Fibroblast growth factor-7 partially reverses murine thymocyte progenitor aging by repression of Ink4a
Open accessAbstract
Involution of the thymus results in reduced production of naive T cells, and this in turn is thought to contribute to impaired immunity in the elderly. Early T-cell progenitors (ETPs), the most immature intrathymic T-cell precursors, harvested from the involuted thymus exhibit a diminished proliferative potential and increased rate of apoptosis and as a result their number is significantly reduced. In the present study, we show that these age-induced alterations result in part from increased expression of the Ink4a tumor-suppressor gene in ETPs. We also show that repression of Ink4a in aged ETPs results in their partial rejuvenation and that this can be accomplished by in vivo fibroblast growth factor 7 administration. These results define a genetic basis for thymocyte progenitor aging and demonstrate that the senescence-associated gene Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging.
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Written from the paper’s full text.
TL;DR
Aging-related loss of early T-cell progenitors in mice is linked to higher expression of the tumor suppressor Ink4a, but not Arf. Treating old mice with fibroblast growth factor 7 lowers Ink4a in thymocyte progenitors and partially restores their proliferation, though it does not fully restore differentiation.
Key findings
- In old mice, Ink4a expression was elevated in ETPs and in DN2 and DN3 thymocytes, while Arf was not detected in ETPs and did not differ significantly in DN populations. Among regulators tested, Hmga2 was reduced in old ETPs, whereas Bmi-1, Ets-1, Ets-2, Id-1, Ezh2, and Let-7b did not show the same age-related change.
- Forcing Ink4a expression in young ETPs blocked their expansion in fetal thymic organ culture and increased death on OP9-DL1 stroma. Reducing Ink4a in old ETPs with shRNA increased recovery roughly 2-fold at 1 week and yielded about 1 million cells at 2 weeks versus about 5-fold fewer in controls, but did not reach young ETP levels; Ink4a was reduced by only about 20%.
- Fgf7 treatment increased total thymocyte numbers, ETP numbers, and DN2/DN3/DN4 numbers in old mice, and increased Ki-67 expression in these populations. It also lowered Ink4a in ETPs and DN cells and changed cell-cycle-related genes, including increased Ccnd1 and Egr-1 and reduced Gsk3b.
- Fgf7-treated old ETPs still differentiated into CD4- and/or CD8-expressing cells less efficiently than young ETPs, indicating only partial reversal of the aging phenotype.
Methods
- Young and old mice were compared, with ages including 4–6 weeks or 4–8 weeks for young and 18 months, 18–20 months, or 15–18 months for old animals. ETPs and DN thymocyte subsets were resolved by flow cytometry using lineage markers and CD44/CD25/c-kit.
- Gene expression was measured by qRT-PCR and a mouse senescence PCR array. Retroviral vectors expressing Ink4a/GFP or Ink4a/GFP shRNA were used to overexpress or knock down Ink4a in ETPs, followed by fetal thymic organ culture or OP9-DL1 stromal culture.
- In vivo Fgf7 treatment consisted of three daily injections of 5 mg/kg/day recombinant human Fgf7 per round, with PBS vehicle controls; some experiments used monthly repeated rounds. Statistical comparisons used two-tailed unpaired Student t tests with α = 0.05.
Limitations
- The paper states that the mechanism by which Fgf7 affects thymocyte progenitors remains undefined because the Fgf7 receptor is expressed on thymic epithelial cells rather than thymocytes. It also states that whether reduced Hmga2 causes increased Ink4a, and whether suppression of a senescence-associated secretory phenotype lowers Ink4a, remain to be determined.
- The paper acknowledges that Fgf7 did not correct all age-related deficiencies: proliferation improved, but old ETPs still differentiated less efficiently than young ETPs, so the reversal is partial rather than complete.
- Evident from the text: the work is limited to murine systems, relies on retroviral manipulation and in vitro culture systems, and the Ink4a knockdown achieved only about 20% reduction, which may explain why old ETPs did not reach young levels.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 31 cited sources checked · 0 supported · 0 flagged
- Findingown data
There is no difference in Ink4a expression between young and old DN4 cells.
