CoChat
Sign Up
Cited by 359SARS-CoV-2 and COVID-19 ResearchCOVID-19 Clinical Research StudiesImmune responses and vaccinations

SARS-CoV-2, COVID-19 and the aging immune system

Open access
Bartleson, Juliet M., Radenkovic, Dina, Covarrubias, Anthony J., Furman, David, Winer, Daniel A., Verdin, Eric·2021·Nature Aging
DOI 10.1038/s43587-021-00114-7PMC PMC8570568
Open this paper in CoChat — free accountOpen PDF

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease. Recent advances in the science of ageing have highlighted how ageing pathways control not only lifespan but also healthspan, the healthy years of life. Here, we discuss the ageing immune system and its ability to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We specifically focus on the intersect of severe COVID-19 and immunosenescence to highlight pathways that may be determinant for the risk of complications and death following infection with SARS-CoV-2. New or adapted therapeutics that target ageing-associated pathways may be important tools to reduce the burden of death and long-term disability caused by this pandemic. Proposed interventions aimed at immunosenescence could enhance immune function not only in the elderly but in susceptible younger individuals as well, ultimately improving complications of severe COVID-19 for all ages.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that age-related immune changes—especially chronic inflammation, impaired type I interferon responses, poor T cell priming/diversity, and dysregulated innate responses—overlap with the immune profile of severe COVID-19, helping explain why older adults face worse outcomes. It also surveys candidate interventions targeting aging pathways, including senolytics, mTOR inhibitors, NAD+ precursors, and diet/caloric modulation, while cautioning that evidence remains limited.

Key findings

  • Age is described as the strongest single risk factor for COVID-19 mortality; CDC data cited as of May 24, 2021, report nearly 590,000 US deaths, about 80% in people aged 65+, with hospitalization/death rates roughly 1,300-fold higher at ages 65–74 and 8,700-fold higher at 85+ compared with ages 5–17.
  • Severe COVID-19 is characterized by early type I IFN defects, lymphopenia, reduced naive T cell/TCR diversity, impaired antigen presentation, and elevated proinflammatory cytokines such as IL-6, IL-1β, and TNFα—features that overlap with inflammageing and immunosenescence.
  • Aging and severe COVID-19 share prothrombotic and innate immune dysregulation, including monocyte/neutrophil changes, NLRP3 inflammasome activation, senescent cell/SASP effects, and ACE2/RAAS imbalance.
  • Proposed aging-targeted approaches include senolytics (fisetin, dasatinib plus quercetin), rapamycin/rapalogs, NAD+ precursors, and dietary/caloric interventions; vaccine data cited show Pfizer 94.7% efficacy in ≥65 (95% CI 66.7–99.9) and Moderna 86.4% (95% CI 61.4–95.2), but one study found 31% of people over 80 had no detectable neutralizing antibodies 17 days after the second Pfizer dose.

Methods

  • Narrative review synthesizing published literature on aging immunology, SARS-CoV-2 pathogenesis, and COVID-19 outcomes.
  • Evidence discussed includes human cohort/clinical studies, mouse models, and nonhuman primate (rhesus macaque) infection studies.
  • Main approach is thematic integration of innate and adaptive immune mechanisms, plus discussion of candidate therapeutic interventions; no systematic search or meta-analysis is described.

Limitations

  • The paper states that more studies are needed to disentangle inflammageing from severe COVID-19 susceptibility and that mechanistic links between reduced type I IFN in aging and severe COVID-19 require further investigation.
  • It notes that most human immune studies use blood rather than tissue, that mouse and human immune aging differ (e.g., naive T cell repertoire control, monocyte subsets), and that long-term vaccine efficacy and post-infection sequelae need follow-up.
  • Evident from the text: as a review, it presents no new primary data and does not report a systematic review protocol or formal risk-of-bias assessment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s43587-021-00114-7

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 233 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In data from Wuhan, age was the main risk factor for COVID-19 progression to acute respiratory distress syndrome and end-organ failure.

    “data from Wuhan, China showed that age was the primary risk factor associated with COVID-19 progression to acute respiratory distress syndrome (ARDS) and end-organ failure7”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [7] Wu, C. et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 180, 934–943 (2020). source

      Not checked in the free run.

    • cites [8] Santesmasses, D. et al. COVID-19 is an emergent disease of aging. Aging Cell 19, e13230 (2020). source

      Not checked in the free run.

    • cites [9] Zheng, Z. et al. Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis. J. Infect. 81, e16–e25 (2020). source

      Not checked in the free run.

    • cites [10] Bajgain, K. T., Badal, S., Bajgain, B. B. & Santana, M. J. Prevalence of comorbidities among individuals with COVID-19: a rapid review of current literature. Am. J. Infect. Control 49, 238–246 (2021). source

      Not checked in the free run.

  • Premisecitation

    Persistent low-grade chronic inflammation is a major contributor to immunosenescence.

    “This persistent, low-grade, chronic inflammation is speculated to drive many chronic diseases associated with ageing, and is also a main contributor to immunosenescence”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). source

      Not checked in the free run.

  • Premisecitation

    Chronological age remains the single greatest risk factor for COVID-19 mortality.

