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Cited by 693T-cell and B-cell ImmunologyImmune responses and vaccinationsGenetics, Aging, and Longevity in Model Organisms

Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention

Open access
Aiello, Anna, Farzaneh, Farzin, Candore, Giuseppina, Caruso, Calogero, Davinelli, Sergio, Gambino, Caterina Maria, Ligotti, Mattia Emanuela, Zareian, Nahid +1 more·2019·Frontiers in Immunology
DOI 10.3389/fimmu.2019.02247PMC PMC6773825
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Abstract

Aging is accompanied by remodeling of the immune system. With time, this leads to a decline in immune efficacy, resulting in increased vulnerability to infectious diseases, diminished responses to vaccination, and a susceptibility to age-related inflammatory diseases. An age-associated immune alteration, extensively reported in previous studies, is the reduction in the number of peripheral blood naïve cells, with a relative increase in the frequency of memory cells. These two alterations, together with inflamm-aging, are considered the hallmarks of immunosenescence. Because aging is a plastic process, it is influenced by both nutritional and pharmacological interventions. Therefore, the role of nutrition and of immunomodulation in immunosenescence is discussed, due to the multifactorial influence on these hallmarks. The close connection between nutrition, intake of bioactive nutrients and supplements, immune function, and inflammation demonstrate the key role of dietary strategies as regulators of immune response and inflammatory status, hence as possible modulators of the rate of immunosenescence. In addition, potential options for therapeutic intervention are clarified. In particular, the use of interleukin-7 as growth factor for naïve T cells, the function of checkpoint inhibitors in improving T cell responses during aging and, the potential of drugs that inhibit mitogen-activated protein kinases and their interaction with nutrient signaling pathways are discussed. Finally, it is suggested that the inclusion of appropriate combinations of toll-like receptor agonists may enhance the efficacy of vaccination in older adults.

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TL;DR

This review defines immunosenescence by three hallmarks—reduced responses to new antigens, memory T-cell accumulation, and inflamm-aging—and surveys nutritional and pharmacological strategies to counter them. It discusses dietary components, IL-7, checkpoint inhibitors, MAPK/mTOR pathway drugs, and TLR-agonist adjuvants as potential interventions, while noting limited and conflicting evidence in older adults.

Key findings

  • The hallmarks of immunosenescence are reduced ability to respond to new antigens, accumulation of memory T cells, and inflamm-aging. At age 50, T cell production is <10% of its previous peak; HCMV-specific clones can occupy >25% of the entire CD8+ pool in older people. A Swedish immunological risk phenotype was present in around 15% of 85-year-olds at baseline and associated with higher 2-, 4-, and 6-year all-cause mortality, but was not confirmed in the Leiden 85-Plus study.
  • Dietary studies report immune effects: zinc supplementation for 12 months (45 mg elemental Zn gluconate/day) lowered infection incidence, raised plasma zinc, and reduced TNF-α and oxidative stress markers; 25 mg zinc sulfate daily for 3 months increased activated T helper and cytotoxic T lymphocytes. A carotenoid mix (30 mg β-carotene, 15 mg lycopene, 9 mg lutein) shifted T cells to a mature phenotype, increased IgA, and increased NK cells; cocoa polyphenols (40 g/day with 500 ml skimmed milk) reduced monocyte VLA-4, CD40, CD36 and circulating P-selectin/ICAM-1; 12 green olives/day for 30 days reduced IL-6 and malondialdehyde in a pilot study of n = 23.
  • Clinical approaches: IL-7 dose-dependently increased circulating CD4+ and CD8+ lymphocytes and decreased Tregs in metastatic cancer patients aged 20–59 years; in HIV-infected patients, repeated recombinant human IL-7 increased naïve and memory CD4+ and mostly naïve CD8+ T cells. A meta-analysis found a 37% reduction in risk of death favoring immune checkpoint inhibitors versus control, though patients ≥75 years obtained less benefit. Low-dose everolimus in >200 older participants improved immune function and decreased PD-1+ lymphocytes; combined BEZ235 and everolimus improved infection control for a year after treatment.
  • Other approaches: combined TLR agonists, including CASAC, enhanced antigen-specific CD8+ T cell responses in aged mice and cytokine secretion by dendritic cells from older adults; in vitro, the combination of TLR7/TLR8 with TLR4 most effectively activated dendritic cells.

Methods

  • Narrative review; no primary experimental data. It synthesizes human trials, mouse models, and ex vivo/in vitro studies on immunosenescence and interventions.
  • Main analysis is a qualitative synthesis of cited literature across innate and acquired immunity, dietary strategies, clinical approaches (IL-7, checkpoint inhibitors, MAPK/mTOR), and TLR-based vaccine adjuvants. No systematic search, meta-analysis, or formal risk-of-bias assessment is described.

Limitations

  • Stated by the authors: heterogeneity among humans (lifestyle and genetic factors) complicates targeted strategies; probiotic/prebiotic randomized controlled trials lack specific biomarkers and reproducibility; fasting studies are limited by small numbers and poor compliance; checkpoint inhibitor data in older adults are conflicting and often lack adequate statistical power; IL-7 effects may require prior restoration of thymic architecture; the correlation between HCMV positivity and impaired responses is controversial; and no evidence exists that males and females respond differently to therapeutic intervention against immunosenescence.
  • Evident from the text: as a narrative review, it does not systematically appraise study quality or quantify pooled effects; many mechanistic claims rely on animal or in vitro/ex vivo data, and several interventions lack data specifically in older adults.

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Integrity signals

Registry

Crossref · 10.3389/fimmu.2019.02247

Cites

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Claims the paper makes

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  • Premisecitation

    The age-related involvement of the immune system leads to a progressive reduction in the ability to trigger effective antibody and cellular responses against infections and vaccinations.

    “The age-related involvement of immune system leads to a progressive reduction in the ability to trigger effective antibody and cellular responses against infections and vaccinations.”
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    • cites [4] Walford, 1969 source

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  • Premisecitation

    HCMV status has a greater impact than age on the immune system, because the virus contributes to shape the immune profile and function during normal human aging.