“We also examined ETP progeny and observed significant increases in Ink4a expression in old DN2 and DN3 thymocytes, whereas no differences were observed between young and old DN4 cells (Figure 1C).”
Quote in the paperNot a substantial claim - Findingown data
Bmi-1 levels did not decline with age in ETPs.
“In contrast to what occurs in aging B-cell progenitors, Bmi-1 levels did not decline with age in ETP (Figure 1D).”
Quote in the paperSubstantial claim - Findingown data
Hmga2 levels were significantly reduced in old ETPs.
“Only levels of Hmga2 were significantly reduced in old ETPs (Figure 1D).”
Quote in the paperSubstantial claim - Findingown data
Ink4a expression is significantly increased in old DN2 and DN3 thymocytes.
“We also examined ETP progeny and observed significant increases in Ink4a expression in old DN2 and DN3 thymocytes, whereas no differences were observed between young and old DN4 cells (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
Ink4a expression is increased in ETPs from old mice compared with young mice.
“The results demonstrated that Ink4a was expressed at increased levels in ETPs from old mice (Figure 1B).”
- Also stated in: § Abstract · plain
“we show that these age-induced alterations result in part from increased expression of the Ink4a tumor-suppressor gene in ETPs.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
Arf was not detected in ETPs at any age.
“However, Arf was not detected in ETPs at any age (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Differences in Arf expression between young and old DN2, DN3, and DN4 cells were not significant.
“Although low levels of Arf could be detected in DN2, DN3, and DN4 cells from young and old mice, differences in expression between these populations were not significant (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment increased Ccnd1 expression in ETPs from old mice.
“In addition, we observed increased expression of cell cycle-promoting genes such as Cyclin D1 (Ccnd1), which is downstream of Ink4a, 12 and its transcriptional activator early growth response protein 1 (Egr-1) 36 and reduced expression of serine/threonine kinase and glycogen synthase kinase-3b (Gsk3b), which triggers cyclin D1 proteasomal degradation 37 (Figure 4C-D).”
Quote in the paperSubstantial claim - Findingown data
Cell production from Ink4a shRNA-transduced old ETPs did not reach the levels seen with young ETPs.
“However, cell production in cultures initiated with Ink4a shRNAtransduced cells did not reach levels observed with young ETPs.”
Quote in the paperSubstantial claim - Findingown data
Overexpression of Ink4a in young ETPs impairs their expansion in fetal thymic organ culture.
“Whereas ETPs transduced with GFP-only vectors expanded in FTOC (Figure 2A-B), Ink4a/GFP-transduced cells failed to grow, likely because they underwent cell-cycle arrest and apoptosis.”
Quote in the paperSubstantial claim - Findingown data
ETPs from Fgf7-treated old mice did not differentiate into CD4- and/or CD8-expressing cells as efficiently as young ETPs.
“However, ETPs obtained from the old Fgf7-treated mice did not differentiate into CD4-and/or CD8-expressing cells with the same efficiency as young ETPs (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment significantly increased the number of proliferating DN cells.
“and, as observed with ETPs, was correlated with a significant increase in the number of proliferating DN cells (Figure 3E).”
Quote in the paperSubstantial claim - Findingown data
Let7b levels remained constant between young and old ETPs.
“Let7b levels remained constant between young and old ETPs (Figure 1D), even though its expression has been reported to increase with age in some tissues.33”
Quote in the paperNot a substantial claim - Findingown data
Fgf7 treatment significantly increased the number of DN2, DN3, and DN4 cells in old mice.
“As shown in Figure 3D, the number of DN2, DN3, and DN4 cells was significantly increased after Fgf7 treatment”
Quote in the paperSubstantial claim - Findingown data
Higher numbers of thymocytes were recovered from fetal thymic lobes seeded with ETPs from Fgf7-treated old mice than from PBS-treated controls.
“Consistent with the in vivo data shown in Figure 3, higher numbers of thymocytes were recovered from lobes seeded with ETPs from Fgf7-treated old mice than from lobes seeded with ETPs from PBS-treated control animals (Figure 5A).”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment decreased Ink4a expression in DN2, DN3, and DN4 thymocytes from old mice.
“This analysis showed that Ink4a expression was decreased in ETPs (Figure 4A) and in DN2, DN3, and DN4 thymocytes (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment significantly increased the number of Ki-67-expressing ETPs.
“This expansion of ETPs was likely because of their increased proliferation, because the number of Ki-67-expressing ETPs was increased significantly (Figure 3C).”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment decreased Ink4a expression in ETPs from old mice.
“This analysis showed that Ink4a expression was decreased in ETPs (Figure 4A) and in DN2, DN3, and DN4 thymocytes (Figure 4B).”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment did not change the frequencies of DN2, DN3, and DN4 cells.
“However, the frequencies of DN2, DN3, and DN4 cells were not changed by Fgf7 treatment (supplemental Figure 1B).”
Quote in the paperNot a substantial claim - Findingown data
Ink4a levels in shRNA-transduced old ETPs that matured to DN2-DN4 were reduced by only 20% compared with DN cells directly harvested from old thymus.
“This may be because Ink4a levels in the former population, which had now matured to the DN2-DN4 stages of development, had been reduced by only 20% compared with levels in DN cells directly harvested from old thymus.”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment reduced Gsk3b expression in ETPs from old mice.
“In addition, we observed increased expression of cell cycle-promoting genes such as Cyclin D1 (Ccnd1), which is downstream of Ink4a, 12 and its transcriptional activator early growth response protein 1 (Egr-1) 36 and reduced expression of serine/threonine kinase and glycogen synthase kinase-3b (Gsk3b), which triggers cyclin D1 proteasomal degradation 37 (Figure 4C-D).”
Quote in the paperNot a substantial claim - Findingown data
One round of Fgf7 treatment significantly increased the number of ETPs in the involuted thymus.
“As shown in Figure 3B, 1 round of Fgf7 treatment increased the number of ETPs in the involuted thymus significantly.”
Quote in the paperSubstantial claim - Findingown data
Fgf7 treatment increased Egr-1 expression in ETPs from old mice.
“In addition, we observed increased expression of cell cycle-promoting genes such as Cyclin D1 (Ccnd1), which is downstream of Ink4a, 12 and its transcriptional activator early growth response protein 1 (Egr-1) 36 and reduced expression of serine/threonine kinase and glycogen synthase kinase-3b (Gsk3b), which triggers cyclin D1 proteasomal degradation 37 (Figure 4C-D).”
Quote in the paperNot a substantial claim - Findingown data
Ink4a-transduced young ETPs cultured on OP9-DL1 stromal cells showed significantly higher death than GFP-expressing controls.
“The fact that Ink4a-transduced cells harvested 7 days after seeding on OP9-⌬1 stromal cells (which have been shown to support early T-cell development in vitro 34 ) exhibited significantly higher levels of death compared with the green fluorescent protein (GFP)-expressing control populations is consistent with this conclusion (Figure 2C).”
Quote in the paperSubstantial claim - Premisecitation
Fgf7 stimulates thymic epithelial cells to secrete various cytokines.
“Fgf7 is known to stimulate the secretion of various cytokines by thymic epithelial cells.25”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Rossi, 2007, Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells., Blood source
Not checked in the free run.
- Premisecitation
Mice engineered to express Ink4a under an lck promoter have a block in T-cell differentiation at the DN3 stage.
“mice engineered to express Ink4a under the control of an lck promoter have a block in T-cell differentiation at the DN3 stage.17”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Lagresle, 2002, Transgenic expression of the p16INK4a cyclin-dependent kinase inhibitor leads to enhanced apoptosis and differentiation arrest of CD4−CD8− immature thymocytes., J Immunol source
Not checked in the free run.
- Premisecitation
ETPs from the involuted thymus retain impaired T-lymphopoietic potential when transferred into a young environment.
