Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection

The study addresses why individuals differ widely in lifespan, health across age, and susceptibility to infectious diseases. The authors hypothesize an immunologic trait—immunologic resilience (IR)—underlies these differences. IR is defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) while controlling inflammation during acute, repetitive, or chronic antigenic (inflammatory) stress. Optimal IR corresponds to a high immunocompetence and low inflammation state (IC high–IF low), and suboptimal/nonoptimal IR reflects failure of immune allostasis (adaptation) resulting in IC low–IF high. The study proposes that individuals exhibit IR erosion-resistant or erosion-susceptible phenotypes, independent of chronological age, potentially explaining why some younger people display impaired immune states and some older people maintain favorable immune states. The work further posits sex differences, with optimal IR more common in females, contributing to observed advantages in immunocompetence and longevity.

Prior work links infections as strong drivers of human evolution and immune trait selection. Sex differences in immunity and longevity are well documented. The authors previously developed two IR metrics: Immune Health Grades (IHGs) based on CD4:CD8 ratio and CD4 counts, and transcriptomic signatures associated with COVID-19 outcomes. They identified a survival-associated signature (SAS-1) enriched for immunocompetence-related genes (e.g., CCR7, IL7R) and a mortality-associated signature (MAS-1) enriched for inflammation-related genes (e.g., C5AR1, MYD88). The IMM-AGE signature from prior literature correlates with immune aging and survival. Cytomegalovirus (CMV) seropositivity has been associated with mortality and age-related diseases, and inverted CD4:CD8 ratios correlate with adverse outcomes in various conditions. Literature surveys also indicate that CD8–CD4 disequilibrium (low CD4:CD8) is associated with poorer vaccine responses, increased cancer risk/progression, and worse survival in aging populations.

Design: A multi-phase, multi-cohort analysis across 48,936 human subjects/samples, 279 nonhuman primates, and 378 mice to evaluate IR metrics under low, moderate, and high antigenic stimulation. Four study phases: (1) characterize erosion/reconstitution of optimal IR (IHG-I) across contexts; (2) link IR phenotypes to immunity-dependent outcomes; (3) connect IHG repertoire to transcriptomic SAS-1/MAS-1 profiles and survival; (4) identify immune correlates of IR independent of age. IR metrics: (1) Immune Health Grades (IHGs I–IV) derived by co-indexing CD4:CD8 ratio (cutoff 1.0) and CD4+ T-cell count (cutoff 800 cells/mm³). Subgrades IIa/IIb/IIc and IVa/IVb/IVc use CD4 thresholds ≥500<800, ≥200<500, and ≤200 cells/mm³. Equilibrium (IHG-I/II) tracks restrained CD8+ expansion; disequilibrium (IHG-III/IV) tracks unrestrained CD8+ expansion. (2) Transcriptomic signatures: SAS-1 (immunocompetence proxy) and MAS-1 (inflammation proxy) identified from peripheral blood RNA profiles predicting COVID-19 outcomes and survival in the Framingham Heart Study (FHS). Cohort-specific z-scores were dichotomized (high/low) and combined into four SAS-1/MAS-1 profiles representing IC/IF states. Cohorts and proxies of antigenic stimulation: Aging cohorts (SardiNIA, FHS Offspring, San Antonio Family Heart Study, Finnish DILGOM, Vitality 90+), acute COVID-19 cohort (VA South Texas), renal transplant recipients (RTRs), systemic lupus erythematosus (SLE), HIV cohorts (primary infection cohort [PIC], early infection cohort [EIC]), female sex workers (FSWs) with behavioral activity score (BAS) and STI indices as exposure proxies, Kenyan children with schistosomiasis (urinary egg counts), and literature survey for IHG distribution. Non-human primates (sooty mangabeys SIV−/+; Chinese rhesus macaques) and Collaborative Cross recombinant inbred intercross (CC-RIX) mice provided evolutionary and genetic context. Endpoints: Distribution and shifts of IHGs with antigenic stimulation; reconstitution of IHG-I upon mitigation (e.g., ART in HIV, reduced BAS in FSWs, convalescence in COVID-19); associations of IHG and SAS-1/MAS-1 with outcomes: COVID-19 hospitalization and 30–90-day mortality; AIDS progression; HIV acquisition; recurrent cutaneous squamous cell carcinoma (CSCC) in RTRs; sepsis survival; viral ARI severity and symptomatology; lifespan in FHS. Immunophenotyping: Fresh whole-blood flow cytometry panels (T-B-NK, Treg, maturation, dendritic cell panels) measured 75 immune traits in SardiNIA. Additional functional assays in HIV cohorts assessed IL-7 responsiveness (%CD3+pSTAT5+), T-cell exhaustion (%PD-1+ CD4+), and plasma IL-6. Transcriptomics: RNA-Seq or microarray datasets from primary and public sources; normalization with DESeq or platform-appropriate methods; generation of z-scored SAS-1, MAS-1, and IMM-AGE signatures; meta-analyses when applicable. Statistics: Logistic regression (odds ratios) for HIV seroconversion; Cox proportional hazards for survival (adjusted for age/sex); Kaplan–Meier for time-to-event (AIDS, CSCC); χ²/Fisher’s exact tests for proportions; ANOVA/linear models and GEE for repeated measures; correlations (Pearson/Spearman); multiple testing control with FDR where specified. Age and sex included as covariates; CMV serostatus considered in stratified analyses. Study design and confounding mitigation detailed in Supplementary Notes.