    “chronological age is still the single greatest risk factor for COVID-19 mortality13”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Ho, F. K. et al. Is older age associated with COVID-19 mortality in the absence of other risk factors? General population cohort study of 470,034 participants. PLoS ONE 15, e0241824 (2020). source

      Not checked in the free run.

  • Premisecitation

    ACE2 mRNA is decreased in multiple tissues of elderly humans compared with younger humans.

    “one study has shown a decrease in ACE2 mRNA in multiple tissues of elderly humans when compared to their younger counterparts64”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Chen, J. et al. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 19, e13168 (2020). source

      Not checked in the free run.

  • Premisecitation

    ACE2 expression is lower in the lungs of old rats than in younger rats.

    “there is a reduction of ACE2 expression in the lungs of old rats when compared to their younger counterparts63”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Xie, X., Chen, J., Wang, X., Zhang, F. & Liu, Y. Age- and gender-related difference of ACE2 expression in rat lung. Life Sci. 78, 2166–2171 (2006). source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 11
  • May combine two claims. 53
  • The quote only partly states this claim. 1

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    COVID-19 is a global health threat that poses especially high risk of severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease.

    “The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Inflammageing is an age-related rise in systemic basal inflammatory mediators that occurs independently of acute immune challenges.

    “As humans age, the presence of systemic basal inflammatory mediators increases independently of acute immune challenges in a phenomenon known as inflammageing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The immune system changes with age in nearly every aspect, generally leading to weaker pathogen immunity.

    “The immune system changes with age in nearly every aspect, generally resulting in a decline in pathogen immunity with increased age.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [1] Yoshikawa, T. T. Epidemiology and unique aspects of aging and infectious diseases. Clin. Infect. Dis. 30, 931–933 (2000). source

      Not checked in the free run.

    • cites [2] Goodwin, K., Viboud, C. & Simonsen, L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24, 1159–1169 (2006). source

      Not checked in the free run.

    • cites [3] Melegaro, A. & Edmunds, W. J. The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the elderly: a comparison of meta-analyses. Eur. J. Epidemiol. 19, 353–363 (2004). source

      Not checked in the free run.

    • cites [4] Wolters, B., Junge, U., Dziuba, S. & Roggendorf, M. Immunogenicity of combined hepatitis A and B vaccine in elderly persons. Vaccine 21, 3623–3628 (2003). source

      Not checked in the free run.

    • cites [5] Kaml, M. et al. Booster vaccination in the elderly: their success depends on the vaccine type applied earlier in life as well as on pre-vaccination antibody titers. Vaccine 24, 6808–6811 (2006). source

      Not checked in the free run.

    • cites [6] Hainz, U. et al. Insufficient protection for healthy elderly adults by tetanus and TBE vaccines. Vaccine 23, 3232–3235 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ageing is associated with high morbidity and mortality from various infections and with substantially lower vaccine efficacy.

    “ageing is associated with high morbidity and mortality rates for various infections and significant reductions in vaccine efficacy1-6”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [1] Yoshikawa, T. T. Epidemiology and unique aspects of aging and infectious diseases. Clin. Infect. Dis. 30, 931–933 (2000). source

      Not checked in the free run.

    • cites [2] Goodwin, K., Viboud, C. & Simonsen, L. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24, 1159–1169 (2006). source

      Not checked in the free run.

    • cites [3] Melegaro, A. & Edmunds, W. J. The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the elderly: a comparison of meta-analyses. Eur. J. Epidemiol. 19, 353–363 (2004). source

      Not checked in the free run.

    • cites [4] Wolters, B., Junge, U., Dziuba, S. & Roggendorf, M. Immunogenicity of combined hepatitis A and B vaccine in elderly persons. Vaccine 21, 3623–3628 (2003). source

      Not checked in the free run.

    • cites [5] Kaml, M. et al. Booster vaccination in the elderly: their success depends on the vaccine type applied earlier in life as well as on pre-vaccination antibody titers. Vaccine 24, 6808–6811 (2006). source

      Not checked in the free run.

    • cites [6] Hainz, U. et al. Insufficient protection for healthy elderly adults by tetanus and TBE vaccines. Vaccine 23, 3232–3235 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ACE2 is downregulated in people with cardiovascular disease and diabetes, conditions that also correlate with severe COVID-19.

    “ACE2 is also downregulated in humans with cardiovascular disease and diabetes, which also correlate with severe COVID-1965.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Tikellis, C. & Thomas, M. C. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int. J. Pept. 2012, 256294 (2012). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    SARS-CoV-2 is the causative agent of COVID-19.

    “SARS-CoV-2 is the causative agent of COVID-19, declared a global pandemic by the World Health Organization on March 11, 202035.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In COVID-19, ARDS appears as diffuse alveolar damage on autopsy and is linked to lung immune cell infiltration, cytokine storm and tissue damage.

    “During COVID-19, ARDS manifests as a diffuse alveolar damage pattern seen on autopsies of COVID-19 patients, and is linked to a combination of lung immune cell infiltration, cytokine storm, and tissue damage from secreted proteases, reactive oxygen species (ROS), and viral killing 49,50.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422 (2020). source

      Not checked in the free run.