“because ETPs from the involuted thymus still exhibit impaired T-lymphopoietic potential when they are transferred to a young environment.8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Min, 2004, Reduction in the developmental potential of intrathymic T cell progenitors with age., J Immunol source
Not checked in the free run.
- Premisecitation
Thymus size is increased in mouse strains deficient in Ink4a.
“thymus size is increased in Ink4a-deficient mouse strains, 15,16”
Quote in the paperNot a substantial claim0 of 2 sources checked - Premisecitation
Ink4a is an important regulator of thymopoiesis.
“Evidence from loss-and gain-of-function studies indicates that Ink4a is an important regulator of thymopoiesis.”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [15] Sharpless, 2001, Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis., Nature source
Not checked in the free run.
- cites [16] Bianchi, 2006, The tumor suppressor p16Ink4a regulates T lymphocyte survival., Oncogene source
Not checked in the free run.
- cites [17] Lagresle, 2002, Transgenic expression of the p16INK4a cyclin-dependent kinase inhibitor leads to enhanced apoptosis and differentiation arrest of CD4−CD8− immature thymocytes., J Immunol source
Not checked in the free run.
- cites [18] Liu, 2011, Expression of p16Ink4a prevents cancer and promotes aging in lymphocytes., Blood source
Not checked in the free run.
- Premisecitation
ETPs from old mice do not differentiate as efficiently as ETPs from young mice.
“In addition to proliferative defects, ETPs from old mice do not differentiate as efficiently as their young counterparts, 8”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8] Min, 2004, Reduction in the developmental potential of intrathymic T cell progenitors with age., J Immunol source
Not checked in the free run.
- Premisecitation
Conditional deletion of Ink4a in thymocytes significantly delays thymic involution.
“Liu et al conditionally deleted Ink4a in thymocytes by mating mice with a floxed Ink4a allele to lck-Cre mice and demonstrated that thymic involution was delayed significantly.18”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Liu, 2011, Expression of p16Ink4a prevents cancer and promotes aging in lymphocytes., Blood source
Not checked in the free run.
- Premisecitation
Fgf7 is particularly effective at restoring thymus cellularity in old mice to levels seen in young mice.
“Of the above factors, Fgf7 is particularly effective, because thymus cellularity in old mice administered multiple rounds of Fgf7 is restored to levels observed in the young.24”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Min, 2007, Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging., Blood source
Not checked in the free run.
- Premisecitation
Thymic epithelial cells decline in number with age.
“First, it is known that thymic epithelial cells that constitute a key element of the thymus microenvironment decline in number with age.7”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Manley, 2012, Structure and function of the thymic microenvironment., Front Biosci
Not checked in the free run.
- Premisecitation
Exogenous factors in the microenvironment can affect the senescent state of target cells by regulating gene expression in them.
“A key tenet of the model shown in Figure 6 is that exogenous factors in the microenvironment can affect the senescent state of target cells by regulating gene expression in them.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [42] Chen, 2011, PDGF signalling controls age-dependent proliferation in pancreatic beta-cells., Nature source
Not checked in the free run.
- Interpretationreasoning
Factors in addition to Ink4a contribute to thymic involution.
“Factors in addition to Ink4a that contribute to thymic involution are likely to be operative.”
Quote in the paperSubstantial claim - Premisecitation
Ink4a expression is increased in pro-B cells from old mice.
“We previously demonstrated decreased expression of Bmi-1 and increased levels of Ink4a in pro-B cells from old mice.26”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Signer, 2008, Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf., Genes Develop source
Not checked in the free run.
- Interpretationreasoning
The regulation of Ink4a expression in aging B-cell and T-cell progenitors differs.
“The regulation of Ink4a expression in aging B-and T-cell progenitors also appears to differ.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Signer, 2008, Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf., Genes Develop source
Not checked in the free run.
- Interpretationown data
Ink4a is a biomarker of T-lineage aging.
“These results indicate that increased expression of Ink4a in young ETPs results in their diminished proliferative potential and increased apoptosis, and that Ink4a is both a biomarker and effector of T-lineage aging.”
