The DOI matches its Crossref record; 31 of the 32 references it cites were found in a registry or an index; 9 of the 19 sources its claims cite were checked for support.
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Open accessAbstract
Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
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Written from the paper’s full text.
TL;DR
The paper describes INK-ATTAC, a transgenic mouse system that allows drug-inducible removal of p16Ink4a-positive senescent cells. In a BubR1 hypomorphic progeroid background, clearing these cells delayed or slowed several age-related phenotypes in adipose tissue, skeletal muscle, and eye, supporting a causal role for cellular senescence in age-related dysfunction.
Key findings
- INK-ATTAC expression overlapped with endogenous p16Ink4a: GFP+ cells from aged BubR1H/H;INK-ATTAC adipose tissue had higher p16Ink4a and other senescence markers than GFP− cells, and AP20187 killed most rosiglitazone-induced senescent bone marrow cells within 48 h in vitro.
- Life-long AP20187 treatment from 3 weeks of age in BubR1H/H;INK-ATTAC lines 3 and 5 delayed lordokyphosis and cataracts, increased muscle fibre diameter, improved treadmill exercise duration/distance/work, and prevented adipose tissue loss; these delays were absent in BubR1H/H mice without the transgene.
- Late-life treatment starting at 5 months and assessed at 10 months improved muscle fibre size and exercise performance and increased fat depots and adipocyte size, but cataracts that had already matured remained unchanged; the effects reflected slowed progression rather than reversal of ageing.
- p16Ink4a-independent phenotypes such as cardiac arrhythmias and arterial wall stiffening were not attenuated, and overall survival was not substantially extended, likely because cardiac failure is the main cause of death in this model. No overt side effects were observed in WT;INK-ATTAC mice treated until 8 months.
Methods
- The INK-ATTAC construct used a 2,617-bp murine p16Ink4a promoter fragment to drive FKBP–Casp8, with an IRES-EGFP reporter; nine transgenic founder lines were generated and bred onto the BubR1 hypomorphic background, with lines 3 and 5 selected for study.
- AP20187 was injected intraperitoneally every 3 days at 0.2 μg/g body weight from weaning (life-long) or from 5 months (late-life); phenotypes were assessed by lordokyphosis and cataract checks, muscle and fat histology, DEXA, treadmill exercise, BrdU incorporation, SA-β-Gal staining, qRT–PCR, and FACS.
- In vitro, bone marrow cells were treated with 1 μM rosiglitazone for 5 days and then 10 nM AP20187 for 48 h; MEFs were induced to senesce by serial passaging (12–15 passages) or H-ras expression, sorted into GFP+ and GFP− populations, and analysed. Statistical comparisons used two-tailed unpaired t tests and log-rank tests.
Limitations
- The paper states that no universal marker expressed solely in senescent cells has been identified, and the approach relies on p16Ink4a promoter activity and two transgenic lines.
- The paper notes that overall survival was not substantially extended, probably because cardiac failure dominates mortality in BubR1H/H mice; p16Ink4a-independent pathologies were unaffected, and mature cataracts did not improve with late-life clearance.
- Evident from the text: the findings are in a progeroid BubR1 hypomorphic mouse model rather than natural ageing, some measurements were performed in female mice, and absence of overt side effects was only tested in WT;INK-ATTAC mice up to 8 months.
