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Cited by 798T-cell and B-cell ImmunologyGenetics, Aging, and Longevity in Model OrganismsImmune responses and vaccinations

Causes, consequences, and reversal of immune system aging

Open access
Montecino-Rodriguez, Encarnacion, Berent-Maoz, Beata, Dorshkind, Kenneth·2013·Journal of Clinical Investigation
DOI 10.1172/jci64096PMC PMC3582124
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Abstract

The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues. As a result, elderly individuals do not respond to immune challenge as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.

Integrity signals

Registry

Crossref · 10.1172/jci64096

Cites

127 of 127 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 118 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Myeloid-biased stem cells in old mice are less robust than those in young mice.

    “Despite the increase in their number, myeloid-biased stem cells are not as robust as their young counterparts (24)”
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    • cites [24] source

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  • Premisecitation

    People aged 70 and older are more vulnerable to influenza.

    “This is illustrated by increased vulnerability of individuals 70 years of age and older to influenza (1)”
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  • Premisereasoning

    Elderly people respond less effectively to immune challenge than young people.

    “As a result, elderly individuals do not respond to immune challenge as robustly as the young.”
    • Also stated in: § Introduction · hedged
      “While elderly individuals are by no means immunodeficient, they often do not respond efficiently to novel or previously encountered antigens.”
    • Also stated in: § Introduction · plain
      “This is illustrated by increased vulnerability of individuals 70 years of age and older to influenza (1), a situation that is exacerbated by their poor response to vaccination (2)(3)(4).”
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  • Interpretationcitation

    The reduced robustness of myeloid-biased stem cells could explain age-related deficiencies in mature myeloid cells such as neutrophils and macrophages.

    “which in turn could underlie the numerous age-related deficiencies observed in mature myeloid cells such as neutrophils and macrophages (25,26).”
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  • Premisecitation

    The shift toward myeloid potential in aged hematopoietic stem cells correlates with higher expression of myeloid lineage genes and lower expression of lymphoid lineage genes.

    “This shift has been correlated with increased expression of myeloid lineage genes and downregulation of those specifying a lymphoid lineage fate (11,17).”
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    Premisecitation

    The most profound immunologic effect of stem cell aging in mice and humans is a reduced ability to generate lymphocytes and an increased myeloid potential.

    “From an immunologic perspective, the most profound effect of stem cell aging in both mice (11,18) and humans (17) is a decreased capacity to produce lymphocytes and an increase in myeloid potential.”
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    Premisecitation

    The number of lymphoid-biased stem cells decreases with age while myeloid-biased hematopoietic stem cells increase.

    “it is now appreciated that the number of lymphoid-biased stem cells declines with age concomitant with an increase in myeloid-biased HSCs (19).”
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    • cites [19] source

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    Premisecitation

    Aging reduces the generation of B and T cells in the bone marrow and thymus and weakens the function of mature lymphocytes in secondary lymphoid tissues.

    “The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in bone marrow and thymus and diminished function of mature lymphocytes in secondary lymphoid tissues.”
    • Also stated in: § Effects of aging on immune system development · plain
      “primary lymphopoiesis in the elderly is significantly diminished, as exemplified by involution of the thymus (8)(9)(10).”
    • Also stated in: § Effects of aging on immune system development · plain
      “the number of B cell (28)(29)(30)(31) and T cell (32,33) progenitors in bone marrow and thymus is markedly reduced with age.”
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    • cites [32] Min, 2004, J Immunol. source

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    • cites [33] Heng, 2005, J Immunol. source

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    Premisecitation

    Hematopoietic stem cells show several age-related changes, including impaired adherence to stromal cells and, in some mouse strains and elderly humans, an increased number.

    “HSCs exhibit multiple age-related changes that include impaired adherence to stromal cells and, in some strains of mice (15,16) and elderly humans (17), an increase in number.”
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    • cites [15] de Haan, 1999, Blood. source

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    • cites [16] Harrison, 1989, J Immunol. source

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    Premisenone given

    Aging affects both the rate at which naive B and T cells are produced and the composition and quality of the mature lymphocyte pool.

    “The effects of aging on the immune system are widespread and affect the rate at which naive B and T cells are produced as well as the composition and quality of the mature lymphocyte pool.”
    • Also stated in: § Aging and the decline of immune function · boosted
      “The answer is that the composition and quality of the mature lymphocyte pool is profoundly altered by aging.”
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    Premisenone given

    Chronic stimulation by persistent viral infections such as CMV can exhaust the naive cell pool and cause oligoclonal memory cell expansion.

    “However, chronic stimulation with persistent viral infections such as CMV can exhaust the naive pool of cells and result in an oligoclonal memory cell expansion.”
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    Interpretationcitation

    The decline in human B cell number is likely due to fewer IgM+ memory and switched memory B cells, because total naive B cells remain unchanged by aging.