    “HCMV status has a greater impact than age on the immune system, because the virus contributes to shape the immune profile and function during normal human aging (16–18).”
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    • cites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

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    • cites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source

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    • cites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

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  • Premisecitation

    Several factors, such as genetics, nutrition, exercise, previous exposure to microorganisms, biological and cultural sex, and HCMV status, can influence immunosenescence.

    “Several factors, such as genetics, nutrition, exercise, previous exposure to microorganisms, biological and cultural sex, and human cytomegalovirus (HCMV) status can influence immunosenescence (3, 6–11).”
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    • cites [3] Caruso, 2016, Immunity and aging source

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    • cites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source

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    • cites [7] Aiello, 2019, Role of immunogenetics in the outcome of HCMV infection: implications for ageing, Int J Mol Sci source

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    • cites [8] Caruso, 2013, Sex, gender and immunosenescence: a key to understand the different lifespan between men and women?, Immun Ageing source

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    • cites [9] Accardi, 2018, Immune-inflammatory responses in the elderly: an update, Immun Ageing source

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    • cites [10] Turner, 2016, Is immunosenescence influenced by our lifetime “dose” of exercise?, Biogerontology source

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    • cites [11] Maijó, 2014, Nutrition, diet and immunosenescence, Mech Ageing Dev source

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    HCMV seropositivity seems related to many functional T cell changes.

    “In particular, HCMV seropositivity seems related to many functional T cell changes.”
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    • cites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

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    • cites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source

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    • cites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

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    Aging more extensively affects acquired immunity than innate immunity.

    “In fact, aging process more extensively affects acquired immunity than innate immunity (3, 5).”
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    • cites [3] Caruso, 2016, Immunity and aging source

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    • cites [5] Nikolich-Žugich, 2018, The twilight of immunity: emerging concepts in aging of the immune system, Nat Immunol source

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    Some data show that immunosenescence develops earlier in men than in women.

    “although some data show that immunosenescence develops earlier in men than in women.”
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    • cites [8] Caruso, 2013, Sex, gender and immunosenescence: a key to understand the different lifespan between men and women?, Immun Ageing source

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    • cites [13] Hirokawa, 2013, Slower immune system aging in women versus men in the Japanese population, Immun Ageing source

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    • cites [14] Dudkowska, 2017, The role of gender and labour status in immunosenescence of 65+ Polish population, Biogerontology. source

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    Immunosenescence is multifactorial and affects both natural and acquired immunity, although T lymphocytes are dramatically affected.

    “This phenomenon, called immunosenescence, a term coined by Roy Walford, is multifactorial, and affects both natural and acquired immunity, although T lymphocytes are dramatically affected (4).”
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    Estrogens increase the immune response, while progesterone and androgens have immune suppressive actions.

    “In general, while estrogens increase the immune response, progesterone and androgens have immune suppressive actions.”
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    • cites [12] Ostan, 2016, Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine, Clin Sci source

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    The reduced ability of older individuals to respond to novel antigens and to vaccines results in an increased susceptibility to infection and in the development of age-related diseases, including cancer.

    “The apparently inevitable consequence of this complex scenario is the reduced ability of older individuals to respond to novel antigens and to vaccines, resulting in an increased susceptibility to infection and in the development of age-related diseases, including cancer (3).”
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    • cites [3] Caruso, 2016, Immunity and aging source

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    NK cell cytotoxicity is well-preserved in centenarians, and an increase in the actual number of NK cells is observed in healthy aging.

    “Briefly, natural killer (NK) cell cytotoxicity is well-preserved in centenarians, and an increase in the actual number of NK cells is observed in healthy aging.”
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    • cites [25] Metcalf, 2015, Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors, Aging Cell source

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    • cites [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

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    Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst.

    “Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst while macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.”
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    • cites [25] Metcalf, 2015, Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors, Aging Cell source

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    • cites [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

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    The hallmarks of immunosenescence include: (i) a reduced ability to respond to new antigens; (ii) the accumulation of memory T cells; (iii) a lingering level of low-grade inflammation termed 'inflamm-aging.'

    “The hallmarks of immunosenescence include: (i) a reduced ability to respond to new antigens; (ii) the accumulation of memory T cells; (iii) a lingering level of low-grade inflammation termed “inflamm-aging.””
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    • cites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source

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    • cites [23] Goronzy, 2013, Understanding immunosenescence to improve responses to vaccines, Nat Immunol source

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    Macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.

    “Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst while macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.”
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    • cites [25] Metcalf, 2015, Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors, Aging Cell source

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    • cites [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

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    The quality and quantity of the T and B cell responses change with increasing age, with consequent changes on the effectiveness of the immune response.

    “The quality and quantity of the T and B cell responses change with increasing age, with consequent changes on the effectiveness of the immune response.”
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    • cites [3] Caruso, 2016, Immunity and aging source

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    The general picture of innate immunity in older people is down-regulation of some functions and up-regulation of others.

    “The general picture of innate immunity in older people, which emerges from several studies, is that of the down-regulation of some functions and the up-regulation of others.”
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    • cites [25] Metcalf, 2015, Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors, Aging Cell source

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    • cites [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

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    Aging is a malleable process, affected by both nutritional and pharmacological interventions.

    “Aging is a malleable process, affected by both nutritional and pharmacological interventions (19, 20).”
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    • cites [19] Longo, 2015, Interventions to Slow aging in humans: are we ready?, Aging Cell. source

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    • cites [20] Aiello, 2019, Slow-aging diets source

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    The life-long chronic antigen load causes the filling of the immunological space by a population of T lymphocytes with a late-differentiated phenotype and the shrinkage of the T cell repertoire.

    “The life-long chronic antigen load causes the filling of the immunological space by a population of T lymphocytes with a late-differentiated phenotype and the shrinkage of the T cell repertoire.”
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    • cites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source

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    • cites [37] Franceschi, 2000, Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space, Vaccine. source

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    Naïve T cells are abundant in youth but may become 'used up' by exposures to microorganisms over the course of life, hence differentiating into memory lymphocyte subsets.

    “Naïve T cells are abundant in youth but may become “used up” by exposures to microorganisms over the course of life, hence differentiating into memory lymphocyte subsets.”
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    • cites [3] Caruso, 2016, Immunity and aging source

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    • cites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source

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    • cites [36] Shanley, 2009, An evolutionary perspective on the mechanisms of immunosenescence, Trends Immunol. source

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    IL-7 is a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus.

    “This process seems related to the increase of sex hormones and to the decrease of IL-7, a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus.”
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    • cites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source

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    • cites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

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    Irrespective of thymic activity, the naïve compartment only moderately decreases in size during the following life decades, while mostly maintaining overall diversity and distribution of clonal sizes.

    “Irrespective of thymic activity, the naïve compartment only moderately decreases in size during the following life decades, while mostly maintaining overall diversity and distribution of clonal sizes.”
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    • cites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source

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    • cites [36] Shanley, 2009, An evolutionary perspective on the mechanisms of immunosenescence, Trends Immunol. source

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    Thymus involution occurs at the time of puberty, and is characterized by atrophy and replacement by adipose tissue.

    “Thymus involution occurs at the time of puberty, and is characterized by atrophy and replacement by adipose tissue.”
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    • cites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source

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    • cites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

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    CD127 is expressed on lymphoid lineage cells at different stages of development, whereas CD132 is shared with other cytokine receptors and expressed on most hematopoietic cells.

    “CD127 is expressed on lymphoid lineage cells at different stages of development, whereas CD132 is shared with other cytokine receptors and expressed on most hematopoietic cells (34, 35).”
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    • cites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source

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    • cites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

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    IL-7 exerts its action through binding to a heterodimeric receptor composed of an α chain (IL-7Rα or CD127) and the common cytokine receptor γ chain (γc or CD132).

    “IL-7 exerts its action through the binding to a heterodimeric receptor composed of an α chain (IL-7Rα or CD127) and the common cytokine receptor γ chain (γc or CD132).”
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    • cites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source

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    • cites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

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    Thymus involution seems related to the increase of sex hormones and to the decrease of IL-7.

    “This process seems related to the increase of sex hormones and to the decrease of IL-7, a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus.”
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    • cites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source

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    • cites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

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    Senescent T cells also express CD57 displaying a high cytotoxic potential, and killer cell lectin-like receptor subfamily G member 1.

    “Senescent T cells also express CD57 displaying a high cytotoxic potential, and killer cell lectin-like receptor subfamily G member 1.”
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    • cites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source

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    • cites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

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    • cites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source

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    • cites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source

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    • cites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source

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    • cites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source

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    • cites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source

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    • cites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source

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    • cites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

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    CD28− cells express high levels of the adhesion molecule integrin CD11a/CD18 and have high levels of perforin and granzyme, responsible for the killing of target cells.

    “These CD28− cells express high levels of the adhesion molecule integrin CD11a/CD18 and have high levels of perforin and granzyme, responsible for the killing of the target cells.”
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    • cites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source

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    • cites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

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    • cites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source

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    • cites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source

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    • cites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source

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    • cites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source

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    • cites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source

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    • cites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source

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    • cites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

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    These cells display a highly differentiated phenotype, expressing CD27, another co-stimulatory molecule, but not CD28.

    “These cells display a highly differentiated phenotype, expressing CD27, another co-stimulatory molecule, but not CD28 (however, in CD28+ subset, CD28−CD27− seem to be more frequent).”
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    • cites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source

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    • cites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

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    • cites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source

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    • cites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source

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    • cites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source

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    • cites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source

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    • cites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source

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    • cites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source

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    • cites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

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    These cells carry short telomeres, lack telomerase and express negative signaling receptors, such as programmed cell death protein (PD)-1.

    “They also carry short telomeres, lack telomerase and express negative signaling receptors, such as programmed cell death protein (PD)-1, which is involved in the down-regulation of the immune system (see paragraph on checkpoints inhibitors; the example of PD-1 and CTLA-4).”
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    • cites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source

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    • cites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

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    • cites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source

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    • cites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source

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    • cites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source

      Not checked in the free run.

    • cites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source

      Not checked in the free run.

    • cites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source

      Not checked in the free run.

    • cites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source

      Not checked in the free run.

    • cites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-related B cell changes are similar to those observed in T cell compartment and the effects on humoral immune response are detrimental as well.

    “Age-related B cell changes are similar to those observed in T cell compartment and the effects on humoral immune response are detrimental as well.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source

      Not checked in the free run.

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

    Premisecitation

    Inflamm-aging defines the systemic state of chronic low-grade inflammation considered a central biological pillar of the aging process and a common pathogenetic mechanism of age-related diseases, as well as a worse prognostic factor for all causes of death.

    “This term defines the systemic state of chronic low-grade inflammation considered a central biological pillar of the aging process and a common pathogenetic mechanism of age-related diseases, as well as a worse prognostic factor for all causes of death (9, 57–59).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Accardi, 2018, Immune-inflammatory responses in the elderly: an update, Immun Ageing source

      Not checked in the free run.

    • cites [57] Franceschi, 2014, Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

    • cites [58] Leonardi, 2018, Ageing: from inflammation to cancer, Immun Ageing. source

      Not checked in the free run.

    • cites [59] Puzianowska-Kuznicka, 2016, Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study, Immun Ageing source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    T cell clones specific for HCMV dominate the repertoire in older people and contribute to the contraction in diversity in the memory compartment.

    “T cell clones specific for HCMV dominate the repertoire in the older people and contribute to the contraction in diversity in the memory compartment (23).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Goronzy, 2013, Understanding immunosenescence to improve responses to vaccines, Nat Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The virus is responsible for the generation of a large population of HCMV-specific CD8+ T cells, with a significant increase in highly differentiated CD8+ effector memory T cells, which expand clonally showing an effector memory phenotype characterized by low CD28 expression.

    “Therefore, the virus is responsible for the generation of a large population of HCMV-specific CD8+ T cells, with a significant increase in highly differentiated CD8+ effector memory T cells, which expand clonally showing an effector memory phenotype characterized by low CD28 expression.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source

      Not checked in the free run.