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Claims the paper makes
31 Own result · 7 No full text of the sources · 4 Partly supported · 4 Own interpretation · 3 Supported · 2 No basis given · 1 Supported so far · accuracy not yet measured
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Although a universal marker that is solely expressed in senescent cells has not been identified, most senescent cells seem to express p16Ink4a, a cyclin-dependent kinase inhibitor and tumour suppressor that enforces growth arrest by activating Rb5,7.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Supportedcites [5] Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011) source
In “What defines a senescent cell?” the paper explicitly states that most senescent cells express p16INK4a. The same section notes that no identified marker is entirely specific to senescence, consistent with the citing sentence’s qualification. (LLM, conf=0.95)
- Not checked — no full text of the sourcecites [7] Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006) source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Furthermore, our data indicate that acquisition of the senescence-associated secretory phenotype (SASP), which enables cells to secrete a variety of growth factors, cytokines and proteases4, contributes to age-related tissue dysfunction.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Supportedcites [4] Coppé, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, e301 (2008) source
The citation is attached to the description of the SASP, not to the citing authors’ conclusion about age-related tissue dysfunction. The source paper’s Discussion describes the SASP as a secretory phenotype and reports high levels of secreted inflammatory cytokines and growth factors; it also suggests that chronic secretion may disrupt tissue function. (LLM, conf=0.87)
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“rosiglitazone, a drug that can induce cellular senescence and p16Ink4a expression through activation of PPARγ16.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Partly supportedcites [16] Gan, Q. et al. PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts. J. Cell Sci. 121, 2235–2245 (2008) sourceExperimental — accuracy not yet measured
The “PPARγ-mediated regulation of p16INK4α expression” section reports that PPARγ overexpression or troglitazone treatment increased p16 protein in human fibroblasts; the RNA-interference section links PPARγ-agonist effects to senescence. The paper’s treatment passages name troglitazone and pioglitazone, not rosiglitazone, so they do not establish the claim for that specific drug. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Senescent cells accumulate in various tissues and organs with ageing3”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Supportedcites [3] Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005) source
In the “Cellular Senescence and Aging” passage, the paper states that cells with characteristics of senescence accumulate with age in multiple tissues in humans and rodents. This supports the citing sentence’s claim. (LLM, conf=0.94)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Supported
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In the paper
“We replaced the Fabp4 promoter with a 2,617-bp fragment of the p16Ink4a gene promoter that is transcriptionally active in senescent, but not non-senescent cells (Fig. 1a)9.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Partly supportedcites [9] Wang, W., Wu, J., Zhang, Z. & Tong, T. Characterization of regulatory elements on the promoter region of p16INK4a that contribute to overexpression of p16 in senescent fibroblasts. J. Biol. Chem. 276, 48655–48661 (2001) sourceExperimental — accuracy not yet measured
The Discussion reports that the tested p16INK4a promoter fragments were 5–7 times more active in senescent than in young fibroblasts, supporting senescence-associated activity. It does not identify a 2,617-bp fragment, and its measurements of promoter activity in young cells do not support the claim that the promoter is inactive in non-senescent cells. (LLM, conf=0.84)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Skeletal muscle and eye had a similar reduction in senescence indicators (Fig. 3c, d and Supplementary Fig. 6b, c).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“Age-related phenotypes of BubR1H/H mice that arise in a p16Ink4a-independent fashion, such as cardiac arrhythmias and arterial wall stiffening14, were not attenuated in AP20187-treated BubR1H/H;INK-ATTAC mice (Supplementary Fig. 5a, b).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Not checked — no full text of the sourcecites [14] Matsumoto, T. et al. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke 38, 1050–1056 (2007) source
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The above age-related phenotypes were not delayed upon AP20187 treatment of BubR1H/H mice lacking INK-ATTAC (Fig. 2b and Supplementary Fig. 4).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that the vast majority of cells from both transgenic lines were either dead or in the process of dying 48 h after adding AP20187 (Fig. 2a).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The IAT of AP20187-treated BubR1H/H;INK-ATTAC mice showed a marked decrease in SA-β-Gal staining compared with the IAT of untreated counterparts (Fig. 3a).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 4
- It may state two separate claims as one. 8
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Additionally, the expression of p16Ink4a is known to increase with ageing in several rodent and human tissues8.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Partly supportedcites [8] Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004) sourceExperimental — accuracy not yet measured
The 'Expression of Ink4a/Arf in vivo' section reports increased p16INK4a expression with age across many mouse and rat tissues. Table 1 compares those findings with published human tissue staining, but does not show age-related increases across several human tissues; the References name evidence for aging human kidney specifically. The claim's extension to several human tissues is therefore not established by this copy (no page numbers available). (LLM, conf=0.86)
boosteddirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“senescence-associated secretory phenotype (SASP), which enables cells to secrete a variety of growth factors, cytokines and proteases4”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Partly supportedcites [4] Coppé, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, e301 (2008) sourceExperimental — accuracy not yet measured
In the Results section on senescent fibroblasts (page unavailable), the paper identifies cytokines and growth factors as SASP components and reports increased secretion of SASP proteins. The passages in our copy do not identify secreted proteases as SASP components, so that part of the claim is unsupported. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells1,2.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Supportedcites [1] Campisi, J. Cellular senescence: putting the paradoxes in perspective. Curr. Opin. Genet. Dev. 21, 107–112 (2011) source
In “Senescent cells – in culture and in vivo,” the paper describes an essentially irreversible growth arrest in response to stresses including DNA damage and dysfunctional telomeres. In “Cellular senescence and tumor suppression,” it says that this growth arrest suppresses malignant tumorigenesis and that dismantling the senescence response accelerates progression from premalignant lesions to malignant tumors. (LLM, conf=0.93)
- Supportedcites [2] Kuilman, T., Michaloglou, C., Mooi, W. J. & Peeper, D. S. The essence of senescence. Genes Dev. 24, 2463–2479 (2010) source
In “Replicative cellular senescence,” the paper says that sufficiently severe DNA damage can lead to senescence rather than continued proliferation. “Cellular senescence as a pathophysiological phenomenon” describes oncogene-induced proliferation arrest as a defense against tumor formation, and “Secreted factors in senescence” says senescence limits the expansion of early malignant cells. Page numbers are not available in our copy. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Importantly, late-life treated animals had increased mean muscle fibre diameters and showed improved performance in treadmill exercise tests (Fig. 4a, b).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data indicate that senescent cells were cleared from tissues and that this delays acquisition of age-related dysfunction in BubR1 hypomorphic mice.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, most fat depots of these animals were enlarged and adipocyte cell size and subdermal adipose layer thickness were significantly increased (Fig. 4c–e).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“treadmill exercise tests revealed that duration of exercise, distance travelled and overall amount of work performed were all significantly increased in the animals treated with AP20187 (Fig. 2e), indicating preservation of muscle function.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed GFP fluorescence in two of these strains, BubR1H/H;INK-ATTAC-3 and -5 (Fig. 1b and Supplementary Fig. 1a).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plain- 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 result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Skeletal muscle and lens tissue of aged BubR1H/H;INK-ATTAC mice are SA-β-Gal negative (data not shown), but both these tissues expressed other markers of senescence (Fig. 1f and Supplementary Fig. 3a).”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“AP20187, a synthetic drug that induces dimerization of a membrane-bound myristoylated FK506-binding-protein–caspase 8 (FKBP–Casp8) fusion protein expressed specifically in adipocytes via the minimal Fabp4 promoter6.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Not checked — no full text of the sourcecites [6] Pajvani, U. B. et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nature Med. 11, 797–803 (2005) source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“BubR1H/H mice have a markedly shortened lifespan and exhibit a variety of age-related phenotypes, including infertility, lordokyphosis, sarcopenia, cataracts, fat loss, cardiac arrhythmias, arterial wall stiffening, impaired wound healing and dermal thinning12–14.”
§ Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders > Abstract
What the sources say
- Not checked — no full text of the sourcecites [12] Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet. 36, 744–749 (2004) source
- Not checked — no full text of the sourcecites [13] Hartman, T. K., Wengenack, T. M., Poduslo, J. F. & van Deursen, J. M. Mutant mice with small amounts of BubR1 display accelerated age-related gliosis. Neurobiol. Aging 28, 921–927 (2007) source
- Not checked — no full text of the sourcecites [14] Matsumoto, T. et al. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke 38, 1050–1056 (2007) source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The authors state this as an assumption.
Cardiac failure is the main cause of death in BubR1H/H mice.
“Cardiac failure is presumably the main cause of death in BubR1H/H mice (data not shown)”
The paper relies on this without support.
Before this study, it was unknown whether senescent cells are causally implicated in age-related dysfunction and whether removing them is beneficial.
“However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“Reducing highly p16Ink4a+-expressing cells, some of which are senescent, in INK-ATTAC transgenic mice starting from mid-adulthood (age 12 months) reportedly extends median lifespan49.”
