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Cited by 439Immune responses and vaccinationsImmune Response and InflammationGenetics, Aging, and Longevity in Model Organisms

Aging of the immune system: Focus on inflammation and vaccination

Open access
Pinti, Marcello, Appay, Victor, Campisi, Judith, Frasca, Daniela, Fülöp, Tamas, Sauce, Delphine, Larbi, Anis, Weinberger, Birgit +1 more·2016·European Journal of Immunology
DOI 10.1002/eji.201546178PMC PMC5156481
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Abstract

Major advances in preventing, delaying, or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching eight to nine decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T‐cell or B‐cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly.

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Crossref · 10.1002/eji.201546178

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  • Findingcitation

    Age-related intrinsic B-cell defects responsible for sub-optimal antibody responses in elderly to infections and vaccines have been identified.

    “Age-related intrinsic B-cell defects, responsible for sub-optimal antibody responses in elderly individuals to infections and vaccines have been identified [95, 121–123]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [95] Wistuba-Hamprecht K Frasca D Blomberg B Pawelec G Derhovanessian E Age-associated alterations in gammadelta T-cells are present predominantly in individuals infected with Cytomegalovirus Immun Ageing 2013 10 26 23822093 PMC3703274 source

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    • cites [121] Frasca D Diaz A Romero M Landin AM Blomberg BB High TNF-alpha levels in resting B cells negatively correlate with their response Exp Gerontol 2014 54 116 122 24440385 PMC3989457 source

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    • cites [122] Frasca D Diaz A Romero M Landin AM Blomberg BB Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine Vaccine 2015 33 1433 1439 25659271 PMC4352374 source

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    • cites [123] Frasca D Diaz A Romero M Mendez NV Landin AM Blomberg BB Effects of age on H1N1-specific serum IgG1 and IgG3 levels evaluated during the 2011–2012 influenza vaccine season Immun Ageing 2013 10 14 23607926 PMC3639840 source

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  • Findingcitation

    The percentage of switched memory B cells decreases with age.

    “Using these markers, it has been shown that the percentage of switched memory B cells, the predictors of optimal antibody responses [114], decreases with age [115, 116].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [115] Frasca D Landin AM Lechner SC Ryan JG Schwartz R Riley RL Blomberg BB Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells J Immunol 2008 180 5283 5290 18390709 source

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    • cites [116] Shi Y Yamazaki T Okubo Y Uehara Y Sugane K Agematsu K Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell J Immunol 2005 175 3262 3267 16116217 source

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  • Findingcitation

    These intrinsic B-cell defects include decreases in expression and function of the transcription factor E47.

    “and include decreases in expression and function of the key transcription factor E47 (see below), along with a reduction in activation-induced cytidine deaminase (AID), the enzyme of class switch recombination and somatic hypermutation.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [95] Wistuba-Hamprecht K Frasca D Blomberg B Pawelec G Derhovanessian E Age-associated alterations in gammadelta T-cells are present predominantly in individuals infected with Cytomegalovirus Immun Ageing 2013 10 26 23822093 PMC3703274 source

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    • cites [121] Frasca D Diaz A Romero M Landin AM Blomberg BB High TNF-alpha levels in resting B cells negatively correlate with their response Exp Gerontol 2014 54 116 122 24440385 PMC3989457 source

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    • cites [122] Frasca D Diaz A Romero M Landin AM Blomberg BB Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine Vaccine 2015 33 1433 1439 25659271 PMC4352374 source

      Not checked in the free run.

    • cites [123] Frasca D Diaz A Romero M Mendez NV Landin AM Blomberg BB Effects of age on H1N1-specific serum IgG1 and IgG3 levels evaluated during the 2011–2012 influenza vaccine season Immun Ageing 2013 10 14 23607926 PMC3639840 source

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  • Findingcitation

    E47 mRNA expression is decreased in B cells from elderly individuals.

    “E47 mRNA expression has also been shown to be decreased in B cells from elderly individuals [115].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] Frasca D Landin AM Lechner SC Ryan JG Schwartz R Riley RL Blomberg BB Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells J Immunol 2008 180 5283 5290 18390709 source

      Not checked in the free run.

  • Findingcitation

    The percentage of late/exhausted memory B cells increases with age.

    “Conversely, the percentage of late/exhausted memory B cells, the antigen-experienced and pro-inflammatory B-cell subset, increases with age [117, 118].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Fecteau JF Cote G Neron S A new memory CD27-IgG+ B cell population in peripheral blood expressing VH genes with low frequency of somatic mutation J Immunol 2006 177 3728 3736 16951333 source

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    • cites [118] Colonna-Romano G Bulati M Aquino A Pellicano M Vitello S Lio D Candore G Caruso C A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people Mech Ageing Dev 2009 130 681 690 19698733 source

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  • May combine two claims. 63
  • Classified as probably not a substantial claim. 6

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    Findingcitation

    In influenza vaccination, decreased T-cell function and loss of CD28 expression are among the characterized defects.

    “For example, in the case of influenza vaccination, the following defects have been characterized: decreased T-cell function and loss of CD28 expression, reduced specificity and class of antibody produced and decreased memory B cells, reduced natural killer cell cytotoxicity on a per cell basis, and reduced number and/or function of circulating dendritic cells (reviewed in [120]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Frasca D Blomberg BB Aging, cytomegalovirus (CMV) and influenza vaccine responses Hum Vaccin Immunother 2015 PMC4964725 26588038 source

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    Findingcitation

    Serum antibody response to seasonal and pandemic influenza vaccines, and in vitro B-cell response after vaccination, both decrease with increasing age and are significantly correlated.

    “For example, the serum antibody response to both seasonal and pandemic influenza vaccines, as well as the in vitro B-cell response after vaccination, are both decreased with increasing age and are significantly correlated [114, 124, 125].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [114] Frasca D Diaz A Romero M Phillips M Mendez NV Landin AM Blomberg BB Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine Int Immunol 2012 24 175 182 22281510 PMC3621378 source

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    • cites [124] Khurana S Frasca D Blomberg B Golding H AID activity in B cells strongly correlates with polyclonal antibody affinity maturation in-vivo following pandemic 2009-H1N1 vaccination in humans PLoS Path 2012 8 e1002920 PMC3441753 23028320 source

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    • cites [125] Frasca D Diaz A Romero M Landin AM Phillips M Lechner SC Ryan JG Blomberg BB Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans Vaccine 2010 28 8077 8084 20974306 PMC3223387 source

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  • May combine two claims.