    • cites [51] Khan, 2002, Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals, J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Our immune system is quite efficient in fighting acute infections in young people, but not particularly efficient in responding to chronic stimuli, especially when they occur late in life.

    “Our immune system is quite efficient in fighting acute infections in young people, but not particularly efficient in responding to chronic stimuli, especially when they occur late in life.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Puzianowska-Kuznicka, 2016, Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study, Immun Ageing source

      Not checked in the free run.

    • cites [60] Licastro, 2005, Innate immunity and inflammation in ageing: a key for understanding age-related diseases, Immun Ageing source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inflamm-aging is responsible for a high expression of micro (mi)-RNAs that interfere with B cell activation, driving tumor necrosis factor (TNF)-α production and inhibiting B cell activation as measured in vitro.

    “In fact, inflamm-aging is responsible for a high expression of micro (mi)-RNAs that interfere with B cell activation, driving tumor necrosis factor (TNF)-α production and inhibiting B cell activation as measured in vitro (69).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Frasca, 2015, MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals, J Immunol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxidative stress also plays an important role in determining and maintaining this low-grade inflammation, which, in turn contributes to oxidative stress.

    “Oxidative stress also plays an important role in determining and maintaining this low-grade inflammation, which, in turn contributes to oxidative stress (61, 62).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] De la Fuente, 2009, An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging, Curr Pharm Des. source

      Not checked in the free run.

    • cites [62] Biswas, 2016, Does the Interdependence between oxidative stress and inflammation explain the antioxidant paradox?, Oxid Med Cell Longev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Persistent antigenic challenges lead to a poor response to newly encountered microbial antigens, as well as to a shift in the immune system toward an inflammatory, autoimmune, T helper (Th) 2 profile.

    “Persistent antigenic challenges lead to a poor response to newly encountered microbial antigens, as well as to a shift in the immune system toward an inflammatory, autoimmune, T helper (Th) 2 profile.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Caruso, 2016, Immunity and aging source

      Not checked in the free run.

    • cites [9] Accardi, 2018, Immune-inflammatory responses in the elderly: an update, Immun Ageing source

      Not checked in the free run.

    • cites [57] Franceschi, 2014, Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases, J Gerontol A Biol Sci Med Sci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Immunosenescence represents the most important contributor to inflamm-aging, in turn, contributing to impaired immune responses.

    “However, as previously stated, immunosenescence represents the most important contributor to inflamm-aging, in turn, contributing to impaired immune responses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    This is accompanied by an impaired ability to produce high affinity protective antibodies against infectious agents and the shrinkage of the repertoire diversity.

    “This is accompanied by an impaired ability to produce high affinity protective antibodies against infectious agents and the shrinkage of the repertoire diversity.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source

      Not checked in the free run.

    • cites [75] Bulati, 2017, From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”, Ageing Res Rev source

      Not checked in the free run.

    • cites [76] Listì, 2006, A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence, Ann N Y Acad Sci. source

      Not checked in the free run.

    • cites [77] Colonna-Romano, 2009, A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people, Mech Ageing Dev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    They showed an increase in suppressor cell numbers but no change in the number of peripheral blood leucocytes or in the differential counts.

    “They showed an increase in suppressor cell numbers but no change in the number of peripheral blood leucocytes or in the differential counts (93).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Neuvonen, 1984, Effects of short-term starvation on the immune response, Nutr Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The reduced serum levels of IgM and IgD suggest a shift in the balance from the naïve (CD27) toward the memory compartment (CD27+), although this is not observed in all studies.

    “The reduced serum levels of IgM and IgD suggest a shift in the balance from the naïve (CD27) toward the memory compartment (CD27+), although this is not observed in all studies (71, 75–77).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source

      Not checked in the free run.

    • cites [75] Bulati, 2017, From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”, Ageing Res Rev source

      Not checked in the free run.

    • cites [76] Listì, 2006, A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence, Ann N Y Acad Sci. source

      Not checked in the free run.

    • cites [77] Colonna-Romano, 2009, A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people, Mech Ageing Dev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age also affects B cell numbers and B cell repertoire diversity, as well as immunoglobulin isotypes and receptor repertoire with a decrease in specific humoral immune responses against new extracellular pathogens.

    “Age also affects B cell numbers and B cell repertoire diversity, as well as immunoglobulin isotypes and receptor repertoire with a decrease in specific humoral immune responses against new extracellular pathogens (71).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The main target of dietary strategies is inflamm-aging, because diet, biotics, and nutraceuticals can show anti-inflammatory and anti-oxidant properties.

    “Data discussed below show that the main target of dietary strategies is inflamm-aging, because diet, biotics, and nutraceuticals can show anti-inflammatory and anti-oxidant properties.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These dietary patterns explicate their activity, particularly, during the refeeding period, reducing the rate of aging because of their antioxidant and anti-inflammatory effects, and possibly counteracting some other aspects of immunosenescence.

    “These dietary patterns explicate their activity, particularly, during the refeeding period, reducing the rate of aging because of their antioxidant and anti-inflammatory effects, and possibly counteracting some other aspects of immunosenescence.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Aiello, 2019, Slow-aging diets source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The efficacy of the Mediterranean diet results as an attenuation of inflammation and oxidative stress, and from the maintenance of a condition of eubiosis of the microbiota, involved in the general improvement of immune response in these populations.

    “The efficacy of this diet results as an attenuation of inflammation and oxidative stress, and from the maintenance of a condition of eubiosis of the microbiota, involved in the general improvement of immune response in these populations (68, 83–86).”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [68] Vasto, 2014, Mediterranean diet and healthy ageing: a Sicilian perspective, Gerontology. source

      Not checked in the free run.

    • cites [83] Trichopoulou, 2019, Impact of Mediterranean diet on longevity source

      Not checked in the free run.

    • cites [84] Martinez-Gonzalez, 2009, Mediterranean food pattern and the primary prevention of chronic disease: recent developments, Nutr Rev source

      Not checked in the free run.

