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

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Aggregate data presented for these cohorts in the current study are provided in the source data file.
Immunophenotyping data from SardiNIA cohort used in Fig. 10  Sex was self-reported. No data on gender were collected. Cohort characteristics are described in Methods and Supplementary Information. The reported findings apply to both sexes. Yes, sex and gender were considered in study design. The sex and/or gender was determined based on self-reporting. The source data are provided as Source Data file.

March 2021
Population characteristics

Recruitment
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Life sciences study design
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Sample size
Data exclusions

Blinding
The overall numbers from multiple cohorts shown in sample size below and details are provided in the Supplementary Information and Supplementary Data 2. Sex based analysis was performed and reported where data was collected and available. No priori sample size calculation was performed as this is an epidemiological-mechanistic study and these were secondary analyses. The study involves varied cohorts with 48,936 human samples, 279 non-human primates and 378 mice samples in total. All samples from the cohort were used, unless specifically stated in the statistical section of the specific analysis. Furthermore, given the wide range of cohorts (including several large datasets like SardiNIA [n=3,896]; Framingham Heart Study [n=2,308]), conditions (Aging, HIV, COVID-19, sepsis, influenza etc.), and model systems (humans, non-human primates, and mice) where IHGs were examined under, we believe that the sample size are large enough and sufficient for the results to be highly reproducible in the dataset tested. All data presented are reproducible using the appropriate datasets and criteria used.
No data were excluded from the analyses that were designed to test the hypothesis following cohort specific inclusion/exclusion criteria, unless specifically stated in the statistical section of the figure panel.
This study examines metrics of immunological resilience in a wide-range of contexts, including acute/chronic infections, autoimmunity, aging, cancers, and vaccines. An extensive Methods section has been added that includes a Statistics & Reproducibility section. This section provides general information on the study design and how statistical analyses were conducted and detailed in the statistics per panel section in the Supplementary Information. In addition, each figure is linked with a source document for reproducibility. Furthermore, given the wide range of cohorts and conditions that IHGs were examined under, we believe these results to be highly reproducible. All data presented are reproducible using the appropriate datasets and criteria used.
All samples were grouped according to predefined criteria and covariates were adjusted as appropriate. This was not an interventional study, or primary analyses, therefore no pre-hoc randomization was used.
This was not an interventional study, therefore no blinding was used.