and treatment strategies for chronic diseases such as cardiovascular disease, COVID-19, HIV/AIDS, and cancers,” noted Lee.

Insights from the Framingham Heart Study

The study team further divided participants from the Framingham Heart Study into four groups based on the gene expression markers of immune resilience. Muthu Saravanan Manoharan, MS, a co-author and senior research scientist at the VA Center for Personalized Medicine and UT Health Science Center San Antonio, highlighted that “participants with optimal immune resilience, defined by gene expression markers signifying high immunocompetence and low inflammation, lived longer after controlling for the effects of age and sex.” On the other hand, participants with markers signifying low immunocompetence and high inflammation had a shorter lifespan, while those with a combination of high immunocompetence and high inflammation, or low immunocompetence and low inflammation, fell somewhere in between.

Insights from Influenza and Other Studies

The research team also examined gene expression markers of immune resilience in a population of healthy college students and community individuals under the age of 50. Blood samples were taken before the influenza season began. On the day they exhibited the first symptoms, most participants, including those with optimal immune resilience before the flu-like illness, showed gene expression profiles indicating low immunocompetence and high inflammation, characteristics often associated with shorter lifespans. Although many individuals managed to restore their initial level of immune resilience during recovery, even some of those with optimal immune resilience prior to the influenza infection failed to do so. Nathan Harper, MS, a co-author and senior biostatistician at the VA Center for Personalized Medicine and Foundation for Advancing Veterans’ Health Research, highlighted the striking finding that “six months after their flu, some people continued to exhibit gene expression signatures of poor immune health,” indicating that inflammatory stressors like influenza can have long-term detrimental effects on vulnerable individuals’ immune health.

Furthermore, the study examined female sex workers in Kenya and observed that their immune health grades declined over time with unprotected sex. “Most of the HIV acquisition occurred in women who had lower immune health grades,” stated Lyle R. McKinnon, PhD, a co-author and associate professor at the University of Manitoba, Canada. However, women who engaged in safer sex practices and had a lower frequency of unprotected sex over a 10-year period managed to restore their optimal immune resilience, suggesting that eliminating immunological stressors could lead to the restoration of a healthier immune status.

The study also highlighted a rare ability to maintain a high level of immunocompetence with low inflammation despite chronic inflammatory stress in one of the cohorts. “Interestingly, we found that some younger adults preserved optimal immune resilience markers despite HIV infection,” added Jason F. Okulicz, MD, a U.S. Air Force infectious disease physician and senior member of the study team. “The preservation of these markers was associated with resistance to developing AIDS and having a low level of HIV in the blood. Notably, after initiating early antiviral therapy, some HIV-positive individuals displayed markers of optimal immune resilience typically observed in younger adults without HIV infection.”

The Impact on COVID-19 and Kidney Transplant Recipients

The association between immune resilience and the response to infection was evident in COVID-19 cases. Around 80% of individuals presented with poor immune health grades upon acute COVID-19 infection, and their immune grade accurately predicted mortality, regardless of age. Justin Meunier, BS, a co-author and research scientist at the VA Center for Personalized Medicine, noted that even among patients with severe community-acquired pneumonia and sepsis, those with higher levels of gene expression markers of immune resilience upon admission to the intensive care unit had a higher likelihood of survival.

Immune resilience was also measured in kidney transplant recipients, a population with a significantly increased risk of developing skin cancer. Each participant had experienced this cancer once after the transplant. Matthew J. Bottomley, MD, DPhil, an academic clinical lecturer at the University of Oxford, revealed the findings: “We explored the risk of developing a second cancer based on the immune health grades at the time each participant had the first cancer. We found that those with optimal immune resilience at the time of the first cancer were less likely to develop a second cancer.”

Additional Insights and Gender Disparities

In collaboration with investigators from Sardinia, the study examined the blood immune cell profiles of nearly 4,000 healthy individuals. Edoardo Fiorillo, PhD, a co-author from the Institute for Genetic and Biomedical Research, National Council of Research, Lanusei, Italy, shared their observations: “Irrespective of age, individuals with poor immune resilience displayed immune cell profiles indicating increased immune activation. Interestingly, nonhuman primates with poor immune resilience exhibited similar immune cell profiles.”

A consistent finding throughout the populations studied was that age alone does not determine an individual’s response to inflammatory stress. Some younger individuals with poor immune resilience exhibited the same signatures and immune health grades commonly observed in older individuals. This suggests that the ability to restore and maintain immunocompetence at younger ages may be linked to longer lifespans. Additionally, the study revealed that higher levels of optimal immune resilience were more frequently observed in females than males. Genetic studies in humans and evaluations of mice with genetic variations associated with lower immune resilience suggest that immune resilience may be influenced by genetic variations. Notably, mice with lower immune resilience were most susceptible to severe Ebola infection.

Understanding the Risks

Assessing immune health grades through the measurement of CD8+ and CD4+ counts provides a simple way to monitor immune resilience, according to Sunil Ahuja. He emphasized that such assessments are valuable in understanding who may be at a greater risk of developing immune system-related diseases, monitoring treatment responses, and predicting the extent and likelihood of recovery.

In conclusion, the research study introduces the groundbreaking concept of immune resilience and demonstrates its impact on health outcomes and lifespan, challenging the conventional notion that age alone determines immune resilience. By unraveling the intricate balance between immunocompetence and inflammation, researchers hope to uncover new strategies for preventing and treating chronic diseases, such as cardiovascular disease, COVID-19, HIV/AIDS, and cancers. The findings provide a foundation for immune checkups that could have significant public health implications, allowing for a better understanding of individual immune resilience and the potential risks associated with it.

Reference: “Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection” published in Nature Communications on June 13, 2023.
DOI: 10.1038/s41467-023-38238-6

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• Nature Communications: “Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection”