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Email Send. Immune Resilience. asthma, rhinitis later on life. WAO White Book on Allergy. Published on , Wisconsin contributing to the epidemic in non-communicable diseases NCDs.

As you grow older, the functioning of your immune system declines. Overall, the immune system responds slower and less effectively, thereby becoming less efficient in its defences and increasing the risk of getting ill.

Besides ageing, the immune system can also be impacted by malnutrition, disease or genetic disorders. When the immune system functions less effectively, this leads to a higher risk of a variety of health issues, such as: slower recovery, infections, chronic inflammation, cancer, immobility or autoimmune disorders.

Many of our immune cells live in the gastrointestinal tract 2 West CE, et al. J Allergy Clin Immunol. Published on Jan; 1 along with the trillion gut bacteria that make up the gut microbiota. As the gut is a major entrance for pathogens, toxins and allergens, one of the main roles of the immune system in the gastrointestinal tract is to distinguish between harmless antigens, such as food, and health hazards.

The development and preservation of a healthy immune system coincides with the establishment and maintenance of a healthy gut microbiota, and is directly linked to nutrition.

R, Orel ed ;. Ljubljana Institute for Probiotics and Functional Foods. Published on , 4 Azad MB, et al. Clin Exp Allergy. Published on ;45 3 An imbalance of gut microbiota is associated with inappropriate immune responses like allergic diseases, chronic inflammation and the development of NCDs.

Published on ; 2 e2 Conversely, a healthy gut microbiota is associated with improved health later in life, fewer NCDs, including a reduced risk of allergies and a lower persistence of allergic diseases. In this model, each new antigenic challenge may be met with ever-lower immunocompetence and ever-higher inflammation i.

a Immunologic resilience IR erosion-resistant and erosion-susceptible phenotypes and predicted outcomes. Phenotypes are defined by sexually dimorphic immune allostasis responses to antigenic Ag stimulation that links high or low immunocompetence IC and inflammation IF states to the indicated immunity-dependent health outcomes.

Arrows depict induction red and reversibility blue of IR states with Ag stimulation on and off respectively. RIX, recombinant inbred inter-cross. DILGOM dietary, lifestyle and genetic determinants of obesity and metabolic syndrome, SIV simian immunodeficiency virus.

Abbreviations frequently used in this study are noted. b Model. IC and IF changes during an immune injury-repair cycle in response to a single instance of Ag stimulation. c Ordinate, IC-IF states associated with the degree of deviation from optimal IR during increased Ag stimulation in individuals with the IR erosion-resistant versus -susceptible phenotypes.

The alignment of optimal, suboptimal, and nonoptimal IR status with phenotypes is noted. Abscissa, time window overlapping with a period of increased Ag stimulation that could be acute, chronic, or repetitive irrespective of age. In this model, since age is a proxy, albeit imperfect, for antigenic experience, individuals with the IR erosion-susceptible phenotype may manifest suboptimal or nonoptimal IR with advancing age.

With this framework Fig. Some persons may resist this degradation or rapidly reconstitute IR to pre-exposure levels. Hence, we envisaged two IR phenotypes.

Age serves as a proxy, albeit imperfect, for antigenic exposures. Hence, in individuals with the IR erosion-susceptible phenotype, IR may erode with the accumulation of antigenic exposures over lifespan Fig. However, some older individuals resist IR erosion IR erosion-resistant phenotype Fig. In contrast, some younger individuals may exhibit degraded IR similar to that seen with advanced age IR erosion-susceptible Fig.

For these reasons, the lower immune status often observed with age may be driven by two co-existing mechanisms: one is dependent on age e. The latter is the focus of the current research. Here, to test these concepts, we evaluate IR metrics in individuals represented in varied, well-defined infectious and non-infectious models of acute, repetitive, and chronic immune stimulation.

These findings have implications for risk stratification of immune health across the age spectrum, as well as improving health outcomes. We previously developed two peripheral blood metrics of IR Fig. IHG-I was assigned as an indicator of optimal IR, as we previously found that preservation of IHG-I during infection with SARS-CoV-2 and HIV was associated with resistance to severe COVID and AIDS 6.

a IR metrics. IHGs are described in panel b. Two gene expression transcriptomic signatures termed survival-associated signature-1 SAS-1 and mortality-associated signature-1 MAS-1 are prognosticators of survival and mortality, respectively, after controlling for age and sex.

Representative genes and gene ontology biological process GO-BP terms are shown. e Model and study phases 1 to 4. Far right, figures specific to the outcomes are noted.

f Distribution of IHGs in the HIV— SardiNIA cohort. F, female; M, male. P , for differences in odds by sex and age are depicted. Rest, all other IHGs. h Features of CD8-CD4 equilibrium and disequilibrium grades. Assignment of IHG-I as an indicator of the IR erosion-resistant phenotype.

A non-IHG-I grade signifies the IR erosion-susceptible phenotype. Two-sided tests were used. Statistics are outlined in Supplementary Information Section with IHG-IV during advanced HIV disease 6. The second metric of IR was transcriptomic gene expression profiles that predict survival or mortality Fig.

We previously identified a suite of peripheral blood transcriptomic signatures that were associated with COVID outcomes hospitalization, survival; Supplementary Fig. Here, we focused on the signatures that provided the highest prognostication by Akaike information criteria for survival and mortality in both cohorts, after controlling for age and sex Supplementary Information Section 8.

Higher expression of SAS-1 SAS-1 high likely tracked IC high , as this signature comprised IC-related genes e. Higher expression of MAS-1 MAS-1 high likely tracked IF high , as this signature comprised IF-related genes e.

Congruently, in the FHS, incrementally higher baseline levels of SAS-1 or MAS-1 predicted progressively longer and shorter lifespans, respectively Fig.

Because the combination of SAS-1 high IC high and MAS-1 low IF low was predicted to have the best longevity advantage, the combined SAS-1 high -MAS-1 low IC high -IF low profile was considered an indicator of optimal IR that is overrepresented in individuals with IHG-I Fig.

Evolutionary conservation of IR phenotypes was evaluated in nonhuman primates 18 , 19 , 20 and Collaborative Cross-RIX mice, a large panel of recombinant, inbred intercrosses RIX designed for complex trait analysis 21 Fig.

The distribution and association of CD8-CD4 disequilibrium grades IHG-III or IHG-IV with health outcomes was examined via a large-scale literature survey of 26, humans Fig. Study design features that mitigated confounding are discussed Supplementary Note 2.

To test the proposed framework Fig. In study phases 1 and 3, we determined whether indicators of optimal IR, namely IHG-I and a transcriptomic proxy for an IC high -IF low status SAS-1 high -MAS-1 low profile represent primordial states that are eroded to a non-IHG-I grade or non-IC high -IF low status in settings of increased antigenic stimulation Fig.

In study phases 2 and 3, we examined whether, after controlling for age, resistance to erosion of IR IR erosion-resistant phenotype is associated with superior immunity-dependent health outcomes, including longevity Fig. In study phase 4, we inquired whether, after controlling for age, the IR erosion-resistant phenotype is linked to immunologic traits typically associated with higher IC and lower IF.

In varied cohorts, IHG-I, IHG-II, IHG-III, and IHG-IV tracked the CD8-CD4 profiles of CD8 lower -CD4 highest , CD8 lowest -CD4 lower , CD8 highest -CD4 higher , CD8 higher -CD4 lowest , respectively Fig. preserving IHG-I was more common in males than females Fig. Across age, the odds of having IHG-I vs.

a non-IHG-I grade was greater in females compared with males Fig. The odds of having IHG-II vs. IHG-I, or IHG-III or IHG-IV vs. IHG-I, increased with age; however, these odds were greater in males than females Fig. IHG-III or IHG-IV did not change significantly with age; however, females compared with males were more likely to have IHG-II than IHG-III or IHG-IV Fig.

The IHG distributions during aging Fig. First, across lifespan, there is a strong preference to preserve grades tracking CD8-CD4 equilibrium IHG-I or IHG-II than disequilibrium IHG-III or IHG-IV states.

Second, females compared with males are more likely to preserve CD8-CD4 equilibrium grades IHG-I or IHG-II, including post-menopause. Third, IHG-I is the primordial IHG from which the other IHGs emerge during aging. For this reason, preservation of IHG-I at any age was assigned as an indicator of the IR erosion-resistant phenotype and optimal IR Fig.

Conversely, having a non-IHG-I grade was assigned as an indicator of the IR erosion-susceptible phenotype and suboptimal or nonoptimal IR Fig. Fourth, older and younger persons with the same IHG may share similar immunologic attributes IR-associated traits after controlling for age ; in contrast, a separate set of immunologic traits may track older vs.

younger persons preserving IHG-I or IHG-II, the two most-common grades across age age-associated traits. The validity of these inferences and IHG assignments were tested as described below. In the context of acute antigenic stimulation, the IR erosion phenotypes as gauged by the IHG metric were evaluated in two infection models: schistosomiasis and SARS-CoV-2 infection.

In Kenyan children with schistosomiasis, the level of antigenic stimulation was proxied by urinary egg counts Fig. Akin to younger SardiNIA participants Fig. the zero-egg count stratum had IHG-IV. b — f Acute COVID cohort. convalescence paired : overall, by age and cytomegalovirus CMV serostatus.

c IHG degradation and reconstitution during COVID by CMV serostatus. rates, and CMV seropositivity rates by age strata. F female, M male. Disease severity status defined by World Health Organization WHO ordinal scale: [mild]; 5 [moderate]; 6—8 [severe]. h Primary HIV infection cohort PIC.