    • cites [50] Desai, N. et al. Temporal and spatial heterogeneity of host response to SARS-CoV-2 pulmonary infection. Nat. Commun. 11, 6319 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most patients with severe COVID-19 have substantially elevated serum levels of proinflammatory cytokines and chemokines, which contribute to pneumonia, cytokine storm, ARDS, sepsis and coagulopathy.

    “The majority of patients with severe COVID-19 demonstrate substantially elevated serum levels of proinflammatory cytokines and chemokines, including IL-6, IL-1β, IL-2, IL-8, IL-17, G-CSF, GM-CSF, CXCL10, CCL2, CCL3 and TNF49,54,68.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [49] Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422 (2020). source

      Not checked in the free run.

    • cites [54] Dinnon, K. H. III et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature 586, 560–566 (2020). source

      Not checked in the free run.

    • cites [68] Qin, C. et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin. Infect. Dis. 71, 762–768 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Host TMPRSS2 promotes Spike protein priming and facilitates SARS-CoV-2 entry.

    “Host transmembrane protease serine 2 (TMPRSS2) promotes S protein priming and facilitates viral entry38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Hoffmann, M. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271–280 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    SARS-CoV-2 entry into target cells begins when the viral Spike protein receptor-binding domain engages ACE2.

    “Attachment and entry of SARS-CoV-2 to target cells is initiated when the virus engages its cognate receptor, angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) of the viral Spike protein, also called the S protein37.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Wang, Q. et al. Structural and functional basis of SARS-CoV-2 entry by using human ACE2. Cell 181, 894–904 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In severe COVID-19, ARDS usually begins around day 12 after symptom onset, when viral shedding is mostly resolved, and death or recovery follows about 7-12 days later.

    “The onset of ARDS in severe cases typically occurs around day 12 post-symptom onset44,57, when viral shedding appears to be mostly resolved58, followed by death or recovery around 7-12 days later44,57.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [44] Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020). source

      Not checked in the free run.

    • cites [57] Torres Acosta, M. A. & Singer, B. D. Pathogenesis of COVID-19-induced ARDS: implications for an ageing population. Eur. Respir. J. 56, 2002049 (2020). source

      Not checked in the free run.

    • cites [58] Tay, M. Z., Poh, C. M., Renia, L., MacAry, P. A. & Ng, L. F. P. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These age-related immunological changes weaken responses to most viruses and leave elderly people especially vulnerable to influenza, SARS-CoV-2 and other lethal coronaviruses.

    “These immunological changes weaken the immune responses to most viruses, leaving the elderly particularly vulnerable to influenza, SARS-CoV-2, and other lethal coronaviruses, such as SARS-CoV-1 and Middle East Respiratory Syndrome (MERS)-CoV31.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Nikolich-Zugich, J. et al. SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. GeroScience 42, 505–514 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflammageing is generally accepted to result from accumulated exogenous and endogenous stresses over time and to be mediated mainly by immune cells and senescent cells.

    “It is generally accepted that inflammageing occurs in response to an accumulation of exogeneous and endogenous physiological stresses over time and is primarily mediated by immune cells and senescent cells (Figure 1)14,15.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Ferrucci, L. & Fabbri, E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15, 505–522 (2018). source

      Not checked in the free run.

    • cites [15] Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Lower ACE2 may reduce the potential for SARS-CoV-2 invasion, while further ACE2 reduction caused by viral entry may worsen a proinflammatory response that mediates cytokine storm, acute lung injury and ARDS.

    “Decreased expression of ACE2 could mean less potential for SARS-CoV-2 invasion of host cells, and further ACE2 reduction caused by viral entry may exacerbate a heightened proinflammatory response that helps mediate cytokine storm, acute lung injury, and ARDS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Tikellis, C. & Thomas, M. C. Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease. Int. J. Pept. 2012, 256294 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Old rhesus macaques infected with SARS-CoV-2 had lower ACE2 levels than young macaques, supporting the idea that ACE2 is dysregulated in the elderly across species.

    “a study of SARS-CoV-2 infection in old and juvenile rhesus macaques showed lower levels of ACE2 in old versus young macaques after SARS-CoV-2 infection, supporting the hypothesis that ACE2 is dysregulated in the elderly, even across species67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Rosa, B. A. et al. IFN signaling and neutrophil degranulation transcriptional signatures are induced during SARS-CoV-2 infection. Commun. Biol. 4, 290 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutrophils from elderly individuals also show aberrant migration and enhanced degranulation.

    “neutrophils from the elderly also display aberrant migration and enhanced degranulation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Sapey, E. et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 123, 239–248 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-1β and IL-18 are important in inflammageing, are produced by the NLRP3 inflammasome, and contribute to ageing-related disease pathology.

    “IL-1β and IL-18 are also critical in inflammageing; these cytokines are products of the NLRP3 inflammasome, and contribute to the pathology of ageing-related diseases73.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Youm, Y. H. et al. Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. 18, 519–532 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pro-thrombotic coagulopathy, high D-dimer, venous thromboembolism, arterial thromboses and fibrin-based occlusion of small vessels are associated with severe COVID-19.