From Senolytics improve physical function and increase lifespan in old age (2018) · cites this paper as [49]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Ablating p16+ cells in these mice suppresses age-related disease, extending the health span of two independent strains of transgenic mice: INK-ATTAC and p16-3MR (see Supplemental Figure 1 for a description of the models) (8–10).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“This BubR1H/H progeria model has accelerated and elevated superphysiologic levels of cellular senescence due to chromosome missegregation as well as increasing aneuploidy (8, 80).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [8]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In addition, many immune cell types and subtypes develop a senescence-like state with increased expression of p16, p21, and SASP factors92,93.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [93]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Interestingly, adaptive immune function can be improved by short-term treatment with rapamycin95, which reduces the markers of senescence and SASP in PBMCs93.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [93]
Experimental — accuracy not yet measured
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene.”
From The Achilles' heel of senescent cells: from transcriptome to senolytic drugs (2015) · cites this paper as Baker et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Both recent intervention studies18 and our correlative data presented here strongly underscore the importance of cell senescence for determination of ageing rate and lifespan in mammals.”
From Chronic inflammation induces telomere dysfunction and accelerates ageing in mice (2014) · cites this paper as [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“In pre-clinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multi-morbidity, and accelerated aging phenotypes.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“mice that express low levels of the spindle assembly checkpoint protein BubR1 (BubR1H/H) exhibit multiple age-related phenotypes at 3–5 months of age, including atrophic skeletal muscle fibers, muscle wasting, and impaired skeletal muscle regeneration”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Baker et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Compared to vehicle-treated mice, skeletal muscle of life-long AP20187-treated mice exhibited significantly lower expression of transgene elements (CASP8, EGFP) and senescence markers, including p16, p21, p19, Pai1, Il6, Mmp3, and Mmp13.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Baker et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Transgenic mouse lines where senescent cells can be cleared by a genetic construct and commercially available senolytic drugs should also be considered as sensitivity to senolytic methods is one of the strongest lines of evidence currently used in the literature [167,172–174].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [172]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“depletion of cells expressing the senescence marker cyclin-dependent kinase inhibitor p16INK4A in genetically modified mice prolongs median lifespan and improves overall health (Baker et al. 2016; Farr et al. 2017; Baker et al. 2011; Jeon et al. 2017; Abdul-Aziz et al. 2019; Kim et al. 2019; Patil et al. 2019; Xu et al. 2015; Roos et al. 2016; Baar et al. 2017)”
From Single-cell RNA sequencing identifies senescent cerebromicrovascular endothelial cells in the aged mouse brain (2020) · cites this paper as Baker et al. 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Treatments to target and kill senescent cells, like senolytics, have shown promising results in extending lifespans and ameliorating various diseases.12,13”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“mutant mice with premature aging due to extensive and persistent damage, present dramatic levels of senescence and their progeroid phenotypes are ameliorated by elimination of p16Ink4a or p53”
From The Hallmarks of Aging (2013) · cites this paper as Baker et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Removal of the p16Ink4a-positive senescent cells, for instance, using a suicide gene under the regulation of the Cdkn2a promoter has been shown to attenuate progression of age-related decline and preserve cognitive function in both an accelerated aging AD mouse model and a tauopathy mouse model (Baker et al., 2011; Bussian et al., 2018).”
From Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer’s model (2022) · cites this paper as Baker et al., 2011
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Consistent with this idea is the observation that interference with senescent cell accumulation in BubR1 progeroid mice delays several aging-associated disorders that these animals develop 4 , 5 .”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Although drug-treated BubR1H/H;INK-ATTAC mice did not live longer, they were remarkably protected from several other age-related pathologies, including cataracts, sarcopenia, and loss of subcutaneous fat (128).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [128]
The cited source says what the claim attributes to it.
In the citing paper
“This study provided the first direct evidence that senescent cells can, at least in a premature aging mouse model, drive degenerative age-related pathology.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [128]
The cited source says what the claim attributes to it.