    Findingcitation

    Inflammaging drives TNF-α expression in B cells from elderly individuals, and these levels are positively correlated with serum TNF-α and negatively correlated with the response of the same B cells after in vitro stimulation, measured by AID.

    “Inflammaging not only induces higher expression of inflammatory miRs, but has also been shown to drive TNF-α expression in B cells from elderly individuals, and these levels are positively correlated with serum TNF-α and negatively correlated with the response of the same B cells after in vitro stimulation, which is measured by AID [121].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Frasca D Diaz A Romero M Landin AM Blomberg BB High TNF-alpha levels in resting B cells negatively correlate with their response Exp Gerontol 2014 54 116 122 24440385 PMC3989457 source

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  • May combine two claims.

    Findingnone given

    Aging is associated with expansion of highly differentiated mature CD57+CD56dimCD16+ NK cells and dysfunctional CD56−CD16+ NK cells.

    “and with the expansion of highly differentiated mature CD57+CD56dimCD16+ and dysfunctional CD56−CD16+ NK cells.”
    Quote in the paperSubstantial claim

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    Findingcitation

    Pharmacological inhibition of SHP-1 recovers TCR/CD28-dependent lymphocyte proliferation and IL-2 production, suggesting possible improvement of T-cell responses in healthy elderly.

    “Importantly, pharmacological inhibition of SHP-1 resulted in recovery of TCR/CD28-dependent lymphocyte proliferation and IL-2 production, suggesting the possibility of improving T-cell responses in the healthy elderly [138].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] LePage A Fortin C Garneau H Allard N Tsvetkova K Larbi A Dupuis G Modulation of Signaling in Lymphocytes from Elderly Donors. Inhibition of SRC Homology 2 Domain-Containing Phosphatase-1 (SHP-1) Leads to Recovery of T Cell Cell Commun Signal 2014 12 2 10.1186/1478-811X-12-2 24405902 PMC3896791 source

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    Findingcitation

    Pre-vaccination expression of genes associated with T-cell and B-cell function is positively correlated with influenza-specific antibody responses, while monocyte- and inflammation-related genes are negatively correlated.

    “Pre-vaccination expression of genes associated with T-cell and B-cell function were positively correlated with influenza-specific antibody responses, while monocyte- and inflammation-related genes were negatively correlated with influenza-specific antibody responses, supporting the concept that inflammatory responses at baseline might be detrimental to vaccine-induced antibody responses [155].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Nakaya HI Hagan T Duraisingham SS Lee EK Kwissa M Rouphael N Frasca D Systems Analysis of Immunity to Influenza Vaccination across Multiple Years and in Diverse Populations Reveals Shared Molecular Signatures Immunity 2015 43 1186 98 26682988 PMC4859820 source

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    Findingcitation

    Several studies found age-related alterations in T-cell signaling pathways, including impairment of PTK phosphorylation, decreased Ca2+ mobilization, and lowered PKC, PI3K and MAPK activation.

    “Several studies found age-related alterations in T-cell signaling pathways [135], including impairment of PTK phosphorylation, decreased Ca2+ mobilization, and lowered PKC, PI3K and MAPK activation [136].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [135] Aspinall R Lapenna A Lynch C Lang PO Cellular signalling pathways in immune aging and regeneration Biochem Soc Trans 2014 42 651 656 24849233 source

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    • cites [136] Goronzy JJ Li G Yu M Weyand CM Signaling pathways in aged T cells - A reflection of T cell differentiation, cell senescence and host environment Semin Immunol 2012 24 365 372 22560928 PMC3435478 source

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    Findingcitation

    The 13-valent conjugate vaccine has clinical efficacy of 45.6% for confirmed vaccine-type community-acquired pneumonia and 75.0% for vaccine-type invasive disease in elderly persons.

    “Recently, a 13-valent conjugate vaccine has been licensed for adults and its clinical efficacy was 45.6% (95.2% CI 21.8–62.5, p<0.001) for confirmed vaccine-type community-acquired pneumonia and 75.0% (95% CI 41.4–90.8, p<0.001) for vaccine-type invasive disease in a large randomized placebo-controlled study enrolling more than 84,000 elderly persons [168].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [168] Bonten MJ Huijts SM Bolkenbaas M Webber C Patterson S Gault S van Werkhoven CH Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults N Engl J Med 2015 372 1114 1125 25785969 source

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    Findingcitation

    Cholesterol content in the T-cell membrane is increased with aging, interfering with coalescence of lipid rafts necessary for adequate signaling.

    “Intrinsic alterations have been demonstrated at the level the T-cell membrane, as the cholesterol content in the membrane was found to be increased, interfering with the coalescence of the lipid rafts that are necessary for adequate signaling [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Larbi A Dupuis G Khalil A Douziech N Fortin C Fulop T Jr Differential role of lipid rafts in the functions of CD4+ and CD8+ human T lymphocytes with aging Cell Signal 2006 18 1017 1030 16236485 source

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    Findingcitation

    Dysregulation of the Csk/PAG/CD45 loop in aged T cells favors the inactive form of Lck, providing a molecular clue to altered T-cell responses in aging.

    “Dysregulation of the Csk/PAG/CD45 loop in aged T cells favors the inactive form of Lck [138], providing a molecular clue to altered T-cell responses in aging.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [138] LePage A Fortin C Garneau H Allard N Tsvetkova K Larbi A Dupuis G Modulation of Signaling in Lymphocytes from Elderly Donors. Inhibition of SRC Homology 2 Domain-Containing Phosphatase-1 (SHP-1) Leads to Recovery of T Cell Cell Commun Signal 2014 12 2 10.1186/1478-811X-12-2 24405902 PMC3896791 source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Inhibition of PI3K significantly improves neutrophil functions by restoring migratory accuracy in elderly subjects, whose PI3K signaling in resting neutrophils is constitutively increased.

    “For example, it has been recently demonstrated that the inhibition of PI3K, whose signaling in resting human neutrophils is constitutively increased in elderly subjects, significantly improves their functions by restoring neutrophil migratory accuracy [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Sapey E Greenwood H Walton G Mann E Love A Aaronson N Insall RH Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence Blood 2014 123 239 248 24191150 PMC3888290 source

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  • May combine two claims.

    Findingcitation

    Frailty impacts susceptibility to influenza and responsiveness to influenza vaccine in elderly patients.