    • cites [85] Mitsou, 2017, Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population, Br J Nutr source

      Not checked in the free run.

    • cites [86] Sofi, 2010, Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis, Am J Clin Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changes in phenotypic features, mainly loss of teeth and alterations in taste receptors, and gut disorders as well, determine a variation in both quality and quantity of food intake, contributing to general alterations in metabolism.

    “Changes in phenotypic features, mainly loss of teeth and alterations in taste receptors, and gut disorders as well, determine a variation in both quality and quantity of food intake, contributing to general alterations in metabolism (100).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Leslie, 2015, Aging, nutritional status and health, Healthcare (Basel) source

      Not checked in the free run.

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

    Premisecitation

    Because vitamin C is water-soluble and humans have low storage capacity, its regular intake is up to 100-fold higher than that for many other vitamins.

    “Because vitamin C is water-soluble and humans have low storage capacity, its regular intake is up to 100-fold higher than that for many other vitamins (116, 117).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] Huijskens, 2015, Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy, Cytotherapy. source

      Not checked in the free run.

    • cites [117] 2000

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The complexity of randomized controlled trials and lack of specific biomarkers in humans make difficult the reproducibility of the data.

    “However, the complexity of randomized controlled trials and lack of specific biomarkers in humans make difficult the reproducibility of the data (124).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Suez, 2019, The pros, cons, and many unknowns of probiotics, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Undernutrition, which is common in older people, is associated with an immunocompromised state, linked to altered T cell numbers, a reduced response to antigens, impaired release of mediators, such as cytokines, and decreased phagocytosis and NK cell activity.

    “Contrarily to caloric restriction, undernutrition, which is common in older people, is associated with an immunocompromised state, linked to altered T cell numbers, a reduced response to antigens, impaired release ofmediators, such as cytokines, and decreased phagocytosis and NK cell activity.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98] Nova, 2007, Immunomodulatory effects of probiotics in different stages of life, Br J Nutr source

      Not checked in the free run.

    • cites [99] Shlisky, 2017, Nutritional considerations for healthy aging and reduction in age-related chronic disease, Adv Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The active form of thymulin induces expression of markers of T lymphocyte activation, promoting T-mediated functions, acting on both early and late phases of lymphocyte differentiation.

    “The active form of thymulin induces the expression of markers of T lymphocyte activation, promoting T-mediated functions, acting both on the early and on the late phases of lymphocyte differentiation (109, 110).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [109] Consolini, 2000, Distribution of age-related thymulin titres in normal subjects through the course of life, Clin Exp Immunol source

      Not checked in the free run.

    • cites [110] Savino, 2000, Neuroendocrine control of thymus physiology, Endocr Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Micronutrients are needed in trace quantities, because the homeodynamic range is small, but the maintenance of a correct amount and balance is very rare in older people (often even in adults and young), both for scarcity and for excess due to unnecessary supplementation.

    “They are needed in trace quantities, because the homeodynamic range is small, but the maintenance of a correct amount and balance is very rare in older people (often even in adults and young), both for scarcity and for excess due to unnecessary supplementation (78, 103).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] Maggini, 2018, Immune function and micronutrient requirements change over the life course, Nutrients source

      Not checked in the free run.

    • cites [103] Elmadfa, 2009, European Nutrition and Health Report 2009, Ann Nutr Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increasing intake of some nutraceuticals above habitual and recommended dose levels can enhance some aspects of immune function, reduce inflammatory status, and increase cellular resistance to aging.

    “They provide evidence that increasing intake of some of them above the habitual and recommended dose levels can enhance some aspects of immune function, and reduce the level of inflammatory status, increasing cellular resistance to aging (131–133).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [131] López-Varela, 2002, Functional foods and the immune system: a review, Eur J Clin Nutr source

      Not checked in the free run.

    • cites [132] Molfino, 2014, The role for dietary omega-3 fatty acids supplementation in older adults, Nutrients source

      Not checked in the free run.

    • cites [133] Pae, 2017, Nutritional modulation of age-related changes in the immune system and risk of infection, Nutr Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Carotenoids primarily exert antioxidant, hence anti-inflammatory, effects, but individual carotenoids may also act through other mechanisms, including immune-enhancing activities.

    “They primarily exert antioxidant, hence anti-inflammatory, effects, but individual carotenoids may also act through other mechanisms, including immune-enhancing activities (134, 135).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [134] Davinelli, 2018, Astaxanthin in skin health, repair, and disease: a comprehensive review, Nutrients source

      Not checked in the free run.

    • cites [135] Wood, 2000, Beta-carotene and selenium supplementation enhances immune response in aged humans, Integr Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Metformin can trigger AMPK, a pathway activated by energy depletion, i.e., by low levels of intracellular ATP, leading to the extension of healthy lifespan in model organisms.

    “Metformin can trigger AMPK, a pathway activated by energy depletion, i.e., by low levels of intracellular adenosine triphosphate (ATP), leading to the extension of healthy lifespan in model organisms (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Martin-Montalvo, 2013, Metformin improves healthspan and lifespan in mice, Nat Commun source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The profound structural remodeling that characterizes thymic involution also affects thymic epithelial cells, with a consequent reduction in the intrathymic production of IL-7.

    “In fact, the profound structural remodeling that characterizes the thymic involution also affects thymic epithelial cells with a consequent reduction in the intrathymic production of IL-7 (155, 156).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [155] Masters, 2017, Immune senescence: significance of the stromal microenvironment, Clin Exp Immunol source

      Not checked in the free run.

    • cites [156] Fry, 2005, The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance, J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Immune checkpoint inhibitor therapy is less efficient in patients ≥75 years, probably due to a greater degree of immunosenescence.

    “accordingly, the therapy is less efficient in patients ≥75 years (see below), probably due to a greater degree of immunosenescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Dietary polyphenols are found in fruits, vegetables, grains, and other plant foods, the consumption of which has been linked to reduction in risk of major age-related diseases.

    “They are in fruits, vegetables, grains, and other plant foods, the consumption of which has been linked to reduction in risk of major age-related diseases (141, 142).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [141] Tsao, 2010, Chemistry and biochemistry of dietary polyphenols, Nutrients source

      Not checked in the free run.