    “This decline is likely due to decreased numbers of IgM + memory and switched memory B cells, because the total number of naive B cells remains unchanged by aging (51,52).”
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    • cites [52] Shi, 2005, J Immunol. source

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    Interpretationreasoning

    A shift from a salutary to an inflammatory milieu may negatively affect the ability of naive lymphocytes to lodge in organs such as the spleen and the function of mature lymphocytes already resident there.

    “Regardless of how the shift occurs from a salutary to an inflammatory milieu, the end result may be a negative effect on the ability of naive lymphocytes from the bone marrow or thymus to lodge in an organ such as the spleen as well as the function of mature lymphocytes already resident in that tissue.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Early T lineage progenitors and double-negative cells from old mice show age-related proliferation defects and high apoptosis rates.

    “Similar to B cell progenitors, ETPs and DN cells from old mice also exhibit age-related defects in proliferation and high rates of apoptosis (ref.32 and Figure 1).”
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    • cites (ref.32)

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    Premisecitation

    Oligoclonal expanded CD8+ memory T cells in humans are distinguished by loss of CD28 expression and impaired immune function.

    “These oligoclonal expanded CD8 + memory T cells are further distinguished in humans by loss of expression of the CD28 co-stimulatory molecule (47,48) and impaired immune function.”
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    Accumulation of CD8+CD28- T cells and CMV seropositivity are components of the immune risk profile.

    “The accumulation of CD8 + CD28 -T cells and CMV seropositivity are components of the immune risk profile, which has been proposed as a predictor of mortality in individuals 65 and older (49)”
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    Interpretationcitation

    Lymphoid-biased hematopoietic stem cells in old mice accumulate defects that may impair self-renewal and contribute to their decline.

    “Lymphoid-biased HSCs in old mice also appear to accumulate deficiencies that, as discussed below, may compromise their selfrenewal potential and contribute to the decline of this population (27).”
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    Premisereasoning

    Age-related microenvironmental changes have a major impact in the thymus, where T cell development depends on an intact thymic milieu.

    “Age-relat-ed microenvironmental changes also have a major impact in the thymus, where T cell development is dependent upon an intact thymic milieu composed of fibroblasts, macrophages, dendritic cells, and thymic epithelial cells.”
    Quote in the paperSubstantial claim

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    Premisecitation

    B cell number in mice is unchanged by aging, but in human peripheral blood the absolute number is reduced.

    “B cell number in mice is unchanged by aging, but in human peripheral blood their absolute number is reduced (51).”
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    The number of thymic epithelial cells declines over time and they are not replaced because of impaired proliferation.

    “It is clear that the number of thymic epithelial cells declines over time and that they are not replaced, as a result of impaired proliferation (38).”
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    Common lymphoid progenitors, pre-pro-B cells, and pro-B cells from old mice proliferate less and undergo apoptosis more than young cells.

    “For example, common lymphoid progenitors, pre-pro-B cells, and pro-B cells from old mice do not proliferate as extensively as do young cells, and they exhibit significantly higher rates of apoptosis.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [29] Min, 2006, J Immunol. source

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    • cites [32] Min, 2004, J Immunol. source

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    Premisecitation

    ROS levels in cells may be regulated by ATM kinase, and age-related declines in ATM expression can increase ROS.

    “Levels of ROS in cells may also be regulated by ataxia telangiectasia mutated (ATM) kinase, and age-related declines in expression of ATM can result in an increase in ROS in cells (77,78).”
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    Premisecitation

    CD4+ T cells show reduced T cell receptor signaling intensity and altered cytokine production after antigen binding.

    “CD4 + T cells exhibit reduced T cell receptor signaling intensity and altered production of various cytokines following antigen binding (70,71).”
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    • cites [70] Maue, 2009, Curr Opin Immunol.

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    Interpretationcitation

    Repeated cell division may cause progressive telomere shortening, leading to DNA damage that cannot be repaired efficiently because of age-related defects in DNA repair.

    “Thus, repeated cell division may result in progressive telomere shortening that in turn results in DNA damage that can no longer be repaired efficiently due to agerelated defects in DNA repair mechanisms (75).”
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    Premisecitation

    Growth hormone and IGF-1 bind to receptors expressed on thymocytes and thymic epithelial cells.

    “GH and IGF-1 bind to receptors expressed on thymocytes (101) and thymic epithelial cells (102)”
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    Premisecitation

    Mice with hypomorphic DNMT1 expression have relatively normal myeloerythroid potential but a significant block in lymphoid development.

    “mice with hypomorphic expression of DNMT1 exhibit relatively normal myeloerythroid potential but show a significant block in lymphoid development (92).”
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    Premisecitation

    Loss of DNMT3a impairs hematopoietic stem cell differentiation while increasing their number in the bone marrow.

    “In this regard, loss of DNMT3a impairs differentiation of HSCs while their number increases in the bone marrow (91)”
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    Premisecitation

    BATF levels increase in hematopoietic stem cells in response to DNA damage, causing lymphoid-biased stem cells to differentiate at the expense of self-renewal.