    “In elderly patients, frailty, a multifactorial syndrome characterized by reduced stress resistance and physiological reserve [151, 152], and associated with increased serum levels of IL-6 [153], has been shown to impact susceptibility to influenza and responsiveness to influenza vaccine [154].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [154] Yao X Hamilton RG Weng NP Xue QL Bream JH Li H Tian J Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults Vaccine 2011 29 5015 21 21565245 PMC3129421 source

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    Findingcitation

    Elderly individuals have decreased numbers of B-cell lineages but increased pre-vaccination mutation load in their repertoire, resulting in a less efficient response, and lineage diversity is greatly reduced compared with young individuals.

    “Moreover, elderly individuals have decreased numbers of B-cell lineages but increased pre-vaccination mutation load in their repertoire, resulting in a less efficient response, and the diversity of the lineages is thus greatly reduced as compared with that in young individuals [131].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [131] Jiang N He J Weinstein JA Penland L Sasaki S He XS Dekker CL Zheng NY Lineage structure of the human antibody repertoire in response to influenza vaccination Sci Transl Med 2013 5 171ra119 PMC3699344 23390249 source

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  • May combine two claims.

    Findingcitation

    The defective ERK signaling was caused by DUSP6, whose protein expression increased with age due to a decline in repression by miR-181a.

    “The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Li G Yu M Lee WW Tsang M Krishnan E Weyand CM Goronzy JJ Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity Nat Med 2012 18 1518 1524 23023500 PMC3466346 source

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    Findingcitation

    The 23-valent polysaccharide vaccine against S. pneumoniae has efficacy against invasive disease, but efficacy against pneumonia is frequently in doubt because clinical study results are inconclusive.

    “A 23-valent polysaccharide vaccine against Streptococcus pneumoniae has been used for many years in the older population. Meta-analyses reported efficacy against invasive disease, but the efficacy against pneumonia is frequently in doubt, as results from clinical studies are inconclusive [167].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [167] Melegaro A Edmunds WJ The 23-valent pneumococcal polysaccharide vaccine. Part I. Efficacy of PPV in the elderly: a comparison of meta-analyses Eur J Epidemiol 2004 19 353 363 15180106 source

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    Findingcitation

    Activation of CD28 results in decreased levels of reduced glutathione (GSH) and increased levels of cytosolic ROS.

    “Activation of CD28 has been shown to result in decreased levels of reduced glutathione (GSH) and increased levels in cytosolic ROS [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Larbi A Kempf J Pawelec G Oxidative stress modulation and T cell activation Exp Gerontol 2007 42 852 858 17604927 source

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    Findingcitation

    Elderly individuals have a significant reduction in B-cell repertoire diversity, and this correlates with their health status.

    “Elderly individuals have a significant reduction in B-cell repertoire diversity and this correlates with their health status [128, 129].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [128] Tabibian-Keissar H Hazanov L Schiby G Rosenthal N Rakovsky A Michaeli M Shahaf GL Aging affects B-cell antigen receptor repertoire diversity in primary and secondary lymphoid tissues Eur J Immunol 2016 46 480 492 26614343 source

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    • cites [129] Gibson KL Wu YC Barnett Y Duggan O Vaughan R Kondeatis E Nilsson BO B-cell diversity decreases in old age and is correlated with poor health status Aging Cell 2009 8 18 25 18986373 PMC2667647 source

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    Findingcitation

    The live-attenuated herpes zoster vaccine reduces the incidence of herpes zoster by 51.3% and post-herpetic neuralgia by 66.5% compared to placebo.

    “A live-attenuated vaccine is available, which has been shown to reduce the incidence of herpes zoster by 51.3% (95% CI: 44.2–57.6) and of post-herpetic neuralgia, a severe complication occurring frequently in the elderly, by 66.5% (95% CI: 44.5–79.2) in the vaccinated population compared to placebo [170].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Oxman MN Levin MJ Johnson GR Schmader KE Straus SE Gelb LD Arbeit RD A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults N Engl J Med 2005 352 2271 2284 15930418 source

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    Findingcitation

    Pertussis is relevant for older age groups and does not solely affect infants.

    “Epidemiological data show that pertussis is relevant for older age groups and does not solely affect infants [177].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [177] Kaml M Weiskirchner I Keller M Luft T Hoster E Hasford J Young L 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 2006 24 6808 6811 16872725 source

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    Findingcitation

    The novel inactivated herpes zoster vaccine containing glycoprotein E adjuvanted with AS01B has clinical efficacy of 97.2% against herpes zoster for persons over age 50 and did not decrease for older age groups (>70 years).

    “In a phase III randomized placebo-controlled trial clinical efficacy against herpes zoster was 97.2% (95% CI: 93.7–99.0, p<0.001) for persons over the age of 50 and did not decrease for older age groups (>70 years) [171].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [171] Lal H Cunningham AL Godeaux O Chlibek R Diez-Domingo J Hwang SJ Levin MJ Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults N Engl J Med 2015 372 2087 2096 25916341 source

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    Findingcitation

    The protective effect of the live-attenuated herpes zoster vaccine against post-herpetic neuralgia was independent of age, whereas clinical efficacy against herpes zoster declined to 27.6% in persons older than 69 years.

    “The protective effect against post-herpetic neuralgia was independent of age, whereas clinical efficacy against herpes zoster declined to only 27.6% in persons older than 69 years.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Oxman MN Levin MJ Johnson GR Schmader KE Straus SE Gelb LD Arbeit RD A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults N Engl J Med 2005 352 2271 2284 15930418 source

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    Findingcitation

    The AS01B adjuvant system efficiently induces IgE-specific CD4+ T cells and cell-mediated immunity; antibody responses are higher compared with those induced by the live-attenuated vaccine.

    “The AS01B adjuvant system efficiently induces IgE-specific CD4+ T cells [172] and cell-mediated immunity; antibody responses are also higher compared with those induced by the live-attenuated vaccine [173].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [172] Chlibek R Bayas JM Collins H de la Pinta ML Ledent E Mols JF Heineman TC Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults >=50 years of age J Infect Dis 2013 208 1953 61 23904292 source

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    • cites [173] Leroux-Roels I Leroux-Roels G Clement F Vandepapelière P Vassilev V Ledent E Heineman TC A phase 1/2 clinical trial evaluating safety and immunogenicity of a varicella zoster glycoprotein e subunit vaccine candidate in young and older adults J Infect Dis 2012 206 1280 90 22872734 source

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    Premisecitation

    Inflammaging is a hallmark of nearly every major age-related disease and phenotype and a defining pathological feature of aging tissues across multiple species.