    • cites [142] Davinelli, 2016, Polyphenols: a promising nutritional approach to prevent or reduce the progression of prehypertension, High Blood Press Cardiovasc Prev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-7 produced by thymic epithelial cells provides survival and proliferative signals to immature double negative CD4−CD8− thymocytes and promotes V(D)J recombination of the T cell receptor γ-c locus.

    “IL-7 produced by thymic epithelial cells provides survival and proliferative signals to immature double negative CD4−CD8− thymocytes and promotes V(D)J recombination of the T cell receptor (TCR) γ-c locus (157).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [157] Peschon, 1994, Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice, J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The expression of PD-1 increases on T cells of older adults and its blockade partially restores T cells to functional competence.

    “Interestingly, the expression of PD-1 increases on T cells of older adults and its blockade partially restores T cells to functional competence (166–168).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [166] McDermott, 2013, PD-1 as a potential target in cancer therapy, Cancer Med. source

      Not checked in the free run.

    • cites [167] Chen, 2013, Molecular mechanisms of T cell co-stimulation and co-inhibition, Nat Rev Immunol source

      Not checked in the free run.

    • cites [168] Viganò, 2012, Positive and negative regulation of cellular immune responses in physiologic conditions and diseases, Clin Dev Immunol source

      Not checked in the free run.

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

    Premisecitation

    TSLP provides normally a co-mitogenic activity that is less potent than that of IL-7.

    “TSLP provides normally a co-mitogenic activity that is less potent than that of IL-7 (161).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [161] Sims, 2000, Molecular cloning and biological characterization of a novel murine lymphoid growth factor, J Exp Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Because dose, timing of administration, and participant age are important modulating factors of the effect of n-3 PUFAs, contrasting results exist and only few studies focus on their use in older adults.

    “However, because dose, timing of administration, and participant age are important modulating factors of the effect of these molecules, contrasting results exist and only few studies focus on their use in older adults (149–154).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [149] Thies, 2001, Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults, Lipids source

      Not checked in the free run.

    • cites [150] Thies, 2001, Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y, Am J Clin Nutr source

      Not checked in the free run.

    • cites [151] Thies, 2001, Dietary supplementation with gamma-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans, J Nutr source

      Not checked in the free run.

    • cites [152] Rees, 2006, Dose-related effects of eicosapentaenoic acid oninnate immune function in healthy humans: a comparison ofyoung and older men, Am J Clin Nutr source

      Not checked in the free run.

    • cites [153] Bechoua, 2003, Influence of very low dietary intake of marine oil on some functional aspects of immune cells in healthy elderly people, Br J Nutr source

      Not checked in the free run.

    • cites [154] Meydani, 1991, Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women, J Nutr source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resveratrol induces a significant increase in T helper cells and in the delayed-type hypersensitivity response of aged rats.

    “For example, resveratrol, a polyphenol typically found in red wine, grape skins, and berries, induces a significant increase in T helper cells and in the delayed-type hypersensitivity response of aged rats (147).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Yuan, 2012, Dietary intake of resveratrol enhances the adaptive immunity of aged rats, Rejuv Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The rescuing effect of spermidine did not involve inhibition of apoptosis, as the percentage of apoptotic cells was not influenced by spermidine.

    “The rescuing effect did not involve inhibition of apoptosis, as the percentage of apoptotic cells was not influenced by spermidine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [190] Eisenberg, 2009, Induction of autophagy by spermidine promotes longevity, Nat Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These data imply selective proliferation of CD28+ cells by PD-1 therapy and highlight one mechanistic explanation why cancer patients older than 75 years may not respond as well to immunotherapy as younger patients.

    “Therefore, these data, which imply selective proliferation of CD28+ cells by PD-1 therapy, highlight one mechanistic explanation why cancer patients older than 75 years may not respond as well to immunotherapy as younger patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The p38-MAPK pathway is critical for the production of inflammatory cytokines, positively regulating the production of IFN-γ in CD4 and CD8 cells.

    “The p38-MAPK pathway is critical for the production of inflammatory cytokines, positively regulating the production of IFN-γ in CD4 and CD8 cells (187, 188).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [187] Merritt, 2000, Activation of p38 mitogen-activated protein kinase in vivo selectively induces apoptosis of CD8+ but not CD4+ T cells, Mol Cel Biol source

      Not checked in the free run.

    • cites [188] Zhang, 2000, The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-gamma expression, J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IFN-α signal can activate p38, triggering cellular senescence, and leading to inhibition of proliferation and telomerase activity in non-senescent T cells.

    “However, IFN-α signal can activate p38, triggering cellular senescence, and leading to inhibition of proliferation and telomerase activity in non-senescent T cells (189).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [189] Lanna, 2013, IFN-α inhibits telomerase in human CD8+ T cells by both hTERT downregulation and induction of p38 MAPK signaling, J Immunol source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Some clinical trials suggest a significant benefit of immunotherapy in older patients, with the exception of patients ≥75 years, who obtain less benefit from these treatments.

    “In spite of several controversial points, some clinical trials suggest a significant benefit of immunotherapy in older patients, with the exception of patients ≥75 years that obtain less benefit from these treatments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The use of spermidine dramatically improved the CD8+ T cell response to vaccination and infection in aged mice in an autophagy-dependent manner, contributing to increased numbers of antigen-specific CD8+ T cells.

    “Moreover, the use of spermidine dramatically improved the CD8+ T cell response to vaccination and infection in aged mice in an autophagy-dependent manner, contributing to the increased numbers of antigen-specific CD8+ T cells (191).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [191] Puleston, 2014, Autophagy is a critical regulator of memory CD8(+) T cell formation, Elife source

      Not checked in the free run.

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

    Premisecitation

    Fecal microbiota composition of 26 patients with metastatic melanoma, using 16S rRNA, at time 0 and before each Ipilimumab treatment, was clustered on microbiota patterns.