Behavioral acitivty score BAS is the sum of scores of these risk factors. STI scores were derived based on direct and indirect indicators of STI. By comparing IHG distribution patterns at presentation in HIV-seronegative patients with COVID baseline vs.

convalescence, with preferential emergence of IHG-II and less so of IHG-IV Fig. CMV serostatus influenced the nature of the IHGs that emerged during COVID Fig. Since CMV seropositivity rates increase with age Fig. The association between CD8-CD4 disequilibrium grades IHG-III or IHG-IV and high rates of CMV seropositivity was confirmed in persons without COVID Supplementary Note 3.

baseline Fig. The IHG distribution patterns in cohorts of persons without SardiNIA or with acute COVID showed three similarities. Second, within each age stratum of both cohorts, some persons resisted erosion of IHG-I Figs.

hospitalized patients, those with mild disease severity status indexed by WHO ordinal scale 28 of 1—4 , and survivors Fig. Third, females preserved IHG-I to a greater extent than males Figs.

Taken together, these findings convey two key inferences. First, the IHG at presentation with acute COVID is dependent on five factors: age, sex, CMV serostatus, the IR erosion phenotype, and the IHG present before COVID, as IHG-I during acute COVID is mostly possible in persons who had the same grade before SARS-CoV-2 infection.

Thus, persons preserving IHG-I before and at presentation with acute COVID have the IR erosion-resistant phenotype. Second, erosion of IHG-I can be temporary, and even older persons can retain the capacity to reconstitute IHG-I during convalescence.

Compared with age-matched SardiNIA participants Fig. Level of HIV-associated antigenic stimulation was proxied by HIV viral load HIV-VL.

However, within each HIV-VL stratum, a small subset preserved IHG-I IR erosion-resistant phenotype. The interval between the estimated date of infection and starting ART was 3. We focused on the elite subset 5. During five years of the therapy-naïve disease course, the capacity to preserve IHG-I decreased, resulting in the emergence of the other grades Fig.

IR erosion phenotypes in the context of repetitive, moderate-grade antigenic stimulation was examined in FSWs Supplementary Fig. The extent of moderate-grade antigenic stimulation was proxied by behavioral frequency of unprotected sex and biological [sexually transmitted infection STI ] risk factors for HIV acquisition.

Behavioral risk factors and baseline IHG status were available for FSWs Supplementary Fig. To mitigate confounding attributable to a false-negative HIV seronegative test, the association between baseline IHG and subsequent incident HIV seroconversion was restricted to FSWs with at least 2 HIV seronegative tests performed at least 3 months apart Supplementary Fig.

Of these, 53 women subsequently seroconverted Supplementary Fig. The median interval between baseline and HIV seroconversion was 4.

Prevalence of IHGs was similar regardless of the duration of sex work Fig. Among those without IHG-III or IHG-IV at baseline, a higher baseline BAS was associated with an increased hazard of subsequently developing these grades Supplementary Fig. Hence, higher BAS and STI scores were risk factors for having or developing IHG-III or IHG-IV.

After baseline measurements, FSWs were provided education and interventions e. Right, behavioral activity score BAS. g Groups based on IHG at baseline and predicted IHG before COVID top. Model 1, by baseline IHG; and model 2, by CMV serostatus.

h Time to second occurrence of cutaneous squamous cell carcinoma CSCC by IHG at time of first occurrence of CSCC in renal transplant recipients.

P, for differences in HIV-VL vs. IHG-I is shown. j HIV-VL by entry IHG in the primary HIV infection cohort PIC. k HIV-VL at entry and subsequent 5 years of therapy-naïve follow-up in EIC participants. Differences in HIV-VL are between participants with IHG-I vs.

rest i. For box plots: center line, median; box, interquartile range IQR ; whiskers, rest of the data distribution and outliers greater than ±1. Pre- and post-HIV seroconversion IHG data were available on 43 FSWs.

Akin to the elite group of individuals accrued during early HIV infection who preserved IHG-I at presentation Fig. Sooty mangabeys without and with natural simian immunodeficiency virus SIV infection allowed for evaluation of the additive impact of a single non-SIV source vs. two non-SIV and SIV 18 sources of antigenic stimulation on erosion of IHG-I.

Akin to humans Fig. Evolutionary parallels were also observed in the Collaborative Cross-RIX mice Groups of mice strains categorized into those who manifested relative resistance vs.

susceptibility to lethal Ebola virus infection Thus, resistance vs. susceptibility to lethal Ebola in mice may partly relate to a genetically associated capacity to preserve IHG-I or develop IHG-IV, respectively, before infection. Consistent with our model Fig.

The juxtaposition of findings in human vs. nonhuman primate cohorts suggest three evolutionary parallels.

First, in both species, IHG-I is the primordial grade from which non-IHG-I grades emerge with increased antigenic stimulation. Third, akin to FSWs who acquired HIV, sooty mangabeys categorized into those preserving IHG-I after SIV infection group 1 Fig. Thus, a key evolutionary difference was that IHG-III and IHG-IV were much less frequent in otherwise healthy humans Fig.

The higher prevalence of IHG-III and IHG-IV in nonhuman primates vs. humans may be attributable to differences in types and levels of antigenic exposures between species and suggests a potential survival benefit for humans to preserve CD8-CD4 equilibrium grades IHG-I or IHG-II vs. disequilibrium grades IHG-III or IHG-IV.

First, at any age, increased antigenic stimulation induces a shift from IHG-I to non-IHG-I grades. Second, the extent of the deviation or shift from IHG-I is proportionate to the level of antigenic stimulation.

These similarities across human cohorts have clinical relevance, as they suggest that i cohorts with varying host characteristics may comprise individuals with similar levels of immunosuppression linked to a non-IHG-I grade, ii immunosuppression may antedate HIV seroconversion, and iii development of a non-IHG-I grade may explain why some younger patients with HIV or SLE prematurely manifest immune and clinical features of age-associated diseases 31 , Third, reconstitution of IHG-I is possible.

For example, in three different contexts [COVID Fig. Fourth, individuals may have multiple concurrent sources of increased antigenic stimulation; hence, reconstitution of IHG-I may be impaired without mitigation of all sources. Thus, the age-associated erosion of IHG-I to a non-IHG-I grade may be partly attributable to accumulated antigenic experience.

Fifth, consistent with our model Fig. In study phase 2 below , we examined whether preservation of IHG-I was associated with superior immunity-dependent health outcomes. Juxtaposition of the IHG distribution patterns across age in persons without Fig.

with Fig. Group A comprises patients presenting with IHG-I; based on the above-noted results Fig. Group B is a conflated group of individuals presenting with IHG-II or IHG-IV; these grades before COVID could have been IHG-I or IHG-II. Group C was envisaged based on having IHG-IV at presentation and before COVID While age was associated with a stepwise increase in the likelihood of hospitalization and death Supplementary Fig.

IHG-I group A was associated with a significantly higher odds ratio of hospitalization Fig. CMV serostatus was not associated with hospitalization or death Fig. These findings suggest that i the capacity to preserve IHG-I both before and during early SARS-CoV-2 infection was associated with less-severe COVID nonhospitalization, survival , and ii while CMV serostatus may influence the nature of the IHG that emerges during COVID Fig.

RTRs are at a heightened up to fold risk of developing recurrent cutaneous squamous cell carcinoma CSCC We examined the risk of a second episode of CSCC according to the IHG at the time of initial diagnosis of CSCC baseline.

In a prospective RTR cohort Supplementary Data 5 15 , the hazard of a second episode of CSCC was lowest, intermediate, and highest in individuals who, at the time of the first episode of CSCC, had IHG-I, IHG-II, and IHG-III or IHG-IV, respectively Fig.

In persons with recurrent CSCC, duration of immunosuppression or age did not differ substantially by baseline IHG Supplementary Data 5. Thus, In participants of the early HIV infection cohort, the rates of progression to AIDS were slowest, intermediate, and fastest in patients who at presentation had IHG-I, IHG-II or IHG-III, and IHG-IV, respectively Fig.

HIV-VL in participants from the early Fig. those who developed IHG-II, IHG-III, or IHG-IV Fig. Thus, the elite capacity to preserve IHG-I during HIV infection was associated with greater immunocompetence as proxied by lower AIDS risk and restriction of HIV viral replication.

In FSWs, higher baseline BAS and total STI scores were associated with two outcomes: higher rates Fig. However, baseline IHG-III or IHG-IV vs.

IHG-I was also associated with an increased likelihood of HIV seroconversion Fig. In multivariate analysis Supplementary Data 8a , IHG-IV independently associated with a nearly 3-fold increased risk of HIV seroconversion adjusted OR, 2.

a Female sex workers FSWs stratified first by baseline behavioral activity score BAS and then by subsequent HIV seroconversion status. Far right, OR for HIV seroconversion by baseline IHG.

c Associations of CD8-CD4 disequilibrium grades IHG-III and IHG-IV with age and sex; inducers of these grades; and outcomes. Findings are from the literature survey also see Supplementary Table 2 for details and references and our primary datasets.

d — f Models depicting risk of indicated outcomes is lower in persons with the IR erosion-resistant phenotype IHG-I. d HIV-AIDS, e COVID, and f recurrent cutaneous squamous cell cancer CSCC in renal transplant recipients. Pie charts depict relative proportions of the IHGs in the study group. Risk scaled from 1 to 3.

Ag, antigenic; VL, viral load. These findings suggest that risk factor-associated antigenic stimulation increases the risk of developing IHG-III or IHG-IV, and IHG-III and especially IHG-IV prognosticate HIV seroconversion risk after controlling for BAS, a proxy for the level of HIV exposure.