    “Inflammaging is a hallmark of virtually every major age-related disease and phenotype and has been shown to be a defining pathological characteristic of aging tissues across multiple species [5].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Finch CE Morgan TE Longo VD de Magalhaes JP Cell resilience in species life spans: a link to inflammation? Aging Cell 2010 9 519 526 20415721 PMC2952360 source

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    Premisecitation

    The gut microbial ecosystem changes with aging, with Bifidobacteria decreasing and facultative anaerobes such as Streptococci, Staphylococci, Enterococci and Enterobacteria increasing.

    “The microbial composition and diversity of the gut ecosystem changes with aging [10], as Bifidobacteria have been reported to decrease [11], while facultative anaerobes, including Streptococci, Staphylococci, Enterococci and Enterobacteria, increase with age [12]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [10] Heintz C Mair W You are what you host: microbiome modulation of the aging process Cell 2014 156 408 411 24485451 PMC3956044 source

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    • cites [11] Mueller S Saunier K Hanisch C Norin E Alm L Midtvedt T Cresci A Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study Appl Environ Microbiol 2006 72 1027 33 16461645 PMC1392899 source

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    • cites [12] Woodmansey EJ McMurdo ME Macfarlane GT Macfarlane S Comparison of compositions and metabolic activities of fecal microbiotas in young adults and in antibiotic-treated and non-antibiotic-treated elderly subjects Appl Environ Microbiol 2004 70 6113 6122 15466557 PMC522128 source

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

    Premisecitation

    Senescent cells have irreversibly arrested proliferation and altered function caused by stresses that increase with age.

    “senescent cells -- cells that have entered a state of irreversibly arrested cell proliferation (growth) and altered function as a consequence of many of the stresses that are known to increase with age [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Campisi J d’Adda di Fagagna F Cellular senescence: When bad things happen to good cells Nature Rev Molec Cell Biol 2007 8 729 740 17667954 source

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    Premisecitation

    Low-level chronic inflammation, called inflammaging, is a commonality among hallmarks of aging that has been linked to the immune system.

    “One of these commonalities has been linked to the immune system: low levels of chronic inflammation, otherwise known as inflammaging or inflamm-ageing [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Cevenini E Monti D Franceschi C Inflamm-ageing Curr Opin Clin Nutr Metab Care 2013 18 14 20 23132168 source

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    Premisecitation

    Inflammaging involves persistent low-level infiltration of immune cells, mainly but not exclusively innate immune cells, and elevated pro-inflammatory cytokines and chemokines in both tissue and systemic environments.

    “Inflammaging is characterized by the low level persistent infiltration of immune cells, primarily but not exclusively cells of the innate immune system, and elevated levels of several pro-inflammatory cytokines and chemokines [6], both within the tissue microenvironment and the systemic milieu.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Fagiolo U Cossarizza A Scala E Fanales-Belasio E Ortolani C Cozzi E Monti D Increased cytokine production in mononuclear cells of healthy elderly people Eur J Immunol 1993 23 2375 2378 8370415 source

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

    Premisecitation

    The hallmarks of aging include stem cell exhaustion, altered intercellular communication, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, altered nutrient and growth factor sensing, mitochondrial dysfunction and cellular senescence.

    “These hallmarks of aging include stem cell exhaustion, altered intercellular communication, genomic instability and telomere attrition, epigenetic alterations, loss of protein homeostasis (proteostasis), altered nutrient and growth factor sensing, mitochondrial dysfunction and cellular senescence [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging Cell 2013 153 1194 1217 23746838 PMC3836174 source

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

    Premisecitation

    A large body of experimental evidence across organisms from yeast to primates indicates at least nine evolutionarily conserved hallmarks of aging that derive from a small number of basic aging processes.

    “a very large body of experimental evidence from a wide variety of organisms ranging from yeast to primates strongly suggests there are at least nine evolutionarily conserved hallmarks of aging that almost certainly derive from a small handful of basic aging processes [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] López-Otín C Blasco MA Partridge L Serrano M Kroemer G The hallmarks of aging Cell 2013 153 1194 1217 23746838 PMC3836174 source

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    Premisecitation

    Neutrophil numbers do not change with age, but neutrophils show profound functional alterations.

    “The number of neutrophils does not change with age, but profound functional alterations have been observed in this cell type [37,38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] Butcher SK Chahal H Nayak L Sinclair A Henriquez NV Sapey E O'Mahony D Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans J Leukocyte Biol 2001 70 881 886 11739550 source

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    • cites [38] Brubaker AL Rendon JL Ramirez L Choudhry MA Kovacs EJ Reduced Neutrophil Chemotaxis and Infiltration Contributes to Delayed Resolution of Cutaneous Wound Infection with Advanced Age J Immunol 2013 190 1746 1757 23319733 PMC3563860 source

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

    Premisecitation

    Adiponectin is anti-inflammatory in adipose tissue by regulating anti-inflammatory cytokine production and polarizing macrophages toward an M2 phenotype.

    “Adiponectin, which is associated with lean states and insulin sensitivity, has been hailed as an anti-inflammatory force in adipose tissue by regulating the production of anti-inflammatory cytokines, and polarizing macrophages toward anti-inflammatory M2 phenotype [25, 26].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Arita Y Kihara S Ouchi N Takahashi M Maeda K Miyagawa J Hotta K Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity Biochem Biophys Res Commun 1999 257 79 83 10092513 source

      Not checked in the free run.

    • cites [26] Ohashi K Parker JL Ouchi N Higuchi A Vita JA Gokce N Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype J Biol Chem 2010 285 6153 6160 20028977 PMC2825410 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Most human data on monocyte TLR responses come from isolated monocytes treated in vitro, and some contrasting results could be due to enhanced responsiveness from cells with progressive differentiation in vitro.

    “most of these data concerning humans have been obtained in isolated monocytes treated in vitro, and some of the contrasting results observed could be due to enhanced responsiveness from cells with progressive differentiation in vitro [50].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Mizel SB Bates JT Flagellin as an adjuvant: cellular mechanisms and potential J Immunol 2010 185 5677 5682 21048152 PMC3756556 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The impairment of pDC cytokine release is likely caused by defects in signal transduction, since TLR expression in pDCs is constant over life.