    “Pro-thrombotic coagulopathy, high levels of D-dimer, venous thromboembolism, arterial thromboses, and fibrin-based occlusion of small blood vessels have all been associated with cases of severe COVID-197,44,49,93-99.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Wu, C. et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern. Med. 180, 934–943 (2020). source

      Not checked in the free run.

    • cites [44] Zhou, F. et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395, 1054–1062 (2020). source

      Not checked in the free run.

    • cites [49] Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated IL-6 is a stable indicator of poor COVID-19 outcomes and is among the most reliable ageing parameters.

    “elevated IL-6 has been an especially stable indicator of poor outcomes in patients with COVID-19, and studies have demonstrated that IL-6 is also among the most reliable ageing parameters69.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Johnson, T. E. Recent results: biomarkers of aging. Exp. Gerontol. 41, 1243–1246 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells accumulate during ageing and have an abnormal secretory phenotype that includes inflammatory cytokines and contributes to inflammageing.

    “senescent cells persist and accumulate during ageing82 and they display an abnormal secretory phenotype characterized by the presence of inflammatory cytokines that contributes to inflammageing.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutrophils from elderly individuals show decreased bactericidal activity, decreased respiratory burst and decreased NET formation.

    “Neutrophils from elderly individuals exhibit some hyporesponsive attributes: decreased bactericidal activity, decreased respiratory burst, and decreased neutrophil extracellular traps (NET) formation85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Ortmann, W. & Kolaczkowska, E. Age is the work of art? Impact of neutrophil and organism age on neutrophil extracellular trap formation. Cell Tissue Res. 371, 473–488 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    If type I interferons are present early and properly localized to infection sites, they can limit viral propagation and support macrophage activation, dendritic cell antigen presentation and enhanced antiviral effector T cell responses.

    “If type I IFNs are present early and properly localized to sites of infection, they can effectively limit viral propagation, as type I IFNs are responsible for optimal activation of macrophages, antigen presentation by DCs, and enhanced anti-viral effector T cell responses106.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [106] McNab, F., Mayer-Barber, K., Sher, A., Wack, A. & O’Garra, A. Type I interferons in infectious disease. Nat. Rev. Immunol. 15, 87–103 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The reduced type I interferon response in humans is partly linked to a reduction in plasmacytoid dendritic cells, which are strong IFNα producers, and this reduction has also been reported in severe COVID-19.

    “The reduced type I IFN responses in humans is in part linked to a reduction of plasmacytoid DCs (pDCs), strong producers of IFNα, which has also been reported in cases of severe COVID-19103.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Zhou, R. et al. Acute SARS-CoV-2 infection impairs dendritic cell and T cell responses. Immunity 53, 864–877 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In ageing patients, SARS-CoV-2 can enhance NLRP3 inflammasome activation, IL-1β and IL-18 levels, pyroptosis and DAMP release, further increasing inflammation and COVID-19 pathogenesis.

    “In ageing patients, SARS-CoV-2 can potentiate NLRP3 inflammasome activation and IL-1β and IL-18 levels, pyroptosis, and the release of DAMPs (including ATP), further heightening inflammation and COVID-19 pathogenesis74,75.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Junqueira, C. et al. SARS-CoV-2 infects blood monocytes to activate NLRP3 and AIM2 inflammasomes, pyroptosis and cytokine release. Preprint at medRxiv https://doi.org/10.1101/2021.03.06.21252796 (2021). source

      Not checked in the free run.

    • cites [75] Rodrigues, T. S. et al. Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients. J. Exp. Med. 218, e20201707 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS increase with age because of mitochondrial dysfunction and inflammation, can drive NLRP3 inflammasome activation, and likely contribute further to COVID-19 pathophysiology in the elderly.

    “ROS increase with age due to mitochondrial dysfunction and inflammation, and can also drive NLRP3 inflammasome activation, likely further contributing to COVID-19 pathophysiology in the elderly58,76,77.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [58] Tay, M. Z., Poh, C. M., Renia, L., MacAry, P. A. & Ng, L. F. P. The trinity of COVID-19: immunity, inflammation and intervention. Nat. Rev. Immunol. 20, 363–374 (2020). source

      Not checked in the free run.

    • cites [76] Zheng, Y. et al. A human circulating immune cell landscape in aging and COVID-19. Protein Cell 11, 740–770 (2020). source

      Not checked in the free run.

    • cites [77] Mishra, S. R. et al. Mitochondrial dysfunction as a driver of NLRP3 inflammasome activation and its modulation through mitophagy for potential therapeutics. Int. J. Biochem. Cell Biol. 136, 106013 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many immune cells from an inflammageing environment are hyporesponsive to acute ex vivo stimuli, while monocytes appear hyperresponsive.

    “many immune cells (including B cells, T cells, and DCs) isolated from an inflammageing environment have been shown to be hyporesponsive to acute ex vivo stimuli, although monocytes appear to standout as being hyperresponsive81.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Sayed, N. et al. An inflammatory aging clock (iAge) based on deep learning tracks multi-morbidity, immunosenescence, frailty and cardiovascular aging. Nat. Aging 1, 598–615 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Thymic involution prevents the development of new T cells in elderly people, thereby restricting the T cell receptor repertoire.