This inference was supported by our literature survey Fig. This survey also affirmed that i prevalence of IHG-III or IHG-IV increases with age and is higher in males and ii CMV seropositivity rates in HIV— persons increase with age and IHG-III or IHG-IV associated with CMV seropositivity.

Furthermore, these findings suggest that IR status indexed by the IHGs may shape the continuity spectrum from disease susceptibility to outcomes in the context of HIV-AIDS Fig. Toward defining the precise level of IR eroded that prognosticates inferior immunity-dependent health outcomes, we characterized the full repertoire of IHGs that emerge in settings of antigenic stimulation.

a Schema for defining the full repertoire of IHGs. b Distribution of IHGs with subgrades in the SardiNIA cohort by age strata. Age, median age at IHG assessment, baseline or pre-ART are shown.

e Model depicting the enrichment of non-IHG-I grades during aging and at presentation with COVID or HIV infection. IHG-I and IHG-IIa were the first and second-most prevalent grades during aging SardiNIA; Fig.

In comparison with age-matched controls in the SardiNIA cohort Fig. Thus, the IHG repertoires provide a unifying framework of IR: a shared subset of detrimental non-IHG-I grades associated with worse health outcomes emerges in settings of lower e.

The subgrades may provide more precise risk prognostication attributable to where a person may reside along an IR continuum: i we previously found that presentation with subgrades b and c of IHG-II or IHG-IV predicted higher risk of COVIDassociated mortality 6 , after controlling for age; ii HIV acquisition occurred mainly in FSWs presenting with IHG-III and IHG-IVa Supplementary Fig.

Our findings suggest that the IHG repertoire defines three tiers of IR Fig. For these reasons, IHG-III was classified as a detrimental non-IHG-I grade in this study. Thus, the IHGs define a continuum: IHG-I, the most prevalent grade, signified optimal IR tier 1 ; IHG-IIa, the second-most prevalent grade, signified suboptimal IR tier 2 ; and the detrimental and less-frequent non-IHG-I grades signified nonoptimal IR tier 3 Fig.

a Schema for IR continuum. IR tiers and erosion phenotypes defined by the IR metrics IHGs, survival-associated signature SAS -1, and mortality-associated signature MAS Higher expression of SAS-1 and MAS-1 serve as transcriptomic proxies for immunocompetence IC and inflammation IF , respectively.

Groupings of SAS-1 and MAS-1 based on higher or lower levels of these signatures are depicted. with Alzheimer disease AD and other dementia disorders; e persons without control vs. Asymp, asymptomatic. Cohort characteristics and sources of gene expression profile data are in Supplementary Data 13a.

Our hypothesis Figs. To test this proposition, we examined whether the transcriptomic gene expression metrics of IR, namely, survival- vs. To corroborate that SAS-1 high was a transcriptomic proxy for IC high and not IF low , we focused on the findings of Alpert et al.

Higher levels of IMM-AGE based on gene expression associated with lower levels of an immune-aging metric based on immune senescence-associated T-cell subset frequencies 11 as well as survival in the FHS cohort Fig.

We found that, akin to higher SAS-1 expression, higher expression of IMM-AGE was also associated with lower mortality hazards in the COVID cohort Fig. Congruently, expression of SAS-1 and IMM-AGE was positively correlated; conversely, SAS-1 and IMM-AGE expression was negatively correlated with MAS-1 expression Supplementary Fig.

First, the correlation between expression of these gene signatures and age, while statistically significant, was low Supplementary Fig.

Second, while expression levels of SAS-1 and IMM-AGE declined and those of MAS-1 increased with age Supplementary Fig. Thus, the age-associated changes in SAS-1 and MAS-1 levels appeared to be more closely related to accumulated antigenic experience than the direct effects of age per se.

Together, these findings and the gene composition of the signatures Fig. SAS-1 high -MAS-1 low , SAS-1 high -MAS-1 high , SAS-1 low -MAS-1 low , and SAS-1 low -MAS-1 high profiles are considered as representative of IC high -IF low , IC high -IF high , IC low -IF low , and IC low -IF high states, respectively Fig.

First, akin to the age-associated shift from IHG-I to non-IHG-I grades Fig. Second, akin to the overrepresentation of IHG-I in females across age strata Fig. SAS-1 low -MAS-1 high profiles were more prevalent in females than males Fig. These findings were consistent with our observation that, across all ages in the FHS, females compared with males preserved higher levels of SAS-1 and lower levels of MAS-1 Supplementary Fig.

Conversely, representation of SAS-1 low -MAS-1 high was progressively greater with the a, b, and c subgrades of IHG-II and IHG-IV Fig. IHG-III lacked representation of the SAS-1 high -MAS-1 low profile. Thus, IHG-I was hallmarked by nearly complete representation of the SAS-1 high -MAS-1 low profile and underrepresentation of the SAS-1 low -MAS-1 high profile.

In contrast, IHG-IIc and IHG-IVc were hallmarked by complete representation of the SAS-1 low -MAS-1 high profile and absence of the SAS-1 high -MAS-1 low profile. IHG-IIa had some representation of the SAS-1 high -MAS-1 low profile.

Congruent with these findings, expression of SAS-1 was higher, whereas expression of MAS-1 was lower in IHG-I vs. the other grades in three distinct cohorts Supplementary Fig. In the COVID cohort, there was a stepwise decrease in IHG-I with age Fig. Paralleling these findings with IHG-I, the representation of SAS-1 high -MAS-1 low i decreased with age Fig.

hospitalized survivors and absent in nonsurvivors Fig. Conversely, representation of the SAS-1 low -MAS-1 high profile was higher in older persons, nonsurvivors, and individuals with IHG-IV; intermediate in hospitalized survivors and those with IHG-II; and lower or absent in nonhospitalized survivors or those with IHG-I Fig.

Fourth, consistent with our finding that some younger persons develop non-IHG-I grades that are more common in older persons Figs. Furthermore, the relative representation of SAS-1 high -MAS-1 low vs.

Hence, individuals with a survival disadvantage COVID nonsurvivors, patients with AIDS share the hallmark features found in IHG-IIc and IHG-IVc, namely, absence of SAS-1 high -MAS-1 low and enrichment of SAS-1 low -MAS-1 high Fig. We suggest that i the SAS-1 high -MAS-1 low profile is a transcriptomic proxy for IHG-I and that both of these metrics of optimal IR are overrepresented in females Fig.

Compared with the SAS-1 high -MAS-1 low profile, the hazard of dying, after controlling for age and sex, was higher and similar in persons with the SAS-1 high -MAS-1 high and SAS-1 low -MAS-1 low profiles and highest in persons with the SAS-1 low -MAS-1 high profile Fig.

Correspondingly, SAS-1 low -MAS-1 high was overrepresented and SAS-1 high -MAS-1 low was underrepresented at baseline in nonsurvivors Fig. First, among older FHS participants, females lived longer than males, and levels of SAS-1 and MAS-1 further stratified survival rates Supplementary Fig.

The survival rates in older 66—92 years persons were highest in females with SAS-1 high or MAS-1 low , intermediate in females with SAS-1 low or MAS-1 high and males with SAS-1 high or MAS-1 low , and lowest in males with SAS-1 low or MAS-1 high Supplementary Fig.

This survival hierarchy and our findings in Fig. c Model: age, sex, and immunologic resilience IR levels influence lifespan. d Sepsis 1 comprises healthy controls and meta-analysis of patients with community-acquired pneumonia CAP and fecal peritonitis FP stratified by sepsis response signature groups G1 and G2 associated with higher and lower mortality, respectively.

Sepsis 2 comprises healthy controls and patients with systemic inflammatory response syndrome SIRS , sepsis, and septic shock survivors S and nonsurvivors NS. P values asterisks, ns for participants with SAS-1 low -MAS-1 high at pre-ARI right are for their cross-sectional comparison to the profiles at the corresponding timepoints for participants with SAS-1 high -MAS-1 low at pre-ARI middle.

f Schema of the timing of gene expression profiling in experimental intranasal challenges with respiratory viral infection in otherwise healthy young adults with data presented in panels g and h. T, time. g Participants inoculated intra-nasally with respiratory syncytial virus RSV , rhinovirus, or influenza virus stratified by symptom status and sampling timepoint.

symptomatic, Asymp. h Participants inoculated intra-nasally with influenza virus stratified by symptom status and sampling timepoint. i Individuals with severe influenza infection requiring hospitalization collected at three timepoints, overall, and by age strata and severity. Patients were grouped by increasing severity levels: no supplemental oxygen required, oxygen by mask, and mechanical ventilation.

Cohort characteristics and sources of biological samples and gene expression profile data are in Supplementary Data 13a. Based on gene expression profiles obtained at baseline admission , Knight and colleagues categorized four cohorts of individuals into sepsis risk groups that predicted mortality vs.

survival in individuals admitted to intensive care units with severe sepsis due to community-acquired pneumonia or fecal peritonitis 37 , Our evaluations revealed that, irrespective of age, the survival-associated SAS-1 high -MAS-1 low profile was highly underrepresented, whereas SAS-1 low -MAS-1 high and SAS-1 low -MAS-1 low profiles were disproportionately overrepresented in the sepsis risk group associated with mortality G1 group vs.

survival G2 group Fig. Thus, consistent with our model Fig. We next examined whether asymptomatic ARI was associated with the IR erosion-resistant phenotype, i.

symptomatic infection after viral challenge at two timepoints: baseline T1 vs. when symptomatic patients had peak symptoms T2 Fig. Figure 8g shows the combined results of three different viral challenges influenza virus, respiratory syncytial virus, rhinovirus.