- Also stated in: § Discussion · boosted
“The results of the present study establish Ink4a as a biomarker of thymocyte progenitor aging that may be useful in measuring the efficacy of antiaging therapies.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · boosted
- Premisecitation
lck-driven Cre expression is most robust starting at the DN2 stage of development.
“This may have occurred because expression of lck used to drive Cre expression is most robust starting at the DN2 stage of development, 2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Rothenberg, 2010, Multilayered specification of the T-cell lineage fate., Immunol Rev source
Not checked in the free run.
- Premisecitation
The thymus of mice with conditional Ink4a deletion ultimately underwent involution.
“However, the thymus of these mice ultimately underwent involution.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Liu, 2011, Expression of p16Ink4a prevents cancer and promotes aging in lymphocytes., Blood source
Not checked in the free run.
- Interpretationown data
Ink4a is an effector or mediator of T-lineage aging.
“These results indicate that increased expression of Ink4a in young ETPs results in their diminished proliferative potential and increased apoptosis, and that Ink4a is both a biomarker and effector of T-lineage aging.”
- Also stated in: § Discussion · hedged
“In addition, the data suggest that p16 Ink4a is also a mediator of that process.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Interpretationreasoning
Fgf7 does not completely reverse the effects of aging to make old thymocytes young again.
“Therefore, Fgf7 does not completely reverse the effects of aging to make old thymocytes young again.”
Quote in the paperSubstantial claim - Interpretationown data
These results define a genetic basis for thymocyte progenitor aging.
“These results define a genetic basis for thymocyte progenitor aging and demonstrate that the senescence-associated gene Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging.”
Quote in the paperSubstantial claim - Interpretationown data
Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging.
“These results define a genetic basis for thymocyte progenitor aging and demonstrate that the senescence-associated gene Ink4a can be pharmacologically repressed in ETPs to partially reverse the effects of aging.”
Quote in the paperSubstantial claim - Premisecitation
Bmi-1 expression is decreased in pro-B cells from old mice.
“We previously demonstrated decreased expression of Bmi-1 and increased levels of Ink4a in pro-B cells from old mice.26”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Signer, 2008, Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf., Genes Develop source
Not checked in the free run.
- May combine two claims. 13
- Classified as probably not a substantial claim. 8
May combine two claims.
Findingown dataAfter three rounds of Fgf7, ETP numbers increased further but remained below those in young mice.
“Further increases in ETP number were observed after 3 rounds of drug administration (Figure 3B), although their total number still remained below that in young mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAmong the examined Ink4a regulators, only Hmga2 showed a significant age-related reduction in ETPs; Ets-1, Ets-2, Id-1, and Ezh2 did not.
“This result prompted us to examine expression of other regulators of Ink4a that included Ets-1, Ets-2, Id-1, 28 Hmga2, [29][30][31] and Ezh2.32 Only levels of Hmga2 were significantly reduced in old ETPs (Figure 1D).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataA single round of Fgf7 administration increased total thymocyte number in old mice, and the effect was further accentuated with three rounds.
“Consistent with these previous findings, in the present study, a single round of Fgf7 administration increased the total number of thymocytes in old mice, and this effect was further accentuated with 3 rounds of treatment (Figure 3A).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationAge-related increases in Ink4a and Arf expression have been reported in many tissues.
“because an age-related increase in expression of both of these tumorsuppressor genes has been reported in numerous tissues, 13”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Krishnamurthy, 2004, Ink4a/Arf expression is a biomarker of aging., J Clin Invest source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPDGF regulates Ink4a levels in pancreatic beta cells.
“Such a mechanism has been shown recently to operate in the pancreas, where PDGF regulates the levels of Ink4a in pancreatic  cells.42”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Chen, 2011, PDGF signalling controls age-dependent proliferation in pancreatic beta-cells., Nature source
Not checked in the free run.
May combine two claims.
PremisecitationEarly T-cell progenitors from the aged thymus have reduced proliferative capacity and increased apoptosis, which lowers their numbers.
“Early T-cell progenitors (ETPs), the most immature intrathymic Tcell precursors, harvested from the involuted thymus exhibit a diminished proliferative potential and increased rate of apoptosis and as a result their number is significantly reduced.”