    “Moreover, fecal microbiota composition of 26 patients with metastatic melanoma, using 16S rRNA, at time 0 and before each Ipilimumab treatment, was clustered on microbiota patterns.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Chaput, 2017, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Telomerase activity in CD8+/CD45RA+ T cells is improved by blocking only the p38 pathway but not PD-1 signaling, indicating that non-overlapping signaling pathways are involved.

    “However, the telomerase activity in CD8+/CD45RA+ T cells is improved by blocking only the p38 pathway but not the PD-1 signaling, indicating that non-overlapping signaling pathways are involved (193, 194).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [193] Henson, 2012, Reversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade, Immunology source

      Not checked in the free run.

    • cites [194] Wherry, 2007, Molecular signature of CD8+ T cell exhaustion during chronic viral infection, Immunity source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy, by inhibiting cell senescence, is a critical regulator of memory CD8+ formation, and age-related autophagy defect is one explanation why CD8+ T memory formation becomes defective in old age.

    “Autophagy, by inhibiting cell senescence, is a critical regulator of memory CD8+ formation, and age-related autophagy defect is one of the explanations why CD8+ T memory formation becomes defective in old age (38, 185).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [38] Lanna, 2014, The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells, Nat Immunol source

      Not checked in the free run.

    • cites [185] Henson, 2014, p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells, J Clin Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blockade with Ipilimumab can establish an anti-leukemic effect after allogeneic hematopoietic stem cell transplantation and can restore anti-tumor reactivity for patients with relapse.

    “In particular, the blockade with Ipilimumab can establish an anti-leukemic effect after allogeneic hematopoietic stem cell transplantation and can restore anti-tumor reactivity for patients with relapse (174).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Knaus, 2017, Immunomodulatory drugs: immune checkpoint agents in acute leukemia, Curr Drug Targets source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MAPK pathways are involved in the production of pro-inflammatory cytokines, as well as in the intracellular signaling cascades initiated when a cytokine binds to its corresponding receptor.

    “They are also involved in the production of pro-inflammatory cytokines, as well as in the intracellular signaling cascades initiated when a cytokine binds to its corresponding receptor (183).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [183] Patterson, 2014, Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases, Clin Exp Immunol source

      Not checked in the free run.

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

    Premisecitation

    Earlier studies showed central importance of mTOR in innate immunity, specifically in production of anti-inflammatory IL-10 and suppression of pro-inflammatory cytokines IL-21 and IL-1β.

    “These findings conflict with earlier studies showing the central importance of mTOR in innate immunity, specifically in the production of anti-inflammatory IL-10 and the suppression of pro-inflammatory cytokines IL-21 and IL-1β (209).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [209] Weichhart, 2009, The multiple facets of mTOR in immunity, Trends Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In senescent CD8+ T cells, p38-MAPK induces an increase in autophagy through interactions between a p38 interacting protein and autophagy protein 9, in an mTOR-independent manner, suggesting that p38-MAPK blockade reverses senescence via an mTOR-independent pathway.

    “Moreover, in senescent CD8+ T cells, p38-MAPK induces an increase in autophagy through interactions between a p38 interacting protein and autophagy protein 9, in a mTOR-independent manner, suggesting that p38-MAPK blockade reverses senescence via mTOR-independent pathway (185).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [185] Henson, 2014, p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells, J Clin Invest. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockout of sMAC restored T cell activity (antigen-specific proliferation and cytokine production) from older humans, and enhanced responsiveness to influenza vaccination in aged mice.

    “The knockout of sMAC restored T cell activity (antigen-specific proliferation and cytokine production) from older humans, and enhanced responsiveness to influenza vaccination in the aged mice (196).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Lanna, 2017, A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging, Nat Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sestrins stimulate the activation of AMPK (by an unknown mechanism), inhibiting mTORC1 signaling.

    “In particular, sestrins stimulate the activation of AMPK (by an unknown mechanism), inhibiting mTORC1 signaling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [200] Wang, 2017, Recent insights into the biological functions of sestrins in health and disease, Cell Physiol Biochem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a clinical trial of over 200 older participants, two low-dose everolimus regimens improved immune function without causing serious side effects.

    “The two low-dose everolimus regimens improved immune function without causing serious side effects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [206] Mannick, 2018, TORC1 inhibition enhances immune function and reduces infections in the elderly, Sci Transl Med source

      Not checked in the free run.

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

    Premisecitation

    Sestrins, the mammalian products of the Sesn1, Sesn2, and Sesn3 genes, are a family of stress sensing proteins.

    “Sestrins, the mammalian products of the Sesn1, Sesn2, and Sesn3 genes, are a family of stress sensing proteins (196).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [196] Lanna, 2017, A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging, Nat Immunol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This pathway can inhibit telomerase activity, T cell proliferation, and expression of key components of the TCR signalosome.

    “This pathway can inhibit telomerase activity, T cell proliferation, and expression of key components of the TCR signalosome.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Lanna, 2014, The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells, Nat Immunol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    These findings point toward potential use of appropriately selected combination of TLR agonists in future vaccination approaches for older adults to overcome CD4 inability to respond.

    “These findings highlight the efficient effect of adjuvants in the stimulation of cytokine production and point toward the potential use of appropriately selected combination of TLR agonists in future vaccination approaches for older adults to overcome the CD4 inability to respond.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The same immunization drove highly polarized Th1 CD4 responses.

    “In fact, immunization with two or more TLR agonists, an activator anti-CD40 antibody, IFN-γ, and surfactants were sufficient to drive unprecedented levels of CD8 responses to peptides or protein antigens and highly polarized Th1 CD4 responses.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [213] Wells, 2008, Combined triggering of dendritic cell receptors results in synergistic activation and potent cytotoxic immunity, J Immunol source

      Not checked in the free run.

76 of 76

  • The paper relies on this without support.

    Gut microbiota plays an active part in healthy status.

    “Gut microbiota that plays an active part in healthy status, is compromised in older adults due to malnutrition, use of medications and immunosenescence itself.”

  • The paper relies on this without support.

    There is a gap in knowledge of the role of immune checkpoint inhibitors in the control of immune response in older patients because data from randomized clinical trials are conflicting and often lack adequate statistical power.