    “As the expression of TLRs in pDCs is constant over the life [61], it is likely that this impairment is caused by defects in signal transduction, as discussed below.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] do Nascimento MP Pinke KH Penitenti M Ikoma MR Lara VS Aging does not affect the ability of human monocyte-derived dendritic cells to phagocytose Candida albicans Aging Clin Exp Res 2015 27 785 789 25783173 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human monocytes, TNF-α and IL-6 synthesis after TLR1/2 engagement is severely reduced, while TNF-α release after TLR4 stimulation is increased.

    “The synthesis of TNF-α and IL-6 after TLR1/2 engagement, for example, is severely reduced in human monocytes, while release of TNF-α upon TLR4 stimulation is increased [48].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] van Duin D Mohanty S Thomas V Ginter S Montgomery RR Fikrig E Allore HG Age-associated defect in human TLR-1/2 function J Immunol 2007 178 970 975 17202359 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PBMCs from old individuals have delayed and altered transcriptional responses to TLR4, TLR7/8 and RIG-I agonists, with decreased production of TNF-α, IL-6, IL-1β, IFN-α, IFN-γ, CCL2 and CCL7.

    “Peripheral blood mononuclear cells (PBMCs) from old individuals ( 65 years) have been shown to have a delayed and altered transcriptional response to stimulation with TLR4, TLR7/8, and RIG-I agonists; this altered response is accompanied by a decreased production of the pro-inflammatory and antiviral cytokines TNF-α, IL-6, IL-1β, IFN-α, and IFN-γ, and of the chemokines CCL2 and CCL7 [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Metcalf TU Cubas RA Ghneim K Cartwright MJ Grevenynghe JV Richner JM Olagnier DP Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors Aging Cell 2015 14 421 32 25728020 PMC4406671 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutrophils from elderly subjects ingest non-opsonized particles well but have reduced uptake of opsonized particles or pathogens such as Escherichia coli.

    “neutrophils from elderly subjects show a well-preserved capability to ingest non-opsonized particles [24], but a reduced capability to uptake opsonized particles, or pathogens such as Escherichia coli [37,42]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Wiley CD Velarde MC Lecot P Liu S Sarnoski EA Freund A Shirakawa K Mitochondrial dysfunction induces senescence with a distinct secretory phenotype Cell Metab 2016 23 303 314 26686024 PMC4749409 source

      Not checked in the free run.

    • cites [37] Butcher SK Chahal H Nayak L Sinclair A Henriquez NV Sapey E O'Mahony D Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans J Leukocyte Biol 2001 70 881 886 11739550 source

      Not checked in the free run.

    • cites [42] Alonso-Fernandez P Puerto M Mate I Ribera JM de la Fuente M Neutrophils of Centenarians Show Function Levels Similar to Those of Young Adults J Am Geriatr Soc 2008 56 2244 2251 19093924 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-related monocyte dysregulation appears caused by altered surface TLR expression and impaired downstream signaling, including declining TLR1 expression and severely reduced MAPK and ERK1/1 activation after TLR1/2 triggering.

    “Such dysregulation appears to be caused by both alteration in surface TLR expression and impairment of downstream signaling: while TLR2 expression is constant, TLR1 expression declines with age, and activation of MAPK and ERK1/1 pathways after TLR1/2 triggering is severely reduced in cells from elderly subjects [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Qian F Wang XM Zhang L Chen S Piecychna M Allore H Bockenstedt L Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly Aging Cell 2012 11 104 110 22023165 PMC3257374 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elderly people who exercise regularly and are leaner have fewer senescent T cells and lower circulating pro-inflammatory cytokines.

    “elderly subjects who exercise regularly and are leaner have fewer senescent T cells and lower circulating pro-inflammatory cytokines [33]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Simpson RJ Lowder TW Spielmann G Bigley AB LaVoy EC Kunz H Exercise and the aging immune system Ageing Res Rev 2012 11 404 420 22465452 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Monocytes from aged donors show reduced ROS production and phagocytosis, and dysregulated cytokine release after TLR activation.

    “significant age-related reduction of reactive oxygen species (ROS) production and phagocytosis capability have been described [46, 47], along with profound dysregulation in the release of different cytokines after the activation of monocytes through Toll-like receptors (TLR).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [46] Hearps AC Martin GE Angelovich TA Cheng WJ Maisa A Landay AL Jaworowski A Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function Aging Cell 2012 11 867 875 22708967 source

      Not checked in the free run.

    • cites [47] Mclachlan JA Serkin CD Morrey KM Bakouche O Antitumoral properties of aged human monocytes J Immunol 1995 154 832 843 7814887 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mouse models, SASP can promote wound healing and optimize formation of certain embryonic structures.

    “using a mouse model in which senescent cells can be detected in living animals, SASP was also recently shown to promote wound healing and optimize the formation of certain embryonic structures.”
    • Also stated in: § Introduction · plain
      “SASP can optimize the formation of certain embryonic structures [20, 21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Demaria M Ohtani B Youssef SA Rodier F Toussaint W Mitchell JR Laberge RM An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA Dev Cell 2014 31 722 733 25499914 PMC4349629 source

      Not checked in the free run.

    • cites [21] Storer M Mas A Robert-Moreno A Pecoraro M Ortells MC Di Giacomo V Yosef R Senescence is a developmental mechanism that contributes to embryonic growth and patterning Cell 2013 155 1119 1130 24238961 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neutrophils from elderly subjects have reduced migration toward chemotactic signals, probably because of constitutive activation of PI3K.

    “neutrophils from elderly subjects are characterized by a reduced capability to migrate towards a chemotactic signal, probably because of a constitutive activation of the lipid kinase phosphoinositide 3-kinase [PI3 K] [39]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Sapey E Greenwood H Walton G Mann E Love A Aaronson N Insall RH Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence Blood 2014 123 239 248 24191150 PMC3888290 source

      Not checked in the free run.

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

    Premisecitation

    The growth arrest of senescence almost certainly evolved to suppress cancer development.

    “The senescence growth arrest almost certainly evolved to suppress the development of cancer [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Campisi J Senescent cells, tumor suppression and organismal aging: Good citizens, bad neighbors Cell 2005 120 513 522 15734683 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging does not significantly change the absolute number or frequency of overall monocytes in humans, but it changes their relative distribution, reducing classical monocytes and increasing intermediate and non-classical monocytes.