    “Thymic involution, a process wherein the thymus gradually atrophies as we age, prevents the development of new T cells in the elderly, thus restricting the TCR repertoire.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Newly generated naive T cells that enter the aged T cell repertoire show reduced T effector qualities upon activation and generate less effective memory cells.

    “Evidence suggests newly generated naive T cells that do manage to enter the aged T cell repertoire display reduced T effector qualities upon activation and generate less effective memory cells134.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [134] Gruver, A. L., Hudson, L. L. & Sempowski, G. D. Immunosenescence of ageing. J. Pathol. 211, 144–156 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ageing leads to a delay in type I interferon responses linked to changes in viral sensing, a delay also seen in SARS-CoV-1.

    “Ageing leads to a delay in type I IFN responses, linked to changes in viral sensing, which was also seen in SARS-CoV-131.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Nikolich-Zugich, J. et al. SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes. GeroScience 42, 505–514 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Monocyte populations shift in elderly people, with accumulation of non-classical monocytes that downregulate HLA-DR.

    “Monocyte populations shift in the elderly, and there is an accumulation of non-classical monocytes that significantly downregulate HLA-DR123.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Seidler, S., Zimmermann, H. W., Bartneck, M., Trautwein, C. & Tacke, F. Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol. 11, 30 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This RIG-I compromise is associated with reduced type I interferon production in people over 65, impairing their antiviral responses such as to influenza A virus.

    “This is associated with reduced production of type I IFNs in those >65, impairing their anti-viral responses, like to respiratory influenza A virus115.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Molony, R. D. et al. Aging impairs both primary and secondary RIG-I signaling for interferon induction in human monocytes. Sci. Signal. 10, eaan2392 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adaptive responses to SARS-CoV-2 begin about one week after symptoms, and SARS-CoV-2-specific CD4+ and CD8+ T cells can be observed as early as four days after symptom onset.

    “Adaptive responses to SARS-CoV-2 begin around one week after symptoms (Figure 2), with SARS-CoV-2 specific CD4+ and CD8+ T cells being observed as early as four days post-symptom onset126.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Rydyznski Moderbacher, C. et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell 183, 996–1012 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elderly people have reduced total plasmacytoid dendritic cell numbers at baseline and their plasmacytoid dendritic cells often show reduced TLR7 expression.

    “The elderly also display reduced total numbers of pDCs at baseline and their pDCs often show reduced TLR7 expression117”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Feng, E., Balint, E., Poznanski, S. M., Ashkar, A. A. & Loeb, M. Aging and interferons: impacts on inflammation and viral disease outcomes. Cells 10, eaan2392 (2021). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other studies found no differences in CD4+ T cell effector functions between severe and mild COVID-19.

    “Some studies have found reduced effector functions for CD4+ T cells, i.e. IFNγ/IL-2/TNFα production, in patients with severe disease141, while others have seen no differences142.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Mazzoni, A. et al. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. J. Clin. Invest. 130, 4694–4703 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Virtual memory CD8+ T cells could benefit viral clearance but could also damage the host if left unregulated.

    “While this could provide a benefit in the clearance of the virus, it could also prove highly damaging to the host if left unregulated148.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Kim, T. S. & Shin, E. C. The activation of bystander CD8+ T cells and their roles in viral infection. Exp. Mol. Med. 51, 1–9 (2019).

      Not checked in the free run.

    • Rests on an assumption: Virtual memory CD8+ T cells are innate-like, can be activated by cytokines such as IL-15, IL-18, and type I IFNs, and mediate cytotoxic effects without cognate antigen during viral infections.

  • May combine two claims.

    Premisecitation

    A human equivalent of virtual memory CD8+ T cells (CD45RA+KIR+NKG2A+Eomes+) has been identified and positively correlates with age.

    “These ‘virtual memory’ CD8+ T cells have been most widely studied in mice147, but a human equivalent population has been identified (CD45RA+KIR+NKG2A+Eomes+) and similarly positively correlates with age147.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] White, J. T. et al. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat. Commun. 7, 11291 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SARS-CoV-2-specific T Follicular Helper cells are detected concurrently with the antibody response, suggesting a role for T-dependent antibody production.

    “This response occurs concurrently with the detection of circulating SARS-CoV-2 specific T Follicular Helper cells, suggesting a role for T-dependent antibody production126.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Rydyznski Moderbacher, C. et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell 183, 996–1012 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other studies report opposite CD8+ T cell findings in severe COVID-19.

    “For CD8+ T cells, there are reports of diminished CD8+ cytotoxicity and cytokine production in severe cases126,132, while others report the opposite141, and still others find no differences142.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Zheng, H. Y. et al. Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients. Cell. Mol. Immunol. 17, 541–543 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Lack of TCR diversity with age may prevent broad memory T cell development from prior exposures to endemic human coronaviruses.

    “Indeed, the lack of TCR diversity with age may prevent broad memory T cell development from prior exposures to the ‘common cold’ endemic human coronaviruses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Passive transfer of neutralizing antibodies reduces disease severity and offers protection in mouse models of SARS-CoV-2.