Among symptomatic participants, SAS-1 low -MAS-1 high was enriched at T2 vs. T1 Fig. In contrast, among persons who remained asymptomatic, proportions of the SAS-1 low -MAS-1 high profile did not change substantially between T1 and T2; instead at T2, there was a significant enrichment of SAS-1 high -MAS-1 low compared to symptomatic participants Fig.

Similar results were observed in another study in which participants were challenged with influenza virus Fig. Supporting these findings in humans, among pre-Collaborative Cross-RIX mice strains infected with influenza, SAS-1 high -MAS-1 low was overrepresented, whereas SAS-1 low -MAS-1 high was underrepresented in strains that manifested histopathologic features of mild low response vs.

severe high response infection Supplementary Fig. Paralleling the time series shown in Fig. However, regardless of age, the hallmark of less-severe vs. most-severe influenza infection was the capacity to reconstitute a survival-associated SAS-1 high -MAS-1 low profile more quickly Fig.

Figure 9a synthesizes the key findings from study phases 1, 2, and 3. Viral challenge studies in humans Fig. rapid restoration of the survival-associated IC high -IF low state SAS-1 high -MAS-1 low profile during the convalescence phase Fig.

Ag antigenic, F female, H high, IC immunocompetence, IF inflammation, L low, M male b IR erosion-resistant and IR erosion-susceptible phenotypes based on experimental models. c Correlation r ; Pearson between expression levels of genes within SAS-1 and MAS-1 signatures with levels of an indicator for T-cell responsiveness, T-cell dysfunction, and systemic inflammation.

d , e Levels of the indicated immune traits by IHGs in d sooty mangabeys seropositive for simian immunodeficiency virus SIV and e SIV-seronegative Chinese rhesus macaques. Comparisons were made between IHG-I vs. IHG-III and IHG-II vs. To further support the idea that the SAS-1 high -MAS-1 low profile tracks an IC high -IF low state, we determined the correlation between expression levels of genes comprising SAS-1 and MAS-1 with indicators of T-cell responsiveness and dysfunction in peripheral blood 8 , 43 , as well as systemic inflammation plasma IL-6, a biomarker of age-associated diseases and mortality 44 , 45 , 46 Fig.

Genes correlating positively with T-cell responsiveness and negatively with T-cell dysfunction or plasma IL-6 levels were considered to have pro-IR functions; genes with the opposite attributes were considered to have IR-compromising functions Fig.

We found that SAS-1 was enriched for genes whose expression levels correlated positively with pro-IR functions; several of these genes have essential roles in T-cell homeostasis e.

Compared with SAS-1, MAS-1 was enriched for genes whose expression levels correlated with IR-compromising functions e. These associations, coupled with the distribution patterns of the IR metrics across age, raised the possibility that levels of immune traits differed by i IR IHG status, after controlling for age age-independent vs.

ii age, regardless of IR IHG status age-dependent , vs. iii both. Additionally, because we observed evolutionary parallels between humans and nonhuman primates Figs. Trait levels in both species differed to a greater extent by IHG status than age Supplementary Data Thus, CD8-CD4 disequilibrium grades IHG-III and IHG-IV were highly prevalent in nonhuman primates Fig.

In general, IHG-I appeared to be associated with a better immune trait profile e. Contrary to nonhuman primates, CD8-CD4 equilibrium grades IHG-I and IHG-II vs. disequilibrium grades IHG-III or IHG-IV are much more prevalent across age in humans Fig. However, emphasizing evolutionary parallels, we identified similar traits associated with IHG status after controlling for age in both humans and nonhuman primates.

Group 1 comprised 13 immune traits whose levels differed between CD8-CD4 equilibrium vs. disequilibrium grades IHG-I vs. IHG-III or IHG-II vs IHG-IV , after controlling for age and sex.

Group 3 comprised 10 immune traits that differed by attributes of both groups 1 and 2 after controlling for sex. Group 4 neutral comprised 30 immune traits that did not differ by group 1 or 2 attributes Fig. Within each group, traits were clustered into signatures according to whether their levels were higher or lower with IHG-III or IHG-IV, after controlling for age and sex; by age in older or younger persons with IHG-I or IHG-II, after controlling for sex; both; or neither.

cDC, conventional dendritic cells. Two arrows indicate both comparisons for IHG-I vs. IHG-IV or age within IHG-I and IHG-II are significant, one arrow indicates only one of the comparisons for IHG status or age is significant. b Representative traits by age in persons with IHG-I or IHG-II and by IHG status.

Comparisons for the indicated traits were made between IHG-I vs. Median number of individuals evaluated by IHG status and age within IHG-I or IHG-II. ns nonsignificant. c Linear regression was used to analyze the association between log 2 transformed cell counts outcome with age and IHG status predictors.

FDR, false discovery rate P values adjusted for multiple comparisons. d Model differentiating features of processes associated with lower immune status that occur due to aging or via erosion of IR. SAS-1, survival-associated signature-1; MAS-1, mortality-associated signature Figure 10b shows that the levels of a representative trait in signature 6 naïve CD8 bright differed between older vs.

younger persons with IHG-I or IHG-II but did not differ by IHG status. Thus, group 2 immune traits represent traits that are associated with aged CD8-CD4 equilibrium.

Additional trait features of Groups 1—4 are discussed Supplementary Note 8. Thus, suggesting evolutionary parallels, we identified similar immunologic features e. However, since the prevalence of IHG-III or IHG-IV increases with age Fig. Our study addresses a fundamental conundrum.

Conversely, why do some older persons resist manifesting these attributes? This failure indicates the IR erosion-susceptible phenotype. We examined IR levels and responses in varied human and nonhuman cohorts that are representative of different types and severity of inflammatory antigenic stressors.

The sum of our findings supports our study framework that optimal IR is an indicator of successful immune allostasis adaptation when experiencing inflammatory stressors, correlating with a distinctive immunocompetence-inflammation balance IC high -IF low that associates with superior immunity-dependent health outcomes, including longevity Fig.

This IR degradation correlates with a gene expression signature profile SAS-1 low -MAS-1 high tracking an IC low -IF high status linked to mortality both during aging and COVID, as well as immunosuppression e.

Despite clinical recovery from such common viral infections, some younger adults were unable to reconstitute optimal IR. However, since the prevalence of the SAS-1 low -MAS-1 high profile increases steadily with age, it may give the misimpression that this profile relates to the aging process vs.

IR degradation. To test our study framework Fig. These complementary metrics provide an easily implementable method to monitor the IR continuum irrespective of age Figs.

Paralleling the observation that females manifest advantages for immunocompetence and longevity 2 , 3 , 4 , 5 , the IR erosion-resistant phenotype was more common in females including postmenopausal.

Congruently, immune traits associated with some nonoptimal IR metrics were similar in humans and nonhuman primates. Additionally, in Collaborative Cross-RIX mice, the IR erosion-resistant phenotype was associated with resistance to lethal Ebola and severe influenza infection.

That finding may open new avenues for research into longevity. But they did find that more competent immune systems were associated with lower mortality. COVID 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.

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 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 , 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 pandemic, older people were advised to be more cautious.

However, within each age bracket, people differ in their susceptibility to severe COVID outcomes; conceivably, these differences may relate to susceptibility to preserve versus degrade immune resilience during COVID 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 team; Agan BK, Root-Bernstein R, Clark RA, Okulicz JF, He W.

Nat Commun. doi: PMID: But to understand how immune resilience influences health outcomes, they first needed a way to measure or grade this immune attribute. The researchers developed two methods for measuring immune resilience.

IHG-I denotes the best balance tracking the highest level of resilience, and IHG-IV denotes the worst balance tracking the lowest level of immune resilience. An imbalance between the levels of these T-cell types is observed in many people as they age, when they get sick, and in people with autoimmune diseases and other conditions.

The researchers also developed a second metric that looks for two patterns of expression of a select set of genes. One pattern associated with survival and the other with death. The mortality-associated genes are closely related to inflammation, a process through which the immune system eliminates pathogens and begins the healing process but that also underlies many disease states.

Their studies have shown that high expression of the survival-associated genes and lower expression of mortality-associated genes indicate optimal immune resilience, correlating with a longer lifespan.

The opposite pattern indicates poor resilience and a greater risk of premature death. When both sets of genes are either low or high at the same time, immune resilience and mortality risks are more moderate. In the newly reported study initiated in , Ahuja and his colleagues set out to assess immune resilience in a collection of about 48, people, with or without various acute, repetitive, or chronic challenges to their immune systems.

In an earlier study, the researchers showed that this novel way to measure immune status and resilience predicted hospitalization and mortality during acute COVID across a wide age spectrum [2].

The investigators have analyzed stored blood samples and publicly available data representing people, many of whom were healthy volunteers, who had enrolled in different studies conducted in Africa, Europe, and North America. Volunteers ranged in age from 9 to years. They also evaluated participants in the Framingham Heart Study, a long-term effort to identify common factors and characteristics that contribute to cardiovascular disease.

To examine people with a wide range of health challenges and associated stresses on their immune systems, the team also included participants who had influenza or COVID, and people living with HIV.

The short answer is that immune resilience, longevity, and better health outcomes tracked together well. Practice good sanitation like frequent and thorough hand-washing and take social distancing seriously as long as it is recommended. Clean well and clean often.

Wear gloves or wipe down cart handles. Wipe down household surfaces, phones, laptops, bathrooms, doorknobs, etc. frequently with alcohol, hydrogen peroxide, and other cleaning agents. These agents can kill the virus, which can live a few days on surfaces.

Wear a mask in public. Recent reports suggest that this coronavirus can live outside the host longer than other viruses, and that it is airborne. Experts and the CDC now recommend wearing a good-quality, non-surgical mask when leaving the house. Source Nutritional Considerations The following is general information about the actions of certain foods, nutrients, and compounds.