    “However, there is a gap in the knowledge of the role of immune checkpoint inhibitors in the control of immune response in older patients because the data from randomized clinical trials are conflicting and often lack adequate statistical power.”

  • The paper relies on this without support.

    No strong cause-effect relation often exists between the use of probiotics, prebiotics and symbiotics and specific end-points.

    “However, no strong cause-effect relation often exists between their use and specific end-points.”

  • The paper relies on this without support.

    mTOR activity inhibits autophagy.

    “although mTOR activity inhibits autophagy”

  • The paper relies on this without support.

    At high doses, rapamycin is immunosuppressive, blocking both protein synthesis and cell division.

    “At high doses, rapamycin is immunosuppressive, blocking both protein synthesis and cell division.”

  • The paper relies on this without support.

    The increase in lifespan does not coincide with increase in healthspan.

    “However, the increase in lifespan does not coincide with increase in healthspan.”

  • The paper relies on this without support.

    The link between aging and disease is in part a reflection of functional changes in the immune system of older people.

    “The link between aging and disease is in part a reflection of the functional changes in the immune system of older people.”

  • The paper relies on this without support.

    The epilog of an aged immune system is an increased propensity toward reduced resistance to infection, poorer responses to vaccination, and development of age-related diseases.

    “Different factors contribute to the development of age-related immune dysfunction, but the epilog of an aged immune system is an increased propensity toward a reduced resistance to infection, poorer responses to vaccination, and the development of age-related diseases.”

  • The paper relies on this without support.

    HCMV plays a role in the decrease of naïve T cells and increase of memory T cells.

    “Taking into account the role of HCMV in the decrease of naïve T cells and increase of memory T cells”

  • The paper relies on this without support.

    Letermovir inhibits HCMV replication by binding to components of the terminase complex.

    “Letermovir is an antiviral agent that inhibits HCMV replication by binding to components of the terminase complex.”

  • The paper relies on this without support.

    Broad ranges of pharmacological agents with anti-immunosenescence properties have been identified.

    “Broad ranges of pharmacological agents with anti-immunosenescence properties have been identified”
11 of 11

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?

  • Exhaustion of T cells, i.e., a state of poor effector function observed in senescent T cells, is associated with the surface expression of immune checkpoints, such as PD-1.

    “Finally, exhaustion of T cells, i.e., a state of poor effector function observed in senescent T cells, is associated with the surface expression of immune checkpoints, such as PD-1 [339].”

    From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [339]

    The review’s ‘Checkpoint Inhibitors’ section identifies PD-1 as an inhibitory receptor whose expression increases on T cells of older adults. Its ‘MAPK Pathway’ section calls PD-1 a marker of exhaustion, but explicitly says that CD45RA+ T cells with features of immune senescence are not functionally exhausted and retain cytokine secretion. The claim therefore conflates senescence with poor effector function. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • 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.”

    From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [187]

  • The Mediterranean diet modulates many biomarkers of inflammation, including IL-6.

    “The Mediterranean diet also modulates the level of many biomarkers of inflammation, including IL-6187.”

    From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [187]

  • There is mutual interaction between nutrition, immune function, and inflammatory state.

    “There is a mutual interaction between nutrition, immune function, and inflammatory state, as detailed among the hallmarks of immunosenescence187.”

    From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [187]

  • It remains to be definitively proven that probiotic interventions are clinically efficacious.

    “However, it remains to be definitively proven that such interventions are clinically efficacious (Aiello et al., 2019).”

    From Viral Infections, the Microbiome, and Probiotics (2021) · cites this paper as Aiello et al., 2019

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.

  • p38 is said to both increase and inhibit autophagy

    Minor

    The text says p38-MAPK increases autophagy in senescent CD8+ T cells, but the title of the cited study says p38 signaling inhibits autophagy in those cells.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. Gambino, 2017, Triggering of Toll-like receptors in the elderly. A pilot stdudy relevant for vaccination, 13
  2. Sofi, 2010, Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis, Am J Clin Nutr, 92, 1189, 10.3945/ajcn.2010.2967 · DOI
  3. Chung, 2001, The inflammation hypothesis of aging: molecular modulation by calorie restriction, Ann N Y Acad Sci, 928, 327, 10.1111/j.1749-6632.2001.tb05662.x · DOI · Paper page
  4. Elmadfa, 2009, European Nutrition and Health Report 2009, Ann Nutr Metab, 55, 1, 10.1159/000244607 · DOI
  5. Prasad, 2008, Zinc in human health: effect of zinc on immune cells, Mol Med, 14, 353, 10.2119/2008-00033 · DOI
  6. Meydani, 1997, Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial, JAMA, 277, 1380, 10.1001/jama.1997.03540410058031 · DOI · Paper page
  7. 2000, Institute of Medicine (US) Panel on Dietary Antioxidants and Related Compounds. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids

Cited by

Sorted by citations

Authors
Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C. M., Ligotti, M. E., Zareian, N., & Accardi, G.
Affiliations
  • University of Palermo (IT)
  • King's College London (GB)
  • University of Molise (IT)
Corresponding author
Caruso, Calogero
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2019-09-25
Volume
10
Pages
2247-2247
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2019.02247
PMC
PMC6773825
OpenAlex
W2972212509
Cited by
693
References
216
Citations by year
2026: 47 · 2025: 72 · 2024: 109 · 2023: 129 · 2022: 141 · 2021: 132 · 2020: 59 · 2019: 3
FWCI
7.22
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Archivio Istituzionale della Ricerca - Università degli Studi del Molise (submittedVersion)
  • Research Portal (King's College London) (submittedVersion, other-oa)
Funders
Bloodwise
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
immunosenescence, inflammaging, naive T cells, memory T cells, aging, dietary intervention, immunomodulation, bioactive nutrients, IL-7, MAPK inhibitors, TLR agonists, vaccination in older adults
MeSH terms
Immunosenescence, Aged, Cell Count, Hematopoietic Stem Cells, Humans, Immunologic Memory, Inflammation, Nutritional Status, T-Lymphocytes, Interleukin-7

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.

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