The DOI matches its Crossref record; 126 of the 126 references it cites were found in a registry or an index; none of the 118 sources its claims cite is checked for support yet.
Causes, consequences, and reversal of immune system aging
Open accessAbstract
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.
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76 Not checked yet · 14 Own interpretation · 10 No basis given
In the paper
“Despite the increase in their number, myeloid-biased stem cells are not as robust as their young counterparts (24)”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
- Not checked yetcites [24] source
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In the paper
“This is illustrated by increased vulnerability of individuals 70 years of age and older to influenza (1)”
§ Causes, consequences, and reversal of immune system aging > Introduction
What the sources say
- Not checked yetcites [1] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Abstract
What the sources say
- Not checked yetcites [1] source
- Not checked yetcites (2)(3)(4)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Introduction · hedged
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In the paper
“which in turn could underlie the numerous age-related deficiencies observed in mature myeloid cells such as neutrophils and macrophages (25,26).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
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In the paper
“This shift has been correlated with increased expression of myeloid lineage genes and downregulation of those specifying a lymphoid lineage fate (11,17).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
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In the paper
“primary lymphopoiesis in the elderly is significantly diminished, as exemplified by involution of the thymus (8)(9)(10).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
- Not checked yetcites (8)(9)(10)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The causes of this age-related reduction in lymphocyte development are multifactorial and include changes in HSCs and progenitor cells (11,12) as well as the local tissue and systemic environments (13,14).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The age-related increase in expression of myeloid lineage genes in the studies noted above (11,17) likely resulted from the accumulation of myeloid-biased HSCs, as these analyses were performed on unseparated pools of HSCs.”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“a situation that is exacerbated by their poor response to vaccination (2)(3)(4).”
§ Causes, consequences, and reversal of immune system aging > Introduction
What the sources say
- Not checked yetcites (2)(3)(4)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“this has led to the conclusion that age-related changes in the endocrine system contribute to declines in lymphopoiesis.”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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- It may state two separate claims as one. 28
- Probably not a substantial claim. 3
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“it is now appreciated that the number of lymphoid-biased stem cells declines with age concomitant with an increase in myeloid-biased HSCs (19).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
- Not checked yetcites [19] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Abstract
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Effects of aging on immune system development · plain
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Introduction
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Aging and the decline of immune function · boosted
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Aging and the decline of immune function
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Figure 1
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Figure 1
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
- Not checked yetcites (ref.32)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Figure 1
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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)”
§ Causes, consequences, and reversal of immune system aging > Figure 1
What the sources say
- Not checked yetcites [49] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
- Not checked yetcites [27] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“B cell number in mice is unchanged by aging, but in human peripheral blood their absolute number is reduced (51).”
§ Causes, consequences, and reversal of immune system aging > Figure 1
What the sources say
- Not checked yetcites [51] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
- Not checked yetcites [38] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Causes, consequences, and reversal of immune system aging > Effects of aging on immune system development
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Intracellular changes in developing and mature lymphocytes
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“CD4 + T cells exhibit reduced T cell receptor signaling intensity and altered production of various cytokines following antigen binding (70,71).”
§ Causes, consequences, and reversal of immune system aging > Figure 1
What the sources say
- Not checked yetcites [70] Maue, 2009, Curr Opin Immunol.
- Not checked yetcites [71] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Intracellular changes in developing and mature lymphocytes
What the sources say
- Not checked yetcites [75] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“GH and IGF-1 bind to receptors expressed on thymocytes (101) and thymic epithelial cells (102)”
§ Causes, consequences, and reversal of immune system aging > Rejuvenating the aging immune system
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“mice with hypomorphic expression of DNMT1 exhibit relatively normal myeloerythroid potential but show a significant block in lymphoid development (92).”