    “Neutralizing antibodies against the RBD of SARS-CoV-2 have been discovered in both mice and humans149,150, and passive transfer of these antibodies reduces disease severity and offers protection in mouse models of SARS-CoV-2.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [149] Alsoussi, W. B. et al. A potently neutralizing antibody protects mice against SARS-CoV-2 infection. J. Immunol. 205, 915–922 (2020). source

      Not checked in the free run.

    • cites [150] Zost, S. J. et al. Potently neutralizing and protective human antibodies against SARS-CoV-2. Nature 584, 443–449 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Still other studies find no differences in CD8+ T cell function between severe and mild COVID-19.

    “For CD8+ T cells, there are reports of diminished CD8+ cytotoxicity and cytokine production in severe cases126,132, while others report the opposite141, and still others find no differences142.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Mazzoni, A. et al. Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent. J. Clin. Invest. 130, 4694–4703 (2020). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many studies report a correlation between higher IgG antibody titers and severe COVID-19.

    “Many studies have reported a correlation between higher IgG antibody titers and severe disease, but others have seen either the opposite or no correlation between antibody production and disease severity126.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Rydyznski Moderbacher, C. et al. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity. Cell 183, 996–1012 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a cohort of 522 COVID-19 patients, lymphopenia was strongly associated with age in addition to disease severity, with patients older than 60 having the lowest total blood T cell numbers.

    “One cohort of 522 COVID-19 patients revealed a strong association between lymphopenia and age in addition to the association between lymphopenia and disease severity, such that patients older than 60 years had the lowest total number of T cells in their blood139.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [139] Diao, B. et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front. Immunol. 11, 827 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autoantibodies against type I IFNs were found across multiple ages, with higher prevalence in patients over 65.

    “These autoantibodies were found across multiple ages, though there was a higher prevalence in patients over 65.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, eabd4585 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    TNFα production increases with age and could contribute to diminished germinal center formation.

    “TNFα production also increases as we age and could contribute to this observed phenotype161-163.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [161] Fagiolo, U. et al. Increased cytokine production in mononuclear cells of healthy elderly people. Eur. J. Immunol. 23, 2375–2378 (1993). source

      Not checked in the free run.

    • cites [162] Bruunsgaard, H., Andersen-Ranberg, K., Hjelmborg, J., Pedersen, B. K. & Jeune, B. Elevated levels of tumor necrosis factor α and mortality in centenarians. Am. J. Med. 115, 278–283 (2003). source

      Not checked in the free run.

    • cites [163] Penninx, B. W. et al. Inflammatory markers and incident mobility limitation in the elderly. J. Am. Geriatr. Soc. 52, 1105–1113 (2004). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationcitation

    Age cripples the formation of class-switched antibody titers needed to clear SARS-CoV-2 infection.

    “Consistently, the levels of viral spike-protein-specific IgG during early time-points of acute SARS-CoV-2 infection in rhesus macaques are reduced in older macaques compared to young ones, consistent with age crippling the formation of class-switched antibody titers needed to clear the viral infection155.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Singh, D. K. et al. Responses to acute infection with SARS-CoV-2 in the lungs of rhesus macaques, baboons and marmosets. Nat. Microbiol. 6, 73–86 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The quality of the humoral immune response declines with age, as aged B cells have diminished potential to undergo somatic hypermutation.

    “The quality of the humoral immune response declines with age, as aged B cells display a diminished potential to undergo somatic hypermutation154, which could prevent the aged from generating robust neutralizing antibody titers to aid the clearance of natural infection and generate effective immunity against re-infections.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Frasca, D., Diaz, A., Romero, M. & Blomberg, B. B. Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways. Exp. Gerontol. 87, 113–120 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Contradictory results on antibody production and COVID-19 severity might be explained by the dual role of antibodies: neutralizing antibodies are generally beneficial, but early or pre-existing non-neutralizing antibodies can enhance viral entry and induce a severe inflammatory response.

    “These seemingly contradictory results might possibly be explained by the dual role played by antibodies during viral infections: although neutralizing antibodies are generally beneficial to viral clearance, the early production or prior existence of already circulating, non-neutralizing antibodies can lead to antibody-mediated enhancement of viral entry and induce a severe inflammatory response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    Inhibition of mTORC1 could relieve feedback inhibition on other inflammatory and metabolic pathways, thus boosting immunity.

    “One possibility is that inhibition of mTORC1 could be relieving feedback inhibition on other inflammatory and metabolic pathways, thus boosting immunity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    One year of treatment with DHEA, metformin, and recombinant human growth hormone in elderly men resulted in a 1.5-year reduction in epigenetic age and significantly regenerated the thymus.

    “One year of treatment with DHEA, metformin, and recombinant human growth hormone therapy in elderly men resulted in a 1.5 year reduction in ‘epigenetic age’ and significantly regenerated the thymus165.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [165] Fahy, G. M. et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 18, e13028 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rapamycin and rapalogs are immunosuppressive at high doses but exert immunostimulatory effects at lower doses.

    “While they are immunosuppressive at high doses, these compounds exert immunostimulatory effects at lower doses170.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Ferrer, I. R., Araki, K. & Ford, M. L. Paradoxical aspects of rapamycin immunobiology in transplantation. Am. J. Transplant. 11, 654–659 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NMN administration in mice restores NAD+ levels and ameliorates mitochondrial function.