    “Aging has not been shown to significantly alter the absolute number and the frequency of overall monocytes in humans [44], but does determines significant changes in the relative distribution of their subsets, with a marked reduction of the classical subset and an increase in the number of intermediate and non-classical monocytes [46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [44] Metcalf TU Cubas RA Ghneim K Cartwright MJ Grevenynghe JV Richner JM Olagnier DP Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors Aging Cell 2015 14 421 32 25728020 PMC4406671 source

      Not checked in the free run.

    • cites [46] Hearps AC Martin GE Angelovich TA Cheng WJ Maisa A Landay AL Jaworowski A Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function Aging Cell 2012 11 867 875 22708967 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Langerhans cells markedly diminish with age, and this reduction could contribute to the higher risk of skin infection in elderly subjects.

    “it is well established that Langerhans cells (LCs) markedly diminish with age [56, 57], and that such a reduction could contribute to the higher risk of skin infection in elderly subjects [58].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [56] Bhushan M Cumberbatch M Dearman RJ Andrew SM Kimber I Griffiths CEM Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing British Journal of Dermatology 2002 146 32 40 11841364 source

      Not checked in the free run.

    • cites [57] Zavala WD Cavicchia JC Deterioration of the Langerhans cell network of the human gingival epithelium with aging Archives of Oral Biology 2006 51 1150 1155 16919594 source

      Not checked in the free run.

    • cites [58] Laube S Skin infections and ageing Ageing Research Reviews 2004 3 69 89 15163103 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    pDCs from elderly subjects show marked impairment of pro-inflammatory cytokine release upon viral or TLR stimulation, with reduced intracellular TNF-α, IL-6, IL-12, IFN-α, IFN-β and IFN-γ, but phagocytosis appears well preserved.

    “pDCs are characterized by a marked impairment of pro-inflammatory cytokine release with aging: pDCs display a reduction in intracellular levels of TNF-α, IL-6 and IL-12, as well as IFN-α, IFN-β and IFN-γ upon viral or TLR stimulation [52, 53]; however, phagocytosis appears well preserved [41].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] Panda A Qian F Mohanty S van Duin D Newman FK Zhang L Chen S Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response J Immunol 2010 184 2518 2527 20100933 PMC3867271 source

      Not checked in the free run.

    • cites [53] Jing Y Shaheen E Drake RR Chen N Gravenstein S Deng Y Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood Hum Immunol 2009 70 777 784 19596035 PMC5718338 source

      Not checked in the free run.

    • cites [41] Emanuelli G Lanzio M Anfossi T Romano S Anfossi G Calcamuggi G Influence of age on polymorphonuclear leukocytes in vitro: phagocytic activity in healthy human subjects Gerontology 1986 32 308 316 3582991 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged mice have more adipose tissue T cells than young mice, which can contribute to a proinflammatory environment in visceral fat.

    “Concomitant with greater body fat percentage, aged mice also have more adipose tissue T cells (ATTs) than young mice, which can contribute to create a proinflammatory environment in visceral fat [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Lumeng CN Liu J Geletka L Delaney C Delproposto J Desai A Oatmen K Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue J Immunol 2011 187 6208 6216 22075699 PMC3237772 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although SASP can support tissue repair and remodelling, it can become maladaptive and promote aging phenotypes and pathologies when chronically present.

    “Thus, although the SASP can promote tissue repair and remodelling, which also requires a controlled inflammatory response, but it can also become maladaptive and promote aging phenotypes and pathologies when chronically present.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The proportion of CD56bright NK cells appears reduced in the elderly, likely due to impaired production of new NK cells from the bone marrow.

    “The proportion of CD56bright NK cells appears to be reduced in the elderly, which is likely the consequence of an impaired production of new NK cells with advanced age, due to a lower output from the bone marrow [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Wang JW Geiger H Rudolph KL Immunoaging induced by hematopoietic stem cell aging Curr Opin Immunol 2011 23 532 536 21872769 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Basal production of pro-inflammatory cytokines without TLR engagement is higher in cells from older compared with young individuals, suggesting dysregulation that may limit further activation by TLR engagement.

    “basal production of pro-inflammatory cytokines in the absence of TLR engagement has been found to be higher in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Metcalf TU Cubas RA Ghneim K Cartwright MJ Grevenynghe JV Richner JM Olagnier DP Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors Aging Cell 2015 14 421 32 25728020 PMC4406671 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Partial lymphopenia results in increasing naive T-cell homeostatic proliferation, although this is not sufficient to maintain a constant number of these cells.

    “This setting of partial lymphopenia results in increasing naive T-cell homeostatic proliferation, although this is not sufficient to maintain a constant number of these cells [77, 78].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [77] Kohler S Thiel A Life after the thymus: CD31+ and CD31- human naive CD4+ T-cell subsets Blood 2009 113 769 774 18583570 source

      Not checked in the free run.

    • cites [78] Sauce D Larsen M Fastenackels S Roux A Gorochov G Katlama C Sidi D Lymphopenia-driven homeostatic regulation of naive T cells in elderly and thymectomized young adults J Immunol 2012 189 5541 5548 23136199 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These T-cell changes are commonly reported in blood and can also extend to lymphoid tissues and organs such as spleen, lymph nodes, lung and gut in old subjects.

    “These cellular changes are commonly reported in the circulation (i.e., the blood) [73], but can also be extended to lymphoid tissues and organs (e.g., spleen, lymph nodes, lung and gut) of old subjects [74].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [73] Lugli E Pinti M Nasi M Troiano L Ferarresi R Mussi C Salvioli G Subject classification obtained by cluster analysis and principal component analysis applied to flow cytometric data Cytometry (part A) 2007 71A 334 344 17352421 source

      Not checked in the free run.

    • cites [74] Thome JJ Yudanin N Ohmura Y Kubota M Grinshpun B Sathaliyawala T Kato T Spatial map of human T cell compartmentalization and maintenance over decades of life Cell 2014 159 814 828 25417158 PMC4243051 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The general picture is profound dysregulation of innate immune functions, with some functions down-regulated and others up-regulated or enhanced.

    “The general picture that emerges is that of a profound dysregulation of innate immune functions, with some functions down-regulated, and others up-regulated or even enhanced.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    These deficits likely compromise priming of early adaptive immune responses in old individuals, contributing to their susceptibility to infection or cancer.

    “Overall, these deficits likely compromise priming of early adaptive immune responses in old individuals, thus contributing to their susceptibility to infection or cancer.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NK cells from elderly subjects have generally normal IFN-γ production, but defective chemokine secretion after stimulation and reduced cytotoxic potential against MHC class I negative target cell lines.

