The research question addresses the significant variability in human lifespan, health across ages, and susceptibility to infections. The hypothesis is that variations in immune resilience (IR) play a crucial role. Infections have profoundly shaped the human genome; therefore, optimal host responses to microbial challenges likely contributed to evolutionary increases in longevity. The ancestral burden of inflammatory stress from infectious diseases might have driven the evolution of infection-resistance mechanisms, including enhanced immunocompetence and controlled inflammation. In modern times, these mechanisms could offer advantages in reducing comorbidity and promoting longevity. Considering the importance of immunocompetence for maternal and fetal health, the immunologic trait conferring resistance to infections and premature death may have evolved more strongly in females, possibly explaining the observed female advantage in immunocompetence and longevity. This led to the hypothesis that an advantageous immunologic trait promotes longevity, reduces comorbidity burden, and enhances infection resistance. This advantageous trait is proposed to be immunologic resilience (IR), defined as the capacity to maintain or quickly restore immune functions promoting disease resistance (immunocompetence) and inflammation control during immune stimulation (e.g., from infections). Optimal IR is linked to a high immunocompetence (IC)-low inflammation (IF) state (IChigh-IFlow), while failure to preserve or restore IR leads to suboptimal or nonoptimal IR (IClow-IFhigh). The study aims to investigate these IR phenotypes in various models of immune stimulation, analyzing their impact on health outcomes and lifespan, controlling for age and sex.

The paper draws upon existing literature highlighting sex differences in immune responses and lifespan, the impact of infections on the human genome, and the role of immunocompetence in maternal and fetal health. It cites studies on the association between cytomegalovirus (CMV) seropositivity and mortality, and existing research on immune senescence and age-associated diseases. The authors also reference previous work establishing the link between specific immune health grades and resistance to severe COVID-19 and AIDS. Previous work of the authors and others on the association between immune metrics and mortality, as well as various immunity-related traits in aging cohorts, are also referenced.

The study employed a four-phase approach to test the proposed framework. Two peripheral blood metrics were used to measure IR: Immune Health Grades (IHGs) I-IV, reflecting CD8+/CD4+ T-cell proportions, and transcriptomic profiles (survival-associated signature [SAS]-1 and mortality-associated signature [MAS]-1) predicting survival or mortality. Data were collected from diverse human cohorts (n=48,936) representing various levels of antigenic stimulation (low, moderate, and high). These included aging cohorts (e.g., SardiNIA), HIV cohorts, COVID-19 cohorts, cohorts with other infectious diseases like schistosomiasis, and cohorts with autoimmune conditions like SLE. Non-human primate and mouse models were also used to assess evolutionary conservation of IR phenotypes. Study Phase 1 analyzed shifts in IHGs across lifespan and in response to varied antigenic stimulation. Phase 2 investigated the association between the IR erosion-resistant phenotype (IHG-I) and superior immunity-dependent health outcomes (longevity, COVID-19 severity, AIDS progression, cancer risk, HIV acquisition). Phase 3 examined the link between IHGs and SAS-1/MAS-1 profiles to define an IR continuum. Phase 4 explored the immune correlates of IR, comparing traits by IHG status, age, and both, in humans and non-human primates. Statistical analyses included logistic regression, Kaplan-Meier plots, Cox proportional hazards models, and other appropriate methods. Gene expression data was analyzed using RNA-seq and various bioinformatic tools. The study also included a meta-analysis of gene expression datasets from public repositories.

Several key findings emerged: 1. **IHG-I and SAS-1high-MAS-1low profile indicate optimal IR:** IHG-I (CD8-CD4 equilibrium) and the SAS-1high-MAS-1low profile (high immunocompetence, low inflammation) were indicators of optimal IR and were more prevalent in females. These metrics correlated with better health outcomes and longevity. 2. **Antigenic stimulation degrades IR:** Increased antigenic stimulation, regardless of age, shifted IHGs from IHG-I towards non-IHG-I grades (IHG-II, III, IV), indicating IR erosion. This was proportionate to the level of stimulation, indicating that more stimulus resulted in a more prominent shift toward the degraded phenotype. 3. **IR degradation is potentially reversible:** Mitigation of antigenic stimulation (e.g., through ART in HIV, recovery from COVID-19, intervention in FSWs) was associated with IHG-I reconstitution, suggesting that at least some degradation is potentially reversible. 4. **IR erosion-resistant phenotype associated with superior outcomes:** Preservation of IHG-I (IR erosion-resistant phenotype) correlated with superior immunity-dependent health outcomes across various conditions: reduced COVID-19 severity, slower AIDS progression, lower HIV acquisition risk, reduced risk of recurrent skin cancer, improved survival during sepsis, and increased longevity. 5. **IHG repertoire defines an IR continuum:** A full IHG repertoire, including subgrades, was defined, creating a three-tier IR continuum: optimal (IHG-I, SAS-1high-MAS-1low), suboptimal (IHG-IIa), and nonoptimal (other IHGs, SAS-1low-MAS-1high). The nonoptimal tier was linked to worse health outcomes. 6. **Immune correlates of IR:** Specific immune traits were associated with IR status irrespective of age, uniquely with age, and with both age and IR status. CD8-CD4 disequilibrium grades (IHG-III, IV) were linked to immune dysfunction features in both humans and non-human primates, independent of age.

The findings strongly support the hypothesis that immune resilience (IR) is a crucial factor influencing lifespan and health outcomes. The identification of two distinct metrics (IHGs and gene expression profiles) provides a practical framework for assessing IR across the lifespan, independent of age. The observed sex bias (females showing a greater tendency toward optimal IR) highlights the importance of considering sex as a biological variable in immune research. The reversibility of IR degradation suggests that interventions targeting inflammatory stressors may improve immune health. The evolutionary conservation of IR phenotypes underscores the fundamental importance of this trait for survival. This research bridges the gap between basic immunological mechanisms and clinical outcomes, providing new avenues for personalized medicine and public health interventions.

This study provides a novel framework for understanding immune health, defining immunologic resilience (IR) as a critical factor influencing longevity and disease susceptibility. The development of easily implementable IR metrics opens avenues for personalized medicine, improving vaccine responsiveness, and informing public health policies. Future research should focus on further investigation of the genetic and environmental factors contributing to IR, identification of targeted interventions to improve IR, and exploration of IR’s role in various diseases beyond those studied here.

The study's limitations include the use of multiple cohorts to analyze various clinical outcomes, the inability to directly assess immune traits in the same individuals at different ages, and the inability to establish definitive cause-effect relationships. The authors acknowledge that other factors beyond inflammatory stressors could also influence IR metrics. Despite these limitations, the authors argue that their findings support causal inference based on the Bradford-Hill criteria.