Eat colorful, whole, unprocessed plant foods. Source , Source 2. Include healthy fats that provide antioxidants and anti-inflammatory compounds. Nuts and seeds provide selenium and vitamin E : Whole or unprocessed ground nuts and seeds like Brazil nuts, sunflower seeds, and almonds provide important nutrients that support immune health via their antioxidant properties.

Fish and fish oil contain compounds such as EPA , DHA , and lipid mediators that support immune function generally and are critical to the resolution of inflammation. Source Coconut oil is generally considered anti-viral. Source You can cook with coconut oil or blend it into your coffee.

Doing so may increase the formation of volatile compounds that cause negative health effects. Source 3. Choose high-quality proteins, which are essential for immune function.

Protein can be derived from animal foods or combinations of complementary plants like beans and rice or lentils and quinoa.

Undenatured whey protein can also promote immune health by the action of naturally present compounds with antioxidant and antiviral properties. Whey protein can be stored dry and can last several weeks, making it a great functional bulk food option.

Source Zinc is a critical nutrient for immune function that is abundant in some animal foods like oysters, beef, crab, and lobster. Feed your microbiome. Cut out sugars. Get cooking! Source 7. Drink plenty of filtered water. Practice self-care and stress reduction.

Source 9. Get adequate sleep, exercise, and rest. Source

Source Optimizing vitamin D status is a safe and likely helpful measure for protecting against respiratory infections in general. Most people do not have optimal levels of Vitamin D, especially in the winter and early spring. Source Vitamin D is best produced through exposure to sunlight, and supplementation can be helpful if hydroxy vitamin D levels are suboptimal.

Source If supplementation is your best option, your practitioner can help you determine your vitamin D status, which will determine dosing. If you have safe access to the outdoors, get outside for at least minutes a day. If you find yourself mostly indoors, sit by an open window to catch some rays of sunlight.

Connect with a personalized nutrition practitioner. What role does personalized nutrition play in immune resilience? Source Personalized nutrition can play an important role in optimizing immunity and preventing and managing inflammatory chronic conditions in high-risk groups. Source The effects of nutritional interventions in the progression of chronic diseases can take weeks, months, and even years in some cases.

Source This is why it is imperative that you work with a personalized practitioner who understands your immune function, inflammatory status, insulin regulation, and nutrient status. the way we live and interact with our environment is the major determinant of both our individual and collective health.

Follow CDC guidelines. Practice good sanitation like frequent and thorough hand-washing and take social distancing seriously as long as it is recommended. Clean well and clean often. Wear gloves or wipe down cart handles.

Wipe down household surfaces, phones, laptops, bathrooms, doorknobs, etc. frequently with alcohol, hydrogen peroxide, and other cleaning agents. These agents can kill the virus, which can live a few days on surfaces. Wear a mask in public. Recent reports suggest that this coronavirus can live outside the host longer than other viruses, and that it is airborne.

Experts and the CDC now recommend wearing a good-quality, non-surgical mask when leaving the house. Source Nutritional Considerations The following is general information about the actions of certain foods, nutrients, and compounds.

Eat colorful, whole, unprocessed plant foods. Source , Source 2. Include healthy fats that provide antioxidants and anti-inflammatory compounds. Nuts and seeds provide selenium and vitamin E : Whole or unprocessed ground nuts and seeds like Brazil nuts, sunflower seeds, and almonds provide important nutrients that support immune health via their antioxidant properties.

Fish and fish oil contain compounds such as EPA , DHA , and lipid mediators that support immune function generally and are critical to the resolution of inflammation. Source Coconut oil is generally considered anti-viral. Source You can cook with coconut oil or blend it into your coffee.

Doing so may increase the formation of volatile compounds that cause negative health effects. Source 3. Choose high-quality proteins, which are essential for immune function. Abscissa, time window overlapping with a period of increased Ag stimulation that could be acute, chronic, or repetitive irrespective of age.

In this model, since age is a proxy, albeit imperfect, for antigenic experience, individuals with the IR erosion-susceptible phenotype may manifest suboptimal or nonoptimal IR with advancing age.

With this framework Fig. Some persons may resist this degradation or rapidly reconstitute IR to pre-exposure levels. Hence, we envisaged two IR phenotypes. Age serves as a proxy, albeit imperfect, for antigenic exposures. Hence, in individuals with the IR erosion-susceptible phenotype, IR may erode with the accumulation of antigenic exposures over lifespan Fig.

However, some older individuals resist IR erosion IR erosion-resistant phenotype Fig. In contrast, some younger individuals may exhibit degraded IR similar to that seen with advanced age IR erosion-susceptible Fig. For these reasons, the lower immune status often observed with age may be driven by two co-existing mechanisms: one is dependent on age e.

The latter is the focus of the current research. Here, to test these concepts, we evaluate IR metrics in individuals represented in varied, well-defined infectious and non-infectious models of acute, repetitive, and chronic immune stimulation.

These findings have implications for risk stratification of immune health across the age spectrum, as well as improving health outcomes. We previously developed two peripheral blood metrics of IR Fig. IHG-I was assigned as an indicator of optimal IR, as we previously found that preservation of IHG-I during infection with SARS-CoV-2 and HIV was associated with resistance to severe COVID and AIDS 6.

a IR metrics. IHGs are described in panel b. Two gene expression transcriptomic signatures termed survival-associated signature-1 SAS-1 and mortality-associated signature-1 MAS-1 are prognosticators of survival and mortality, respectively, after controlling for age and sex.

Representative genes and gene ontology biological process GO-BP terms are shown. e Model and study phases 1 to 4. Far right, figures specific to the outcomes are noted. f Distribution of IHGs in the HIV— SardiNIA cohort.

F, female; M, male. P , for differences in odds by sex and age are depicted. Rest, all other IHGs. h Features of CD8-CD4 equilibrium and disequilibrium grades.

Assignment of IHG-I as an indicator of the IR erosion-resistant phenotype. A non-IHG-I grade signifies the IR erosion-susceptible phenotype.

Two-sided tests were used. Statistics are outlined in Supplementary Information Section with IHG-IV during advanced HIV disease 6. The second metric of IR was transcriptomic gene expression profiles that predict survival or mortality Fig.

We previously identified a suite of peripheral blood transcriptomic signatures that were associated with COVID outcomes hospitalization, survival; Supplementary Fig.

Here, we focused on the signatures that provided the highest prognostication by Akaike information criteria for survival and mortality in both cohorts, after controlling for age and sex Supplementary Information Section 8.

Higher expression of SAS-1 SAS-1 high likely tracked IC high , as this signature comprised IC-related genes e. Higher expression of MAS-1 MAS-1 high likely tracked IF high , as this signature comprised IF-related genes e.

Congruently, in the FHS, incrementally higher baseline levels of SAS-1 or MAS-1 predicted progressively longer and shorter lifespans, respectively Fig. Because the combination of SAS-1 high IC high and MAS-1 low IF low was predicted to have the best longevity advantage, the combined SAS-1 high -MAS-1 low IC high -IF low profile was considered an indicator of optimal IR that is overrepresented in individuals with IHG-I Fig.

Evolutionary conservation of IR phenotypes was evaluated in nonhuman primates 18 , 19 , 20 and Collaborative Cross-RIX mice, a large panel of recombinant, inbred intercrosses RIX designed for complex trait analysis 21 Fig.

The distribution and association of CD8-CD4 disequilibrium grades IHG-III or IHG-IV with health outcomes was examined via a large-scale literature survey of 26, humans Fig. Study design features that mitigated confounding are discussed Supplementary Note 2. To test the proposed framework Fig.

In study phases 1 and 3, we determined whether indicators of optimal IR, namely IHG-I and a transcriptomic proxy for an IC high -IF low status SAS-1 high -MAS-1 low profile represent primordial states that are eroded to a non-IHG-I grade or non-IC high -IF low status in settings of increased antigenic stimulation Fig.

In study phases 2 and 3, we examined whether, after controlling for age, resistance to erosion of IR IR erosion-resistant phenotype is associated with superior immunity-dependent health outcomes, including longevity Fig.

In study phase 4, we inquired whether, after controlling for age, the IR erosion-resistant phenotype is linked to immunologic traits typically associated with higher IC and lower IF.

In varied cohorts, IHG-I, IHG-II, IHG-III, and IHG-IV tracked the CD8-CD4 profiles of CD8 lower -CD4 highest , CD8 lowest -CD4 lower , CD8 highest -CD4 higher , CD8 higher -CD4 lowest , respectively Fig. preserving IHG-I was more common in males than females Fig.

Across age, the odds of having IHG-I vs. a non-IHG-I grade was greater in females compared with males Fig. The odds of having IHG-II vs. IHG-I, or IHG-III or IHG-IV vs. IHG-I, increased with age; however, these odds were greater in males than females Fig. IHG-III or IHG-IV did not change significantly with age; however, females compared with males were more likely to have IHG-II than IHG-III or IHG-IV Fig.

The IHG distributions during aging Fig. First, across lifespan, there is a strong preference to preserve grades tracking CD8-CD4 equilibrium IHG-I or IHG-II than disequilibrium IHG-III or IHG-IV states. Second, females compared with males are more likely to preserve CD8-CD4 equilibrium grades IHG-I or IHG-II, including post-menopause.

Third, IHG-I is the primordial IHG from which the other IHGs emerge during aging. For this reason, preservation of IHG-I at any age was assigned as an indicator of the IR erosion-resistant phenotype and optimal IR Fig. Conversely, having a non-IHG-I grade was assigned as an indicator of the IR erosion-susceptible phenotype and suboptimal or nonoptimal IR Fig.