    “NK cells from elderly subjects exhibit generally normal IFN-γ production capacity, but a defective capacity to secrete chemokines post-stimulation [101], accompanied by a reduced cytotoxic potential against MHC class I molecule negative target cell lines [99].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [101] Mariani E Meneghetti A Neri S Ravaglia G Forti P Cattini L Facchini A Chemokine production by natural killer cells from nonagenarians Eur J Immunol 2002 32 1524 1529 12115634

      Not checked in the free run.

    • cites [99] Le Garff-Tavernier M Beziat V Decocq J Siguret V Gandjbakhch F Pautas E Debre P Human NK cells display major phenotypic and functional changes over the life span Aging Cell 2010 9 527 535 20477761 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Terminally differentiated CD28−CD57+ T lymphocytes have strong effector functions, including cytotoxins and cytolytic capacity, and a marked inflammatory profile via increased proinflammatory cytokine secretion.

    “Terminally differentiated (CD28−CD57+) T lymphocytes are characterized by strong effector functions such as expression of cytotoxins (e.g., Perforin and Granzyme B) and cytolytic capacity, and a marked inflammatory profile by way of increase proinflammatory cytokine (e.g., IFN-γ, TNF-α, MIP-1β) secretion [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Papagno L Spina CA Marchant A Salio M Rufer N Little S Dong T Immune Activation and CD8(+) T-Cell Differentiation towards Senescence in HIV-1 Infection PLoS Biol 2004 2 E20 14966528 PMC340937 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Terminally differentiated T cells have limited proliferative capabilities and short telomeres, and are largely defined as approaching senescence.

    “However, terminally differentiated T cells are constrained by limited proliferative capabilities in tandem with short telomeres, and to a large extent, have been defined as approaching senescence [86, 87].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] Papagno L Spina CA Marchant A Salio M Rufer N Little S Dong T Immune Activation and CD8(+) T-Cell Differentiation towards Senescence in HIV-1 Infection PLoS Biol 2004 2 E20 14966528 PMC340937 source

      Not checked in the free run.

    • cites [87] Brenchley JM Karandikar NJ Betts MR Ambrozak DR Hill BJ Crotty LE Casazza JP Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells Blood 2003 101 2711 2720 12433688 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, aged subjects show reduced mobilization of Langerhans cells from skin to lymphoid organs upon TNF-alpha stimulation, and an age-associated increase in TLR4- and TLR8-dependent cytokine production in MDDCs.

    “In humans, a reduced mobilization of LCs from the skin to lymphoid organs upon TNF-alpha stimulation have been shown in aged subjects [56], while an age-associated increase in TLR4- and TLR8-dependent cytokine production has been observed in human MDDCs [59].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Bhushan M Cumberbatch M Dearman RJ Andrew SM Kimber I Griffiths CEM Tumour necrosis factor-alpha-induced migration of human Langerhans cells: the influence of ageing British Journal of Dermatology 2002 146 32 40 11841364 source

      Not checked in the free run.

    • cites [59] Agrawal A Agrawal S Cao JN Su HF Osann K Gupta S Altered innate immune functioning of dendritic cells in elderly humans: A role of phosphoinositide 3-kinase-signaling pathway Journal of Immunology 2007 178 6912 6922 17513740 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The γδ T-cell compartment is significantly affected by age, with decline in total γδ T-cell frequency, accumulation of highly differentiated cells, and TCR repertoire changes accentuated by CMV infection.

    “Similarly to the changes observed on αβ T cells, the γδ T-cell compartment is also significantly affected by age. It is characterized by a decline in total γδ T-cell frequency along with phenotypic (accumulation of highly differentiated cells) and TCR repertoire changes (inflation of Vδ2-γδ T cells), phenomena which are accentuated by CMV infection [94, 95].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [94] Roux A Mourin G Larsen M Fastenackels S Urrutia A Gorochov G Autran B Differential impact of age and cytomegalovirus infection on the gammadelta T cell compartment J Immunol 2013 191 1300 1306 23817410 source

      Not checked in the free run.

    • cites [95] Wistuba-Hamprecht K Frasca D Blomberg B Pawelec G Derhovanessian E Age-associated alterations in gammadelta T-cells are present predominantly in individuals infected with Cytomegalovirus Immun Ageing 2013 10 26 23822093 PMC3703274 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CMV may down-regulate B-cell responses directly through TNF-α or indirectly through induction of terminally differentiated and senescent T cells and reduced generation of memory T cells.

    “CMV may down-regulate B-cell responses either directly through TNF-α [118] or indirectly through the induction of terminally differentiated T cells and senescent T cells [126], and reduced generation of memory T cells [127].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [118] Colonna-Romano G Bulati M Aquino A Pellicano M Vitello S Lio D Candore G Caruso C A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people Mech Ageing Dev 2009 130 681 690 19698733 source

      Not checked in the free run.

    • cites [126] Derhovanessian E Theeten H Hahnel K Van Damme P Cools N Pawelec G Cytomegalovirus-associated accumulation of late-differentiated CD4 T-cells correlates with poor humoral response to influenza vaccination Vaccine 2013 31 685 690 23196209 source

      Not checked in the free run.

    • cites [127] McElhaney JE Zhou X Talbot HK Soethout E Bleackley RC Granville DJ Pawelec G The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines Vaccine 2012 30 2060 2067 22289511 PMC3345132 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unusual clonal expansion of NKG2C+CD57+ NK cells has been found in elderly CMV-seronegative donors, indicating that parameters related to aging other than CMV could influence the peripheral repertoire.

    “this unusual clonal expansion of NKG2C+CD57+ NK cells has been found in elderly CMV-seronegative donors, indicating that parameters related to aging other than CMV could influence the peripheral repertoire [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Bayard C Lepetitcorps H Roux A Larsen M Fastenackels S Salle V Vieillard V Coordinated expansion of both memory T cells and NK cells in response to CMV infection in humans Eur J Immunol 2016 46 1168 1179 26910859 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Aging decreases antibody responses to exogenous antigens and vaccines, leading to greater susceptibility of elderly individuals to infectious diseases such as influenza.

    “Aging decreases antibody responses to exogenous antigens and vaccines, leading to greater susceptibility of elderly individuals to infectious diseases such as influenza.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CD16 expression and function is not altered in the elderly, whereas expression of the activating natural cytotoxicity receptors NKp30, NKp46 and DNAM-1 is diminished.