§ Causes, consequences, and reversal of immune system aging > Intracellular changes in developing and mature lymphocytes
What the sources say
- Not checked yetcites [92] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“In this regard, loss of DNMT3a impairs differentiation of HSCs while their number increases in the bone marrow (91)”
§ Causes, consequences, and reversal of immune system aging > Intracellular changes in developing and mature lymphocytes
What the sources say
- Not checked yetcites [91] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Intracellular changes in developing and mature lymphocytes
What the sources say
- Not checked yetcites [27] source
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Intracellular changes in developing and mature lymphocytes
What the sources say
- Not checked yetcites [81] source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Rejuvenating the aging immune system
What the sources say
- Not checked yetcites [105] Napolitano, 2008, J Clin Invest.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Rejuvenating the aging immune system · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and suggest that such interventions could be administered to a large cohort of individuals.”
§ Causes, consequences, and reversal of immune system aging > Caveats in immune system rejuvenation
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it is not unreasonable to expect that this information will continue to be translated into therapies to rejuvenate the aging immune system.”
§ Causes, consequences, and reversal of immune system aging > Conclusions and perspectives
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
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Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Rejuvenating the aging immune system
What the sources say
- Not checked yetcites [82] source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“a tremendous amount is now known regarding the cellular changes that occur in the aging immune system and the molecular events that underlie them.”
§ Causes, consequences, and reversal of immune system aging > Conclusions and perspectives
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may be too vague to check against evidence.
In the paper
“beneficial effects were observed when it commenced in adults but were not evident when initiated in prepubertal or aged non-human primates (112).”
§ Causes, consequences, and reversal of immune system aging > Rejuvenating the aging immune system
What the sources say
- Not checked yetcites [112] source
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Causes, consequences, and reversal of immune system aging > Rejuvenating the aging immune system
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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.”
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?
In the citing paper
“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
In the citing paper
“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]
Citations
Cites
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
Mortality Associated With Influenza and Respiratory Syncytial Virus in the United States
Thompson, W. W., Shay, D. K., Weintraub, E., Brammer, L., Cox, N., Anderson, L. J., & Fukuda, K. (2003) · JAMA · doi:10.1001/jama.289.2.179 · Cited by 3,673
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232
Franceschi, C., Capri, M., Monti, D., Giunta, S., Olivieri, F., Sevini, F., Panourgia, M. P., Invidia, L., Celani, L., Scurti, M., et al. (2007) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2006.11.016 · Cited by 2,087
Insulin and insulin-like growth factor signalling in neoplasia
Pollak, M. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2536 · Cited by 2,059
Ink4a/Arf expression is a biomarker of aging
Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22475 · Cited by 1,486
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Age-related changes in lymphocyte development and function
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Self-citationRegulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells
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Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19
Blanco-Melo, D., Nilsson-Payant, B. E., Liu, W.-C., Uhl, S., Hoagland, D., Møller, R., Jordan, T. X., Oishi, K., Panis, M., Sachs, D., et al. (2020) · Cell · doi:10.1016/j.cell.2020.04.026 · Cited by 4,222
“Given the results here, it is tempting to speculate that an already restricted immune response in the aging population prevents successful inhibition of viral spread at early stages of infection, further exacerbating the morbidity and mortality observed for this age group (Jing et al., 2009; Montecino-Rodriguez et al.…”
Unmasking senescence: context-dependent effects of SASP in cancer
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The senescence-associated secretory phenotype and its physiological and pathological implications
Wang, B., Han, J., Elisseeff, J. H., & Demaria, M. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00727-x · Cited by 948
“185,186), implies increased vulnerability to developing diseases such as osteoarthritis 187 , rheumatoid arthritis and cardiovascular diseases 188 .”
Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity
Shrock, E., Fujimura, E., Kula, T., Timms, R. T., Lee, I.-H., Leng, Y., Robinson, M. L., Sie, B. M., Li, M. Z., Chen, Y., et al. (2020) · Science · doi:10.1126/science.abd4250 · Cited by 678
“Advanced age is a dominant risk factor for severe COVID-19 and is correlated with reduced immune function (20).”
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Metadata
- Authors
- Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Dorshkind, Kenneth
- Venue
- Journal of Clinical Investigation
- Published
- 2013-03-01
- Volume
- 123
- Issue
- 3
- Pages
- 958-965
- ISSN
- 0021-9738 (ISSN-L)
- 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
- bronze
- doi.org
- 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
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.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-06 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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