Fourth, older and younger persons with the same IHG may share similar immunologic attributes IR-associated traits after controlling for age ; in contrast, a separate set of immunologic traits may track older vs.

younger persons preserving IHG-I or IHG-II, the two most-common grades across age age-associated traits. The validity of these inferences and IHG assignments were tested as described below.

In the context of acute antigenic stimulation, the IR erosion phenotypes as gauged by the IHG metric were evaluated in two infection models: schistosomiasis and SARS-CoV-2 infection.

In Kenyan children with schistosomiasis, the level of antigenic stimulation was proxied by urinary egg counts Fig. Akin to younger SardiNIA participants Fig. the zero-egg count stratum had IHG-IV.

b — f Acute COVID cohort. convalescence paired : overall, by age and cytomegalovirus CMV serostatus. c IHG degradation and reconstitution during COVID by CMV serostatus. rates, and CMV seropositivity rates by age strata. F female, M male. Disease severity status defined by World Health Organization WHO ordinal scale: [mild]; 5 [moderate]; 6—8 [severe].

h Primary HIV infection cohort PIC. Behavioral acitivty score BAS is the sum of scores of these risk factors. STI scores were derived based on direct and indirect indicators of STI.

By comparing IHG distribution patterns at presentation in HIV-seronegative patients with COVID baseline vs. convalescence, with preferential emergence of IHG-II and less so of IHG-IV Fig. CMV serostatus influenced the nature of the IHGs that emerged during COVID Fig.

Since CMV seropositivity rates increase with age Fig. The association between CD8-CD4 disequilibrium grades IHG-III or IHG-IV and high rates of CMV seropositivity was confirmed in persons without COVID Supplementary Note 3.

baseline Fig. The IHG distribution patterns in cohorts of persons without SardiNIA or with acute COVID showed three similarities. Second, within each age stratum of both cohorts, some persons resisted erosion of IHG-I Figs. hospitalized patients, those with mild disease severity status indexed by WHO ordinal scale 28 of 1—4 , and survivors Fig.

Third, females preserved IHG-I to a greater extent than males Figs. Taken together, these findings convey two key inferences. First, the IHG at presentation with acute COVID is dependent on five factors: age, sex, CMV serostatus, the IR erosion phenotype, and the IHG present before COVID, as IHG-I during acute COVID is mostly possible in persons who had the same grade before SARS-CoV-2 infection.

Thus, persons preserving IHG-I before and at presentation with acute COVID have the IR erosion-resistant phenotype. Second, erosion of IHG-I can be temporary, and even older persons can retain the capacity to reconstitute IHG-I during convalescence. Compared with age-matched SardiNIA participants Fig.

Level of HIV-associated antigenic stimulation was proxied by HIV viral load HIV-VL. However, within each HIV-VL stratum, a small subset preserved IHG-I IR erosion-resistant phenotype.

The interval between the estimated date of infection and starting ART was 3. We focused on the elite subset 5. During five years of the therapy-naïve disease course, the capacity to preserve IHG-I decreased, resulting in the emergence of the other grades Fig.

IR erosion phenotypes in the context of repetitive, moderate-grade antigenic stimulation was examined in FSWs Supplementary Fig. The extent of moderate-grade antigenic stimulation was proxied by behavioral frequency of unprotected sex and biological [sexually transmitted infection STI ] risk factors for HIV acquisition.

Behavioral risk factors and baseline IHG status were available for FSWs Supplementary Fig. To mitigate confounding attributable to a false-negative HIV seronegative test, the association between baseline IHG and subsequent incident HIV seroconversion was restricted to FSWs with at least 2 HIV seronegative tests performed at least 3 months apart Supplementary Fig.

Of these, 53 women subsequently seroconverted Supplementary Fig. The median interval between baseline and HIV seroconversion was 4. Prevalence of IHGs was similar regardless of the duration of sex work Fig.

Among those without IHG-III or IHG-IV at baseline, a higher baseline BAS was associated with an increased hazard of subsequently developing these grades Supplementary Fig.

Hence, higher BAS and STI scores were risk factors for having or developing IHG-III or IHG-IV. After baseline measurements, FSWs were provided education and interventions e. Right, behavioral activity score BAS. g Groups based on IHG at baseline and predicted IHG before COVID top.

Model 1, by baseline IHG; and model 2, by CMV serostatus. h Time to second occurrence of cutaneous squamous cell carcinoma CSCC by IHG at time of first occurrence of CSCC in renal transplant recipients.

P, for differences in HIV-VL vs. IHG-I is shown. j HIV-VL by entry IHG in the primary HIV infection cohort PIC. k HIV-VL at entry and subsequent 5 years of therapy-naïve follow-up in EIC participants.

Differences in HIV-VL are between participants with IHG-I vs. rest i. For box plots: center line, median; box, interquartile range IQR ; whiskers, rest of the data distribution and outliers greater than ±1.

Pre- and post-HIV seroconversion IHG data were available on 43 FSWs. Akin to the elite group of individuals accrued during early HIV infection who preserved IHG-I at presentation Fig. Sooty mangabeys without and with natural simian immunodeficiency virus SIV infection allowed for evaluation of the additive impact of a single non-SIV source vs.

two non-SIV and SIV 18 sources of antigenic stimulation on erosion of IHG-I. Akin to humans Fig. Evolutionary parallels were also observed in the Collaborative Cross-RIX mice Groups of mice strains categorized into those who manifested relative resistance vs.

susceptibility to lethal Ebola virus infection Thus, resistance vs. susceptibility to lethal Ebola in mice may partly relate to a genetically associated capacity to preserve IHG-I or develop IHG-IV, respectively, before infection.

Consistent with our model Fig. The juxtaposition of findings in human vs. nonhuman primate cohorts suggest three evolutionary parallels. First, in both species, IHG-I is the primordial grade from which non-IHG-I grades emerge with increased antigenic stimulation.

Third, akin to FSWs who acquired HIV, sooty mangabeys categorized into those preserving IHG-I after SIV infection group 1 Fig. Thus, a key evolutionary difference was that IHG-III and IHG-IV were much less frequent in otherwise healthy humans Fig.

The higher prevalence of IHG-III and IHG-IV in nonhuman primates vs. humans may be attributable to differences in types and levels of antigenic exposures between species and suggests a potential survival benefit for humans to preserve CD8-CD4 equilibrium grades IHG-I or IHG-II vs.

disequilibrium grades IHG-III or IHG-IV. First, at any age, increased antigenic stimulation induces a shift from IHG-I to non-IHG-I grades. Second, the extent of the deviation or shift from IHG-I is proportionate to the level of antigenic stimulation.

These similarities across human cohorts have clinical relevance, as they suggest that i cohorts with varying host characteristics may comprise individuals with similar levels of immunosuppression linked to a non-IHG-I grade, ii immunosuppression may antedate HIV seroconversion, and iii development of a non-IHG-I grade may explain why some younger patients with HIV or SLE prematurely manifest immune and clinical features of age-associated diseases 31 , Third, reconstitution of IHG-I is possible.

For example, in three different contexts [COVID Fig. Fourth, individuals may have multiple concurrent sources of increased antigenic stimulation; hence, reconstitution of IHG-I may be impaired without mitigation of all sources.

Thus, the age-associated erosion of IHG-I to a non-IHG-I grade may be partly attributable to accumulated antigenic experience. Fifth, consistent with our model Fig. In study phase 2 below , we examined whether preservation of IHG-I was associated with superior immunity-dependent health outcomes.

Juxtaposition of the IHG distribution patterns across age in persons without Fig. with Fig. Group A comprises patients presenting with IHG-I; based on the above-noted results Fig.

Group B is a conflated group of individuals presenting with IHG-II or IHG-IV; these grades before COVID could have been IHG-I or IHG-II. Group C was envisaged based on having IHG-IV at presentation and before COVID While age was associated with a stepwise increase in the likelihood of hospitalization and death Supplementary Fig.

IHG-I group A was associated with a significantly higher odds ratio of hospitalization Fig. CMV serostatus was not associated with hospitalization or death Fig.

These findings suggest that i the capacity to preserve IHG-I both before and during early SARS-CoV-2 infection was associated with less-severe COVID nonhospitalization, survival , and ii while CMV serostatus may influence the nature of the IHG that emerges during COVID Fig.

RTRs are at a heightened up to fold risk of developing recurrent cutaneous squamous cell carcinoma CSCC We examined the risk of a second episode of CSCC according to the IHG at the time of initial diagnosis of CSCC baseline.

In a prospective RTR cohort Supplementary Data 5 15 , the hazard of a second episode of CSCC was lowest, intermediate, and highest in individuals who, at the time of the first episode of CSCC, had IHG-I, IHG-II, and IHG-III or IHG-IV, respectively Fig.

In persons with recurrent CSCC, duration of immunosuppression or age did not differ substantially by baseline IHG Supplementary Data 5. Thus, In participants of the early HIV infection cohort, the rates of progression to AIDS were slowest, intermediate, and fastest in patients who at presentation had IHG-I, IHG-II or IHG-III, and IHG-IV, respectively Fig.

HIV-VL in participants from the early Fig. those who developed IHG-II, IHG-III, or IHG-IV Fig. Thus, the elite capacity to preserve IHG-I during HIV infection was associated with greater immunocompetence as proxied by lower AIDS risk and restriction of HIV viral replication.