    “Studies of the NAD+ precursor, nicotinamide mononucleotide (NMN) administration in mice have been somewhat promising at restoring NAD+ levels and ameliorating mitochondrial function185.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] Kiss, T. et al. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects. GeroScience 42, 527–546 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Poor adaptive responses to SARS-CoV-2 in the elderly could be partly driven by ineffective T cell priming, lack of naive T cell diversity, diminished antibody maturation, and/or inefficient preexisting memory.

    “Meanwhile, poor adaptive responses to SARS-CoV-2 in the elderly could be partly driven by ineffective T cell priming, a lack of naive T cell diversity, diminished antibody maturation, and/or inefficient preexisting memory; these characteristics of immunosenescence are most likely compounded by viral evasion tactics and improper early innate responses.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    Recurring observations in severe COVID-19 include early defects in type I IFN production and signaling, sub-optimal T cell responses, and dysregulated monocyte and neutrophil inflammation.

    “Research has begun to identify the pathophysiological mechanisms underlying these events in response to SARS-CoV-2, and some recurring observations in cases of severe disease have emerged: 1) early defects in type I IFN production and signaling, 2) sub-optimal T cell responses, and 3) dysregulated monocyte and neutrophil inflammation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Basal inflammageing is driven by NF-κB signaling and generally renders immune cells initially hyporesponsive to acute activation, with the possible exception of monocyte subsets.

    “Basal inflammageing is driven by NF-κB signaling and generally renders immune cells initially hyporesponsive to acute activation, with the possible exception of the monocyte subsets71,81.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Salminen, A. et al. Activation of innate immunity system during aging: NF-kB signaling is the molecular culprit of inflamm-aging. Ageing Res. Rev. 7, 83–105 (2008). source

      Not checked in the free run.

    • cites [81] Sayed, N. et al. An inflammatory aging clock (iAge) based on deep learning tracks multi-morbidity, immunosenescence, frailty and cardiovascular aging. Nat. Aging 1, 598–615 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Lack of early type I IFN responses during severe COVID-19, compounded with JAK/STAT hyporesponsiveness of aged immune cells, could facilitate early viral replication and overburden the immune system in early elderly responses to SARS-CoV-2.

    “A lack of early type I IFN responses during severe COVID-19, compounded with the JAK/STAT hyporesponsiveness of aged immune cells17, could facilitate early viral replication and overburden the immune system in early elderly responses to SARS-CoV-2 invasion.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Shen-Orr, S. S. et al. Defective signaling in the JAK–STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst. 3, 374–384 (2016). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clinical trials using metformin to target ageing have begun.

    “Clinical trials utilizing metformin, which activates AMPK, to target ageing have already begun193.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Justice, J. N. et al. Development of clinical trials to extend healthy lifespan. Cardiovasc. Endocrinol. Metab. 7, 80–83 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Caloric restriction affects NF-κB, mTOR, AMPK, and MAPK pathways involved in ageing and inflammation, downregulating inflammatory markers such as IL-6 and IL-1β.

    “NF-κB, mTOR, AMPK, and MAPK are pathways that are involved in both ageing and inflammation and have been shown to be affected by caloric restriction, resulting in downregulation of inflammatory markers, such as IL-6 and IL-1β191,192.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [191] Chung, K. W. et al. Recent advances in calorie restriction research on aging. Exp. Gerontol. 48, 1049–1053 (2013). source

      Not checked in the free run.

    • cites [192] Chung, H. Y., Kim, H. J., Kim, J. W. & Yu, B. P. The inflammation hypothesis of aging: molecular modulation by calorie restriction. Ann. NY Acad. Sci. 928, 327–335 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Mediterranean diet reduces oxidative stress and inflammation and regulates gut microbiota eubiosis, contributing to improved immune responses.

    “This particular diet results in a reduction in both oxidative stress and inflammation and regulation of eubiosis of the gut microbiota, which in turn all contribute to an improvement in immune responses189.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Mitsou, E. K. et al. Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population. Br. J. Nutr. 117, 1645–1655 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced NAD+ levels are associated with impaired mitochondrial function, immune cell metabolic reprogramming, and cell function.

    “Therapeutics targeting NAD+ metabolism have also been proposed as potential treatments for age-related immune decline, since reduced NAD+ levels are associated with impaired mitochondrial function, immune cell metabolic reprogramming, and cell function182.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [182] Covarrubias, A. J., Perrone, R., Grozio, A. & Verdin, E. NAD+ metabolism and its roles in cellular processes during ageing. Nat. Rev. Mol. Cell Biol. 22, 119–141 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Undernutrition is common in older people and is linked to impaired immune responses.

    “Undernutrition, however, is common in older people, and is also linked to impaired immune responses187.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [187] Aiello, A. et al. Immunosenescence and its hallmarks: how to oppose aging strategically? A review of potential options for therapeutic intervention. Front. Immunol. 10, 2247 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ketones produced during ketogenic diets or fasting can impact immune function and may have therapeutic effects for COVID-19.