- Also stated in: § Introduction · plain
“In addition, the number of ETPs in the aged thymus is significantly reduced because of their diminished proliferative potential and increased rate of apoptosis.8,9”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [8] Min, 2004, Reduction in the developmental potential of intrathymic T cell progenitors with age., J Immunol source
Not checked in the free run.
- cites [9] Heng, 2005, Effects of castration on thymocyte development in two different models of thymic involution., J Immunol source
Not checked in the free run.
- Also stated in: § Introduction · plain
May combine two claims.
PremisecitationThe Fgf7 receptor is expressed on thymic stromal cells but not on thymocytes.
“A third category, typified by fibroblast growth factor 7 (Fgf7; also referred to as keratinocyte growth factor), binds to receptors expressed on thymic stromal cells but not thymocytes.[23][24][25]”
- Also stated in: § Discussion · plain
“because the Fgf7 receptor (F␥fR2IIIb) is expressed by thymic epithelial cells and not by thymocytes, 24,25”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [23] Alpdogan, 2006, Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration., Blood source
Not checked in the free run.
- cites [24] Min, 2007, Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging., Blood source
Not checked in the free run.
- cites [25] Rossi, 2007, Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells., Blood source
Not checked in the free run.
- Also stated in: § Discussion · plain
May combine two claims.
PremisecitationThymic involution reduces naive T-cell production and is thought to contribute to impaired immunity in the elderly.
“Involution of the thymus results in reduced production of naive T cells, and this in turn is thought to contribute to impaired immunity in the elderly.”
- Also stated in: § Introduction · hedged
“a hallmark of immune system aging is involution of the thymus, resulting in a reduced production of naive T cells that has been proposed to underlie, at least in part, the impaired immunity observed in the elderly.4,5”
Quote in the paperSubstantial claim0 of 2 sources checked- Also stated in: § Introduction · hedged
May combine two claims.
PremisecitationThe number and quality of thymic epithelial cells are reduced in the involuted thymus.
“The number and quality of thymic epithelial cells are reduced in the involuted thymus.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Manley, 2012, Structure and function of the thymic microenvironment., Front Biosci
Not checked in the free run.
May combine two claims.
Interpretationown dataFgf7 treatment partially reverses age-related deficiencies in proliferation but does not restore the differentiation potential of aged ETPs.
“These data indicate that whereas Fgf7 treatment partially reverses age-related deficiencies in proliferation, it does not restore the differentiation potential of aged ETPs.”
- Also stated in: § Discussion · plain
“Fgf7 did not correct all of the age-related deficiencies in thymopoiesis.Whereas proliferation of old ETPs was enhanced, these cells still did not differentiate as efficiently as their young counterparts.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
May combine two claims.
InterpretationreasoningFgf7's thymopoietic effects result from increased numbers of ETPs and DN cells, leading to increased total thymus cellularity.
“Rather, its thymopoietic effects result from the fact that the number of ETPs and DN cells is significantly increased, resulting in an increase in total thymus cellularity.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLoss of Bmi-1 is correlated with increased Ink4a expression in pro-B cells from old mice.
“Whereas loss of Bmi-1 was shown to be correlated with increased expression of Ink4a in pro-B cells from old mice, 26 its levels remained constant in old ETPs.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Signer, 2008, Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf., Genes Develop source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe presence of single RT-PCR products was confirmed by melt curve analysis.
“The presence of single RT-PCR products was confirmed by melt curve analysis.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataIncreased Ink4a expression in young ETPs causes diminished proliferative potential and increased apoptosis.
“These results indicate that increased expression of Ink4a in young ETPs results in their diminished proliferative potential and increased apoptosis, and that Ink4a is both a biomarker and effector of T-lineage aging.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductcitationThe Ink4a/GFP shRNA used was previously validated.
“We therefore used a loss-of-function approach in which ETPs isolated from old mice were transduced with a previously validated Ink4a/GFP shRNA 26 or GFP-only-containing retroviral vectors”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Signer, 2008, Aging and cancer resistance in lymphoid progenitors are linked processes conferred by p16Ink4a and Arf., Genes Develop source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were performed in triplicate.