In FSWs, higher baseline BAS and total STI scores were associated with two outcomes: higher rates Fig. However, baseline IHG-III or IHG-IV vs. IHG-I was also associated with an increased likelihood of HIV seroconversion Fig. In multivariate analysis Supplementary Data 8a , IHG-IV independently associated with a nearly 3-fold increased risk of HIV seroconversion adjusted OR, 2.

a Female sex workers FSWs stratified first by baseline behavioral activity score BAS and then by subsequent HIV seroconversion status. Far right, OR for HIV seroconversion by baseline IHG.

c Associations of CD8-CD4 disequilibrium grades IHG-III and IHG-IV with age and sex; inducers of these grades; and outcomes. Findings are from the literature survey also see Supplementary Table 2 for details and references and our primary datasets.

d — f Models depicting risk of indicated outcomes is lower in persons with the IR erosion-resistant phenotype IHG-I. d HIV-AIDS, e COVID, and f recurrent cutaneous squamous cell cancer CSCC in renal transplant recipients.

Pie charts depict relative proportions of the IHGs in the study group. Risk scaled from 1 to 3. Ag, antigenic; VL, viral load. These findings suggest that risk factor-associated antigenic stimulation increases the risk of developing IHG-III or IHG-IV, and IHG-III and especially IHG-IV prognosticate HIV seroconversion risk after controlling for BAS, a proxy for the level of HIV exposure.

This inference was supported by our literature survey Fig. This survey also affirmed that i prevalence of IHG-III or IHG-IV increases with age and is higher in males and ii CMV seropositivity rates in HIV— persons increase with age and IHG-III or IHG-IV associated with CMV seropositivity.

Furthermore, these findings suggest that IR status indexed by the IHGs may shape the continuity spectrum from disease susceptibility to outcomes in the context of HIV-AIDS Fig.

Toward defining the precise level of IR eroded that prognosticates inferior immunity-dependent health outcomes, we characterized the full repertoire of IHGs that emerge in settings of antigenic stimulation.

a Schema for defining the full repertoire of IHGs. b Distribution of IHGs with subgrades in the SardiNIA cohort by age strata.

Age, median age at IHG assessment, baseline or pre-ART are shown. e Model depicting the enrichment of non-IHG-I grades during aging and at presentation with COVID or HIV infection. IHG-I and IHG-IIa were the first and second-most prevalent grades during aging SardiNIA; Fig. In comparison with age-matched controls in the SardiNIA cohort Fig.

Thus, the IHG repertoires provide a unifying framework of IR: a shared subset of detrimental non-IHG-I grades associated with worse health outcomes emerges in settings of lower e. The subgrades may provide more precise risk prognostication attributable to where a person may reside along an IR continuum: i we previously found that presentation with subgrades b and c of IHG-II or IHG-IV predicted higher risk of COVIDassociated mortality 6 , after controlling for age; ii HIV acquisition occurred mainly in FSWs presenting with IHG-III and IHG-IVa Supplementary Fig.

Our findings suggest that the IHG repertoire defines three tiers of IR Fig. For these reasons, IHG-III was classified as a detrimental non-IHG-I grade in this study. Thus, the IHGs define a continuum: IHG-I, the most prevalent grade, signified optimal IR tier 1 ; IHG-IIa, the second-most prevalent grade, signified suboptimal IR tier 2 ; and the detrimental and less-frequent non-IHG-I grades signified nonoptimal IR tier 3 Fig.

a Schema for IR continuum. IR tiers and erosion phenotypes defined by the IR metrics IHGs, survival-associated signature SAS -1, and mortality-associated signature MAS Higher expression of SAS-1 and MAS-1 serve as transcriptomic proxies for immunocompetence IC and inflammation IF , respectively.

Groupings of SAS-1 and MAS-1 based on higher or lower levels of these signatures are depicted. with Alzheimer disease AD and other dementia disorders; e persons without control vs. Asymp, asymptomatic. Cohort characteristics and sources of gene expression profile data are in Supplementary Data 13a.

Our hypothesis Figs. To test this proposition, we examined whether the transcriptomic gene expression metrics of IR, namely, survival- vs. To corroborate that SAS-1 high was a transcriptomic proxy for IC high and not IF low , we focused on the findings of Alpert et al.

Higher levels of IMM-AGE based on gene expression associated with lower levels of an immune-aging metric based on immune senescence-associated T-cell subset frequencies 11 as well as survival in the FHS cohort Fig.

We found that, akin to higher SAS-1 expression, higher expression of IMM-AGE was also associated with lower mortality hazards in the COVID cohort Fig. Congruently, expression of SAS-1 and IMM-AGE was positively correlated; conversely, SAS-1 and IMM-AGE expression was negatively correlated with MAS-1 expression Supplementary Fig.

First, the correlation between expression of these gene signatures and age, while statistically significant, was low Supplementary Fig. Second, while expression levels of SAS-1 and IMM-AGE declined and those of MAS-1 increased with age Supplementary Fig.

Thus, the age-associated changes in SAS-1 and MAS-1 levels appeared to be more closely related to accumulated antigenic experience than the direct effects of age per se. Together, these findings and the gene composition of the signatures Fig. SAS-1 high -MAS-1 low , SAS-1 high -MAS-1 high , SAS-1 low -MAS-1 low , and SAS-1 low -MAS-1 high profiles are considered as representative of IC high -IF low , IC high -IF high , IC low -IF low , and IC low -IF high states, respectively Fig.

First, akin to the age-associated shift from IHG-I to non-IHG-I grades Fig. Second, akin to the overrepresentation of IHG-I in females across age strata Fig. SAS-1 low -MAS-1 high profiles were more prevalent in females than males Fig.

These findings were consistent with our observation that, across all ages in the FHS, females compared with males preserved higher levels of SAS-1 and lower levels of MAS-1 Supplementary Fig.

Conversely, representation of SAS-1 low -MAS-1 high was progressively greater with the a, b, and c subgrades of IHG-II and IHG-IV Fig. IHG-III lacked representation of the SAS-1 high -MAS-1 low profile. Thus, IHG-I was hallmarked by nearly complete representation of the SAS-1 high -MAS-1 low profile and underrepresentation of the SAS-1 low -MAS-1 high profile.

In contrast, IHG-IIc and IHG-IVc were hallmarked by complete representation of the SAS-1 low -MAS-1 high profile and absence of the SAS-1 high -MAS-1 low profile. IHG-IIa had some representation of the SAS-1 high -MAS-1 low profile.

Congruent with these findings, expression of SAS-1 was higher, whereas expression of MAS-1 was lower in IHG-I vs.

the other grades in three distinct cohorts Supplementary Fig. In the COVID cohort, there was a stepwise decrease in IHG-I with age Fig. Paralleling these findings with IHG-I, the representation of SAS-1 high -MAS-1 low i decreased with age Fig.

hospitalized survivors and absent in nonsurvivors Fig. Conversely, representation of the SAS-1 low -MAS-1 high profile was higher in older persons, nonsurvivors, and individuals with IHG-IV; intermediate in hospitalized survivors and those with IHG-II; and lower or absent in nonhospitalized survivors or those with IHG-I Fig.

Fourth, consistent with our finding that some younger persons develop non-IHG-I grades that are more common in older persons Figs. Furthermore, the relative representation of SAS-1 high -MAS-1 low vs. Hence, individuals with a survival disadvantage COVID nonsurvivors, patients with AIDS share the hallmark features found in IHG-IIc and IHG-IVc, namely, absence of SAS-1 high -MAS-1 low and enrichment of SAS-1 low -MAS-1 high Fig.

We suggest that i the SAS-1 high -MAS-1 low profile is a transcriptomic proxy for IHG-I and that both of these metrics of optimal IR are overrepresented in females Fig. Compared with the SAS-1 high -MAS-1 low profile, the hazard of dying, after controlling for age and sex, was higher and similar in persons with the SAS-1 high -MAS-1 high and SAS-1 low -MAS-1 low profiles and highest in persons with the SAS-1 low -MAS-1 high profile Fig.

Correspondingly, SAS-1 low -MAS-1 high was overrepresented and SAS-1 high -MAS-1 low was underrepresented at baseline in nonsurvivors Fig. First, among older FHS participants, females lived longer than males, and levels of SAS-1 and MAS-1 further stratified survival rates Supplementary Fig.

The survival rates in older 66—92 years persons were highest in females with SAS-1 high or MAS-1 low , intermediate in females with SAS-1 low or MAS-1 high and males with SAS-1 high or MAS-1 low , and lowest in males with SAS-1 low or MAS-1 high Supplementary Fig.

This survival hierarchy and our findings in Fig. c Model: age, sex, and immunologic resilience IR levels influence lifespan. d Sepsis 1 comprises healthy controls and meta-analysis of patients with community-acquired pneumonia CAP and fecal peritonitis FP stratified by sepsis response signature groups G1 and G2 associated with higher and lower mortality, respectively.

Sepsis 2 comprises healthy controls and patients with systemic inflammatory response syndrome SIRS , sepsis, and septic shock survivors S and nonsurvivors NS. P values asterisks, ns for participants with SAS-1 low -MAS-1 high at pre-ARI right are for their cross-sectional comparison to the profiles at the corresponding timepoints for participants with SAS-1 high -MAS-1 low at pre-ARI middle.

f Schema of the timing of gene expression profiling in experimental intranasal challenges with respiratory viral infection in otherwise healthy young adults with data presented in panels g and h.

T, time. g Participants inoculated intra-nasally with respiratory syncytial virus RSV , rhinovirus, or influenza virus stratified by symptom status and sampling timepoint.

symptomatic, Asymp. h Participants inoculated intra-nasally with influenza virus stratified by symptom status and sampling timepoint. i Individuals with severe influenza infection requiring hospitalization collected at three timepoints, overall, and by age strata and severity.

Patients were grouped by increasing severity levels: no supplemental oxygen required, oxygen by mask, and mechanical ventilation.