- IR metrics and prevalence across age/sex: - In SardiNIA (n=3896; HIV−), IHG-I predominated in younger adults, with age-associated decline in %IHG-I and reciprocal increases in IHG-II and IHG-III/IV; females were more likely to preserve IHG-I across age (greater odds of IHG-I vs. non-IHG-I than males). - IHG-I designated as a primordial state and indicator of IR erosion-resistant phenotype; non-IHG-I grades indicate erosion-susceptible phenotype. - Acute COVID-19 (n=541): - Baseline acute infection showed reduced %IHG-I and increased %IHG-II/IV vs. convalescence; IHG distributions reconstituted during convalescence to age-appropriate levels. - CMV+ status biased toward IHG-IV/III at presentation, especially in older patients; %IHG-IV decreased at convalescence in older CMV+. - Preservation of IHG-I associated with nonhospitalization, milder WHO severity, and survival. Adjusted analyses: presenting with IHG-II/IV (Groups B/C) vs. IHG-I (Group A) predicted higher odds of hospitalization and higher 30-day mortality hazard, independent of age; CMV serostatus did not independently predict hospitalization/death. - Chronic/repetitive antigenic stimulation: - RTRs (n=114) and SLE (n=157) had lower %IHG-I and higher %IHG-II/IV vs. age-matched controls. - HIV PIC (n=685): Higher HIV viral load (VL) associated with lower %IHG-I and higher %IHG-IV. ART suppression led to progressive reconstitution of IHG-I (46% at year 4 despite ~80% IHG-IV pre-ART). A small subset preserved IHG-I at high VL levels. - HIV EIC (n=4883): Among therapy-naïve individuals who presented with IHG-I, preservation declined over 5 years but ~20% maintained IHG-I at year 5; IHG-I at baseline predicted slower progression to AIDS; HIV-VL gradient at baseline: IHG-IV > III > II > I. - FSWs (n=1050; HIV− at baseline): Higher BAS/STI scores associated with lower %IHG-I and higher %IHG-III/IV; among 449 with ≥2 HIV− tests, IHG-IV independently predicted ~3-fold increased risk of future HIV seroconversion (adjusted OR 2.97; 95% CI 1.05–8.38) controlling for age, BAS, and STI scores. Risk mitigation (lower BAS) associated with reconstitution of IHG-I over years. - Recurrence of cancer in RTRs: At first CSCC, baseline IHG-I conferred the lowest hazard of a second CSCC, IHG-II intermediate, IHG-III/IV highest (age/immunosuppression duration comparable across groups). - Transcriptomic IR metrics and survival: - SAS-1 (IC proxy) and MAS-1 (IF proxy) predicted survival in acute COVID-19 and FHS after adjusting for age/sex: SAS-1 aHR 0.24 (0.08–0.66; P=0.006) in COVID-19 and 0.59 (0.45–0.78; P<0.001) in FHS; MAS-1 aHR 24.38 (3.63–164.01; P=0.001) in COVID-19 and 1.89 (1.31–2.71; P=0.001) in FHS. - SAS-1high–MAS-1low declined with age and was more prevalent in females; SAS-1low–MAS-1high increased with age and was more prevalent in males. - IHG-I was strongly overrepresented with SAS-1high–MAS-1low, while IHG-IIc/IVc were hallmarked by SAS-1low–MAS-1high; IHG-III lacked SAS-1high–MAS-1low representation. - In sepsis datasets, SAS-1low–MAS-1high and SAS-1low–MAS-1low overrepresented in mortality-associated endotypes; SAS-1high–MAS-1low underrepresented in nonsurvivors. - Respiratory viral infections: - Natural ARI cohort (18–49 yrs): SAS-1low–MAS-1high rose acutely (to ~84% on day 0) and reverted toward baseline by day 21; those starting with SAS-1high–MAS-1low reconstituted it more often than those starting with SAS-1low–MAS-1high. - Human viral challenge (influenza/RSV/rhinovirus): Asymptomatic participants maintained/enriched SAS-1high–MAS-1low at peak timepoints vs. symptomatic participants enriched for SAS-1low–MAS-1high, indicating IR erosion-resistant phenotype links to asymptomatic infection. - Evolutionary parallels: - Nonhuman primates: IHG-I more common in younger animals; SIV+ sooty mangabeys had lower %IHG-I vs. SIV− (23% vs. 48%; P=0.001). Disequilibrium grades (IHG-III/IV) associated with increased PD-1 expression and reduced CCR7/CD127+ CD8+ traits, indicating dysfunction; trait differences tracked more with IHG status than age. - CC-RIX mice: Strains resistant to lethal Ebola showed higher baseline %IHG-I; susceptible strains had higher %IHG-IV. - Immune correlates: - SAS-1 genes correlated positively with T-cell responsiveness and negatively with T-cell dysfunction and IL-6; MAS-1 showed opposite correlations, supporting pro-IR vs. IR-compromising functions, respectively. Overall, optimal IR (IHG-I; SAS-1high–MAS-1low) is associated with longevity/survival and resistance to HIV acquisition/AIDS, severe COVID-19, severe/septic outcomes, symptomatic influenza, and recurrent skin cancer; erosion is common with antigenic stress but is potentially reversible.