    “CD16 expression and function, which is a key receptor for antibody-dependent cellular cytotoxicity (ADCC), is not altered in the elderly, whereas the expression of the activating natural cytotoxicity receptors (NCRs), NKp30 and NKp46 and DNAM-1 are diminished [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Sanchez-Correa B Gayoso I Bergua JM Casado JG Morgado S Solana R Tarazona R Decreased expression of DNAM-1 on NK cells from acute myeloid leukemia patients Immunol Cell Biol 2012 90 109 115 21383766 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Most elderly people have a normal NK-cell compartment, but a minority show a breakdown of NK-cell repertoire diversity that might affect immune surveillance.

    “Even if the majority of elderly people exhibit a normal NK-cell compartment, a minority of individuals show a breakdown of NK-cell repertoire diversity which might influence immune surveillance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There is a great need for vaccines tailored to optimally stimulate the aged immune system, because the elderly suffer more frequently from severe infections and experience poorer outcomes compared to younger adults.

    “There is still a great need for vaccines tailored to optimally stimulate the aged immune system, as the elderly suffer more frequently from severe infections and experience poorer outcomes from these infections as compared to younger adults [147].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [147] Gavazzi G Krause KH Ageing and infection Lancet Infect Dis 2002 2 659 666 12409046 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Persistence of low amounts of pro-inflammatory cytokines and increased ROS, both features of inflammaging, converge to diminish T-cell function in older persons, reducing IL-2 production and clonal expansion/proliferation.

    “The persistence of low amounts of pro-inflammatory cytokines, concomitant with increased production of ROS, both of which are features of inflammaging, converge to diminish T-cell function in older persons, in the form of reduced IL-2 production and clonal expansion/proliferation [142].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Griffiths HR Dunston CR Bennett SJ Grant MM Phillips DC Kitas GD Free radicals and redox signalling in T-cells during chronic inflammation and ageing Biochem Soc Trans 2011 39 1273 1278 21936801 source

      Not checked in the free run.

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

    Study design and conductcitation

    The results on MPL/QS21 adjuvant mechanism were obtained in young mice, and it is not known if the mechanisms are preserved in aged animals.

    “However, these results have been obtained in young mice, and it is still not known if this mechanisms are preserved in aged animals [174].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Didierlaurent AM Collignon C Bourguignon P Wouters S Fierens K Fochesato M Dendouga N Enhancement of adaptive immunity by the human vaccine adjuvant AS01 depends on activated dendritic cells J Immunol 2014 193 1920 30 25024381 source

      Not checked in the free run.

66 of 66

  • The paper relies on this without support.

    Aging itself is the underlying cause of the multiple disparate pathologies and loss of function that occur in older individuals.

    “medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself.”

  • The paper relies on this without support.

    Findings from mouse models of immune aging are informative about human immune aging.

    “Data obtained in mice indicate that DC recruitment to lymphoid organs is also impaired with aging”
    “Studies in old mice also revealed a decreased trafficking capacity and reduced motility of naïve CD4+ T cells in lymph nodes prior to antigen encounter”
2 of 2

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 reduction in the frequency of naïve T cells, and the increase in the percentage of terminally differentiated effector T cells are hallmarks of immune aging.

    “The reduction in the frequency of naïve T cells, and the increase in the percentage of terminally differentiated effector T cells are hallmarks of immune aging [328].”

    From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [328]

  • Production of senescence-associated secretory phenotype (SASP) is an important feature of immunosenescence.

    “T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [23]

  • The aging process leads to changes in the distribution of mature B cell subsets and impaired activation after stimulation.

    “The aging process leads to changes in the distribution of mature B cell subsets and impaired activation after stimulation [23, 140].”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [23]

  • Waning adaptive immunity begins in mid adulthood, around age 50, and becomes clinically more relevant in the 7th-10th decades.

    “Evidence of waning adaptive immunity is already apparent in mid adulthood, as early as at the age of 50 years, with increasing clinical relevance in the 7th–10th decade of life”

    From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Pinti et al., 2016

  • The expression of TLRs remains constant during life.

    “As the expression of TLRs remains constant during life, defects in signal transduction should be responsible for this impairment, as discussed by (24).”

    From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [24]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Influenza subtype changes between the two outcome lists

    Minor

    The meta-analysis lists H3N2 for seroconversion but H2N3 for seroprotection, although both lists otherwise name the same influenza antigens. One of the subtype labels appears inconsistent.

1 of 1

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Authors
Pinti, M., Appay, V., Campisi, J., Frasca, D., Fülöp, T., Sauce, D., Larbi, A., Weinberger, B., & Cossarizza, A.
Affiliations
  • University of Modena and Reggio Emilia (IT)
  • Centre d'Immunologie et des Maladies Infectieuses (FR)
  • Buck Institute for Research on Aging (US)
  • University of Miami (US)
  • Division of Geriatrics, Department of Medicine Research Center on Aging University of Sherbrooke Canada
  • Agency for Science, Technology and Research (SG)
  • Universität Innsbruck (AT)
Corresponding author
Cossarizza, Andrea
ORCID
Venue
European Journal of Immunology
Publisher
Wiley
Published
2016-10
Volume
46
Issue
10
Pages
2286-2301
ISSN
  • 0014-2980 (ISSN-L)
  • 1521-4141
DOI
10.1002/eji.201546178
PMC
PMC5156481
OpenAlex
W2518307266
Semantic Scholar
eac354c807138e04b56045dde8195e08dc460c8c
Cited by
439
References
180
Citations by year
2026: 19 · 2025: 22 · 2024: 50 · 2023: 51 · 2022: 61 · 2021: 88 · 2020: 57 · 2019: 32 · 2018: 30 · 2017: 27 · 2016: 2
FWCI
2.93
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 10 d)
Locations
  • European Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • HAL (submittedVersion)
Funders
  • Agence Nationale de la Recherche (ANR; project ANR‐14‐CE14‐0030‐01)
  • National Institutes of Health (R21 AI096446, R21 AG042826,, R56 AG032576)
  • Canadian Institutes of Health Research (106634, 106701)
  • Agency for Science, Technology and Research (JCO DP #1434m00115, SRIS SRG/14018)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
immunosenescence, inflammaging, aging, longevity, innate immunity, T cell development, B cell maturation, signal transduction, vaccine response
MeSH terms
Aged, Aging, Animals, B-Lymphocytes, Humans, Immune System, Immunity, Cellular, Immunity, Innate, Inflammation, Longevity, T-Lymphocytes, Vaccination

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 ›

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