Cohort characteristics and sources of biological samples and gene expression profile data are in Supplementary Data 13a.

Based on gene expression profiles obtained at baseline admission , Knight and colleagues categorized four cohorts of individuals into sepsis risk groups that predicted mortality vs. survival in individuals admitted to intensive care units with severe sepsis due to community-acquired pneumonia or fecal peritonitis 37 , Our evaluations revealed that, irrespective of age, the survival-associated SAS-1 high -MAS-1 low profile was highly underrepresented, whereas SAS-1 low -MAS-1 high and SAS-1 low -MAS-1 low profiles were disproportionately overrepresented in the sepsis risk group associated with mortality G1 group vs.

survival G2 group Fig. Thus, consistent with our model Fig. We next examined whether asymptomatic ARI was associated with the IR erosion-resistant phenotype, i. symptomatic infection after viral challenge at two timepoints: baseline T1 vs. when symptomatic patients had peak symptoms T2 Fig.

Figure 8g shows the combined results of three different viral challenges influenza virus, respiratory syncytial virus, rhinovirus.

Among symptomatic participants, SAS-1 low -MAS-1 high was enriched at T2 vs. T1 Fig. In contrast, among persons who remained asymptomatic, proportions of the SAS-1 low -MAS-1 high profile did not change substantially between T1 and T2; instead at T2, there was a significant enrichment of SAS-1 high -MAS-1 low compared to symptomatic participants Fig.

Similar results were observed in another study in which participants were challenged with influenza virus Fig. Supporting these findings in humans, among pre-Collaborative Cross-RIX mice strains infected with influenza, SAS-1 high -MAS-1 low was overrepresented, whereas SAS-1 low -MAS-1 high was underrepresented in strains that manifested histopathologic features of mild low response vs.

severe high response infection Supplementary Fig. Paralleling the time series shown in Fig. However, regardless of age, the hallmark of less-severe vs. most-severe influenza infection was the capacity to reconstitute a survival-associated SAS-1 high -MAS-1 low profile more quickly Fig.

Figure 9a synthesizes the key findings from study phases 1, 2, and 3. Viral challenge studies in humans Fig. rapid restoration of the survival-associated IC high -IF low state SAS-1 high -MAS-1 low profile during the convalescence phase Fig.

Ag antigenic, F female, H high, IC immunocompetence, IF inflammation, L low, M male b IR erosion-resistant and IR erosion-susceptible phenotypes based on experimental models.

c Correlation r ; Pearson between expression levels of genes within SAS-1 and MAS-1 signatures with levels of an indicator for T-cell responsiveness, T-cell dysfunction, and systemic inflammation. d , e Levels of the indicated immune traits by IHGs in d sooty mangabeys seropositive for simian immunodeficiency virus SIV and e SIV-seronegative Chinese rhesus macaques.

Comparisons were made between IHG-I vs. IHG-III and IHG-II vs. To further support the idea that the SAS-1 high -MAS-1 low profile tracks an IC high -IF low state, we determined the correlation between expression levels of genes comprising SAS-1 and MAS-1 with indicators of T-cell responsiveness and dysfunction in peripheral blood 8 , 43 , as well as systemic inflammation plasma IL-6, a biomarker of age-associated diseases and mortality 44 , 45 , 46 Fig.

Genes correlating positively with T-cell responsiveness and negatively with T-cell dysfunction or plasma IL-6 levels were considered to have pro-IR functions; genes with the opposite attributes were considered to have IR-compromising functions Fig.

We found that SAS-1 was enriched for genes whose expression levels correlated positively with pro-IR functions; several of these genes have essential roles in T-cell homeostasis e.

Compared with SAS-1, MAS-1 was enriched for genes whose expression levels correlated with IR-compromising functions e. These associations, coupled with the distribution patterns of the IR metrics across age, raised the possibility that levels of immune traits differed by i IR IHG status, after controlling for age age-independent vs.

ii age, regardless of IR IHG status age-dependent , vs. iii both. Additionally, because we observed evolutionary parallels between humans and nonhuman primates Figs. Trait levels in both species differed to a greater extent by IHG status than age Supplementary Data Thus, CD8-CD4 disequilibrium grades IHG-III and IHG-IV were highly prevalent in nonhuman primates Fig.

In general, IHG-I appeared to be associated with a better immune trait profile e. Contrary to nonhuman primates, CD8-CD4 equilibrium grades IHG-I and IHG-II vs. disequilibrium grades IHG-III or IHG-IV are much more prevalent across age in humans Fig.

However, emphasizing evolutionary parallels, we identified similar traits associated with IHG status after controlling for age in both humans and nonhuman primates. Group 1 comprised 13 immune traits whose levels differed between CD8-CD4 equilibrium vs.

disequilibrium grades IHG-I vs. IHG-III or IHG-II vs IHG-IV , after controlling for age and sex. Group 3 comprised 10 immune traits that differed by attributes of both groups 1 and 2 after controlling for sex. Group 4 neutral comprised 30 immune traits that did not differ by group 1 or 2 attributes Fig.

Within each group, traits were clustered into signatures according to whether their levels were higher or lower with IHG-III or IHG-IV, after controlling for age and sex; by age in older or younger persons with IHG-I or IHG-II, after controlling for sex; both; or neither.

cDC, conventional dendritic cells. Two arrows indicate both comparisons for IHG-I vs. IHG-IV or age within IHG-I and IHG-II are significant, one arrow indicates only one of the comparisons for IHG status or age is significant.

b Representative traits by age in persons with IHG-I or IHG-II and by IHG status. Comparisons for the indicated traits were made between IHG-I vs. Median number of individuals evaluated by IHG status and age within IHG-I or IHG-II. ns nonsignificant. c Linear regression was used to analyze the association between log 2 transformed cell counts outcome with age and IHG status predictors.

FDR, false discovery rate P values adjusted for multiple comparisons. d Model differentiating features of processes associated with lower immune status that occur due to aging or via erosion of IR.

SAS-1, survival-associated signature-1; MAS-1, mortality-associated signature Figure 10b shows that the levels of a representative trait in signature 6 naïve CD8 bright differed between older vs. younger persons with IHG-I or IHG-II but did not differ by IHG status.

Thus, group 2 immune traits represent traits that are associated with aged CD8-CD4 equilibrium. Additional trait features of Groups 1—4 are discussed Supplementary Note 8. Thus, suggesting evolutionary parallels, we identified similar immunologic features e.

However, since the prevalence of IHG-III or IHG-IV increases with age Fig. Our study addresses a fundamental conundrum. Conversely, why do some older persons resist manifesting these attributes? This failure indicates the IR erosion-susceptible phenotype.

We examined IR levels and responses in varied human and nonhuman cohorts that are representative of different types and severity of inflammatory antigenic stressors. The sum of our findings supports our study framework that optimal IR is an indicator of successful immune allostasis adaptation when experiencing inflammatory stressors, correlating with a distinctive immunocompetence-inflammation balance IC high -IF low that associates with superior immunity-dependent health outcomes, including longevity Fig.

This IR degradation correlates with a gene expression signature profile SAS-1 low -MAS-1 high tracking an IC low -IF high status linked to mortality both during aging and COVID, as well as immunosuppression e. Despite clinical recovery from such common viral infections, some younger adults were unable to reconstitute optimal IR.

However, since the prevalence of the SAS-1 low -MAS-1 high profile increases steadily with age, it may give the misimpression that this profile relates to the aging process vs. IR degradation. To test our study framework Fig. These complementary metrics provide an easily implementable method to monitor the IR continuum irrespective of age Figs.

Paralleling the observation that females manifest advantages for immunocompetence and longevity 2 , 3 , 4 , 5 , the IR erosion-resistant phenotype was more common in females including postmenopausal.

Congruently, immune traits associated with some nonoptimal IR metrics were similar in humans and nonhuman primates.

Additionally, in Collaborative Cross-RIX mice, the IR erosion-resistant phenotype was associated with resistance to lethal Ebola and severe influenza infection. We accrued direct evidence of the benefits of optimal IR during exposure to a single inflammatory stressor by examining young adults during experimental intranasal challenge with common respiratory viruses e.

The hallmark of asymptomatic status after intranasal inoculation of respiratory viruses was the capacity to preserve, enrich, or rapidly restore the survival-associated SAS-1 high -MAS-1 low profile Figs. Findings noted on longitudinal monitoring of IR degradation and reconstitution during natural infection with common respiratory viruses supported this possibility.

During recovery, reconstitution of optimal IR was greater and faster in persons who before infection had the survival-associated SAS-1 high -MAS-1 low vs. the SAS-1 low -MAS-1 high profile Fig. However, despite the elapse of several months from initial infection, some younger persons with the SAS-1 high -MAS-1 low profile before infection failed to reconstitute this profile exemplifying residual deficits in IR Fig.

An impairment in the capacity for reconstitution of optimal IR was also observed in prospective cohorts with other inflammatory contexts FSWs, COVID, HIV infection.

These findings support our viewpoint that the deviation from optimal IR that tends to occur with age could be due to an impairment in the reconstitution of IR in individuals with the IR erosion-susceptible phenotype Fig.

There is significant interest in identifying host genetic factors that mediate resistance to acquiring SARS-CoV-2 or developing severe COVID 59 , 60 , We are currently investigating whether failure to reconstitute optimal IR after acute COVID may contribute to postacute sequelae.

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JOURNAL FREE ACCESS. Published: October 31, Received: August 31, Available on J-STAGE: December 01, Accepted: September 10, Advance online publication: - Revised: -. Download PDF K Download citation RIS compatible with EndNote, Reference Manager, ProCite, RefWorks.

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