    “Wang and colleagues demonstrated that BATF levels increased in HSCs in response to DNA damage and that this resulted in the differentiation of lymphoid-biased HSCs at the expense of their self-renewal (27).”
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    Premisecitation

    Both Ink4a and Arf expression increase in pro-B cells from old mice, and inhibiting their expression can partially reverse aging effects.

    “recent studies have shown that both Ink4a and Arf expression increases in pro-B cells from old mice and that inhibiting their expression can partially reverse the effects of aging (81).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] source

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    Premisecitation

    In HIV-infected adults with low CD4+ T cell counts, one year of daily growth hormone administration increased thymic mass, thymic output, and naive CD4+ T cell numbers.

    “GH treatment resulted in increased thymic mass, increased thymic output as measured by T cell receptor rearrangement excision circles in circulating T cells, and increased numbers of naive CD4 + T cells.”
    • Also stated in: § Rejuvenating the aging immune system · plain
      “It is important to note that the effects of GH were not thymus specific, as the subjects also had expanded numbers of naive peripheral CD4 + T cells (105).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Napolitano, 2008, J Clin Invest.

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

    Interpretationreasoning

    Such pharmacologic interventions could be given to a large group of people.

    “and suggest that such interventions could be administered to a large cohort of individuals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    It is reasonable to expect that knowledge about immune aging will continue to be turned into rejuvenation therapies.

    “it is not unreasonable to expect that this information will continue to be translated into therapies to rejuvenate the aging immune system.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FGF7 treatment downregulates Ink4a expression in early T lineage progenitors and double-negative cells and enhances their proliferation.

    “As predicted, levels of Ink4a expression in ETPs and DN cells harvested from FGF7-treated mice were downregulated, and these cells exhibited enhanced proliferation (82).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] source

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  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationnone given

    Much is known about the cellular changes and molecular events in the aging immune system.

    “a tremendous amount is now known regarding the cellular changes that occur in the aging immune system and the molecular events that underlie them.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In non-human primates, caloric restriction helps when begun in adulthood but not when begun before puberty or in old age.

    “beneficial effects were observed when it commenced in adults but were not evident when initiated in prepubertal or aged non-human primates (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] source

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    Premisecitation

    FGF7 administration to old mice renews the thymic microenvironment, increases early T lineage progenitors, and restores thymus cellularity to young levels.

    “FGF7 is particularly remarkable because its administration to old mice results in a renewal of the thymic microenvironment, increased numbers of ETPs, and a restoration of thymus cellularity to levels observed in the young (106, 107).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [106] source

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    • cites [107] source

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31 of 31

  • The paper relies on this without support.

    The thymic effects of GH, IGF-1, and FGF7 are short-lived, and the thymus returns to its previous size after treatment ends.

    “because their effects are transient and the thymus reverts to its former size following the cessation of treatment.”

  • The paper relies on this without support.

    Aging affects the immune system differently across individuals.

    “It is likely that the effects of aging on the immune system will not be uniform between individuals.”

  • The paper relies on this without support.

    GH, IGF-1, and FGF7 act throughout the body because their receptors are present on cells in many tissues.

    “factors such as GH, IGF-1, and FGF7 have widespread systemic effects due to the expression of their receptors on cells in multiple tissues.”
3 of 3

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?

  • 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 Montecino-Rodriguez et al., 2013

  • Most older people over the age of 60-65 years experience some immune dysregulation that makes them less able to respond to immune challenges.

    “most older people over the age of 60–65 years (although not all) experience some immune dysregulation that makes them less able to respond to immune challenges [33,34].”

    From Immune function and micronutrient requirements change over the life course (2018) · cites this paper as [34]

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Weng, 2009, Trends Genet., 30, 306
  2. Maue, 2009, Curr Opin Immunol., 30, 301
  3. Napolitano, 2008, J Clin Invest., 118, 1085

Cited by

Sorted by citations

Related

Authors
Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K.
Affiliations
University of California, Los Angeles (US)
Corresponding author
Dorshkind, Kenneth
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2013-03-01
Volume
123
Issue
3
Pages
958-965
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci64096
PMC
PMC3582124
OpenAlex
W1978103330
Semantic Scholar
21eeafabbc2cc60c6c46752d238c5688d989e17b
Cited by
793
References
120
Citations by year
2026: 30 · 2025: 47 · 2024: 72 · 2023: 86 · 2022: 96 · 2021: 126 · 2020: 106 · 2019: 64 · 2018: 54 · 2017: 37 · 2016: 21 · 2015: 27 · 2014: 18 · 2013: 9
FWCI
2.12
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R01AG034875, AG034875)
  • David Geffen School of Medicine, University of California, Los Angeles
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
immunosenescence, B cell aging, T cell senescence, thymus, bone marrow, secondary lymphoid organs, lymphocyte function
MeSH terms
Aging, Animals, Hematopoietic Stem Cells, Humans, Immune System, Immunologic Factors, Lymphoid Progenitor Cells

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