The findings support the central hypothesis that an immune trait—immunologic resilience—distinct from chronological aging confers advantages in disease resistance and survival. Across diverse cohorts and stressors, individuals preserving or rapidly restoring optimal IR (IHG-I and SAS-1high–MAS-1low) experienced superior outcomes: longer lifespan during aging, reduced hospitalization and mortality in COVID-19, lower HIV acquisition risk and AIDS progression, fewer CSCC recurrences in RTRs, improved sepsis survival, and milder or asymptomatic respiratory viral infections. These advantages persisted after controlling for age, sex, and antigenic burden, indicating age-independent mechanisms. Conversely, nonoptimal IR (IHG-IIb/IIc/III/IV and SAS-1low–MAS-1high) marked an immunosuppressive-proinflammatory state that predisposed to worse outcomes. Sex dimorphism (female advantage) and evolutionary conservation across primates and mice suggest ancient biological underpinnings. The data imply that repeated inflammatory stressors drive IR degradation over the life course, but mitigation (e.g., ART in HIV, reduced behavioral exposures, infection convalescence) can reconstitute optimal IR, offering a framework for risk stratification, targeted interventions, and integration into clinical and public health strategies.

This study introduces and validates immunologic resilience as a measurable, age-independent trait reflecting the balance between immunocompetence and inflammation. Two scalable IR metrics—the CD8–CD4-based Immune Health Grades and transcriptomic SAS-1/MAS-1 profiles—track an IR continuum and predict immunity-dependent health outcomes and survival across conditions and species. Optimal IR is more prevalent in females, degrades with antigenic stress but can be restored, and its preservation confers resistance to infection acquisition/severity, cancer recurrence, sepsis mortality, and is associated with increased longevity. Future work should: (i) prospectively validate IR metrics in unified cohorts spanning multiple outcomes; (ii) dissect genetic and environmental determinants of IR phenotypes; (iii) test interventions to prevent IR erosion or accelerate reconstitution; (iv) evaluate IR’s role in post-acute sequelae (e.g., post-COVID); and (v) incorporate IR stratification into clinical trials and public health programs.

- Outcomes were assessed across multiple cohorts rather than a single prospective cohort spanning all ages and stressors, limiting unified causal inference. - Lack of within-individual longitudinal samples across decades limits direct separation of aging effects from IR erosion; analyses controlled for age and leveraged cohort comparisons and phased designs to mitigate this. - Observational associations preclude definitive causality, though multiple Bradford-Hill criteria were addressed. - Potential confounders include thymic involution, stem cell dynamics, cell migration/tissue residency, CMV serostatus, and psychosocial stress; these may influence IR metrics independently of antigenic exposures. - Could not evaluate whether eroded IR mitigates autoimmunity; autoimmunity’s higher prevalence in females complicates interpretation given sex differences in IR. - Reconstitution of optimal IR may require addressing multiple concurrent inflammatory stressors and can take months to years; generalizability across settings may vary. - Some analyses rely on public transcriptomic datasets with platform heterogeneity; cross-dataset score comparisons are relative and require caution.