    “Additionally, ketones, which are largely produced during either ketogenic diets or fasting periods, can impact immune function and may have possible therapeutic effects for COVID-19194.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [194] Stubbs, B. J. et al. Investigating ketone bodies as immunometabolic countermeasures against respiratory viral infections. Med 1, 43–65 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fisetin and D+Q reduced SASP and improved survival in a mouse model of β-coronavirus.

    “For example, D+Q resulted in the reduction of SASP-associated proinflammatory cytokines during idiopathic pulmonary fibrosis, an age-related lung disease180, and a recent study showed that Fisetin and D+Q reduced SASP and improved survival in a mouse model of β-coronavirus84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science 373, eabe4832 (2021). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Restricting glucose utilization can be fatal in mice during viral infection, even though it is beneficial for fighting bacterial infections.

    “Restricting glucose utilization can also be fatal in mice during viral infection, even though it proves beneficial for fighting bacterial infections195.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [195] Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512–1525 (2016). source

      Not checked in the free run.

64 of 64

  • The paper relies on this without support.

    Findings about ageing and SARS-CoV-2 from animal models such as mice and rhesus macaques can be generalized to human COVID-19.

    “supporting the hypothesis that ACE2 is dysregulated in the elderly, even across species67”

  • The paper relies on this without support.

    T cell effector functions tend to decrease with age, while T cell exhaustion increases.

    “T cell effector functions tend to decrease with age, while T cell exhaustion increases.”

  • The paper relies on this without support.

    Virtual memory CD8+ T cells are innate-like, can be activated by cytokines such as IL-15, IL-18, and type I IFNs, and mediate cytotoxic effects without cognate antigen during viral infections.

    “Virtual memory CD8+ T cells are innate-like in that they can become activated by cytokines (IL-15, IL-18, and type I IFNs) and mediate cytotoxic effects without the need for their cognate antigen during viral infections.”

  • The paper relies on this without support.

    People of the same chronological age can have widely variable immunological age.

    “People of the same chronological age can have a widely variable ‘immunological age’.”

  • The paper relies on this without support.

    IL-6 is associated with poor COVID-19 outcomes.

    “However, rapamycin has also been observed to enhance expression of IL-6176-178 which is associated with poor COVID-19 outcomes, and patients with type 2 diabetes and COVID-19 had significantly increased mortality rates when receiving insulin treatment during the course of their hospitilization179.”

  • The paper relies on this without support.

    Senolytics clear senescent cells and reduce the proinflammatory and pro-thrombotic effects of SASP.

    “Senolytics, such as Fisetin and Quercetin and Dasatinib (D+Q), clear senescent cells and reduce the proinflammatory and pro-thrombotic effects of SASP.”

  • The paper relies on this without support.

    IL-1β and IL-6 are associated with severe COVID-19.

    “The use of probiotics in older adults has also been shown to regulate inflammatory conditions: specifically, probiotics can attenuate the production of both IL-1β and IL-6190, which are associated with severe COVID-19.”

  • The paper relies on this without support.

    Chronic infections such as CMV greatly affect ageing phenotypes.

    “Chronic infections, such as CMV, greatly affect ageing phenotypes, and it is possible COVID-19 may leave a lasting imprint on human physiology as well.”

  • The paper relies on this without support.

    The first defense against any virus is a properly functioning immune system.

    “Indeed, our first defense against any virus is a properly functioning immune system; thus, we need to further elucidate the mechanisms of immunosenescence and pursue the development of therapeutics that will enhance ‘healthspan’ in a preemptive way.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The underlying reasons for the well-established higher risk in the elderly or in individuals with chronic disease to experience severe COVID-19 or to succumb to SARS-CoV-2 infection are multifactorial.

    “The underlying reasons for the well-established higher risk in the elderly or in individuals with chronic disease to experience severe COVID-19 or to succumb to SARS-CoV-2 infection are multifactorial84,93.”

    From COVID-19 and cellular senescence (2023) · cites this paper as [84]

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 213 · Cited by 359

Authors
Bartleson, J. M., Radenkovic, D., Covarrubias, A. J., Furman, D., Winer, D. A., & Verdin, E.
Affiliations
  • Buck Institute for Research on Aging (US)
  • University of California, Los Angeles (US)
Corresponding author
  • Winer, Daniel A.
  • Verdin, Eric
ORCID
Venue
Nature Aging
Publisher
Springer Science and Business Media LLC
Published
2021-09-14
Volume
1
Issue
9
Pages
769-782
ISSN
2662-8465 (ISSN-L)
DOI
10.1038/s43587-021-00114-7
PMC
PMC8570568
OpenAlex
W3200259362
Cited by
359
References
213
Citations by year
2026: 32 · 2025: 59 · 2024: 71 · 2023: 99 · 2022: 87 · 2021: 11
FWCI
21.70
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Aging (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Buck Institute for Research on Aging
  • National Institutes of Health (AG000266)
  • National Institute on Aging (T32AG000266)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
SARS-CoV-2, COVID-19 pandemic, immunosenescence, aging immune system, older adults, healthspan, age-related diseases, anti-aging therapeutics
MeSH terms
Immunosenescence, COVID-19, SARS-CoV-2, Aging, Humans, Immune System

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review