“All experiments were performed in triplicate and data are expressed as means Ϯ SD.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataFgf7 treatment results in down-regulation of Ink4a in thymocyte progenitors and partial restoration of ETP and DN proliferation.
“Our data support a model in which Fgf7 treatment results in down-regulation of Ink4a in thymocyte progenitors and partial restoration of ETP and DN proliferation (Figure 6).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataqRT-PCR amplification efficiencies were routinely between 95% and 105%, and all reactions were run at least twice in duplicate.
“Amplification efficiencies were routinely found to be between 95% and 105%.All reactions were run at least twice in duplicate.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataInk4a contributes to the age-related decline in ETP proliferation, and these aging deficits can be partially reversed.
“Nevertheless, these results indicate that Ink4a contrib-utes to the age-related decline in ETP proliferation and that these aging deficits can be partially reversed.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataFindings are based on three independent experiments.
“The mean Ϯ SEM based on 3 independent experiments is shown.”
Quote in the paperNot a substantial claim
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?
Increased expression of Ink4a, but not Arf, occurs in early T lineage progenitors and their double-negative progeny.
“We also observed increased expression of Ink4a, but not Arf, in ETPs and their DN progeny (82).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [82]
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).”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [82]
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.
Figure 2C has conflicting culture durations
MinorThe results describe the cells in Figure 2C as harvested seven days after seeding, while the figure caption says they were assessed two weeks after seeding.
“The fact that Ink4a-transduced cells harvested 7 days after seeding on OP9-⌬1 stromal cells (which have been shown to support early T-cell development in vitro 34 ) exhibited significantly higher levels of death compared with the green fluorescent protein (GFP)-expressing control populations is consistent with this conclusion (Figure 2C).”
“(C) Frequencies of 7-aminoactinomycin D ϩ (dead) and annexin V ϩ (apoptotic) cells in cell suspensions harvested from cultures established by seeding Ink4a/GFP-or GFP-only-transduced young ETPs on OP9-⌬1 stromal cells 2 weeks after seeding.”
Ink4a is described as both declining and increasing with age
MinorThe discussion refers to an age-related decline in Ink4a expression, but the same discussion reports a significant age-related increase in ETPs and DN2/DN3 cells.
“The precise basis for the agerelated decline in Ink4a expression in ETPs and DN cells is unclear.”
“Our present results demonstrate that expression of Ink4a is increased significantly with age in ETPs ands in DN2 and DN3 thymocytes.”
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- Authors
- Berent-Maoz, B., Montecino-Rodriguez, E., Signer, R. A. J., & Dorshkind, K.
- Affiliations
- University of California, Los Angeles (US)
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-06-14
- Volume
- 119
- Issue
- 24
- Pages
- 5715-5721
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC3382931
- OpenAlex
- W2011691272
- Semantic Scholar
- 5d66dba4be7444a0d9be7f85b7fe0c503a2fa082
- Cited by
- 46
- References
- 44
- Citations by year
- 2025: 1 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 1 · 2019: 5 · 2018: 3 · 2017: 4 · 2016: 3 · 2015: 4 · 2014: 5 · 2013: 7
- FWCI
- 2.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AI28697, CA16042)
- National Institute on Aging (R01AG034875, AG034875)
- National Cancer Institute (CA-16 042, P30CA016042)
- National Institute of Allergy and Infectious Diseases (AI-28 697, P30AI028697)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Keywords
- fibroblast growth factor 7, INK4A, thymic involution, cellular senescence, immunosenescence, tumor suppressor gene repression, apoptosis
- MeSH terms
- Aging, Animals, Cell Differentiation, Cell Separation, Humans, Mice, Inbred C57BL, Stem Cells, Thymus Gland, Down-Regulation, Up-Regulation, Cellular Senescence, Models, Immunological, Cyclin-Dependent Kinase Inhibitor p16, Cell Proliferation, Mice, Fibroblast Growth Factor 7, Thymocytes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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