In the citing paper
“The idea that senescent cells can drive age-related pathology recently received substantial support from a transgenic mouse model in which senescent cells could be eliminated by administering a drug (128).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [128]
The cited source says what the claim attributes to it.
In the citing paper
“treatment of BubR1 hypomorphic mice harbouring the INK-ATTAC transgene to remove p16-expressing cells beginning at weaning age attenuated the accumulation of senescent cells and premature ageing in skeletal muscle, eye and adipose tissue11”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [11]
The cited source says what the claim attributes to it.
In the citing paper
“Removal of SnCs delays several pathologies7–9 and increases healthy lifespan8.”
From Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment (2017) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“the previously reported INK-ATTAC transgenic mouse model, which expresses the FK506 binding protein–caspase-8 fusion protein under the control of the p16INK4a promoter7,8.”
From Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment (2017) · cites this paper as [7]
The cited source says what the claim attributes to it.
In the citing paper
“Earlier we have shown that, in BubR1 progeroid mice, ATTAC ablates p16 Ink4a -positive senescent cells upon administration of AP20187 (AP), a dimerizer that activates FKBP-fused Casp8 4 .”
From Naturally occurring p16Ink4a-positive cells shorten healthy lifespan (2016) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“Selective removal of p16 INK4A+ cells from BubR1 H/H INK-ATTAC mice delays kyphosis, cataracts, and muscle atrophy”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Baker et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“but it does not delay cardiac arrhythmias and arterial wall stiffening nor does it extend lifespan”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Baker et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“the demonstration that ablation of p16 INK4A expressing cells slowed age-related declines in progeroid BubR1 H/H mice”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Baker et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“provided the first evidence that senescent cells are causal for certain aging phenotypes”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Baker et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“Models of accelerated cellular senescence show premature ageing and increased incidence of age-related pathologies, suggesting that accumulating senescent cells contributes to ageing-related functional compromise and predisposes to age-related disease [38].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
The cited source says what the claim attributes to it.
In the citing paper
“However, senescence has also been implicated both in promoting carcinogenesis 15 and in age-related pathologies 16,17 through its autocrine and paracrine effects, known as the senescence-associated secretory phenotype (SASP) originally described by the Campisi group.18,19”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [16]
The cited source says what the claim attributes to it.
In the citing paper
“Using the Ink-Attac mouse model, in which a drug, AP20187 (AP), induces apoptosis through dimerization of FKBP-fused caspase 8, we previously discovered that clearance of p16-expressing cells improves parameters of physical health and function in progeroid mice31.”
From Cellular senescence mediates fibrotic pulmonary disease (2017) · cites this paper as [31]
The cited source says what the claim attributes to it.
In the citing paper
“Clearance of senescent cells is also beneficial for age-associated disorders 39 .”
From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [39]
The cited source says what the claim attributes to it.
In the citing paper
“elimination of senescent cells in an experimental progeria model delays age-related pathologies”
From The Hallmarks of Aging (2013) · cites this paper as Baker et al., 2011
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Longer term treatments (from 20 to 26 months of age) were effective at opposing several known phenotypes of aging: macrophage infiltration of tissues, a hallmark of chronic inflammation23,25, glomerulosclerosis of the kidney26 and skeletal muscle atrophy27 (Fig. 4e).”
From L1 drives IFN in senescent cells and promotes age-associated inflammation (2019) · cites this paper as [27]
Experimental — accuracy not yet measuredIn the citing paper
“Seminal discoveries, first by Hayflick and Moorehead, and lately by Baker et al., concretized cellular senescence as a major driver of aging with the age-associated accumulation of senescent cells”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Baker et al. 2011
In the citing paper
“and attenuation of age-related tissue dysfunction after their removal, even late in life (Hayflick and Moorhead 1961, Baker et al. 2011).”
From Benefits of Metformin in Attenuating the Hallmarks of Aging (2020) · cites this paper as Baker et al. 2011
In the citing paper
“Of note, we and our colleagues recently identified a possibly causal link between cellular senescence and aging phenotypes by showing that the clearance of senescent cells in a mouse progeroid model in vivo can delay age-related tissue dysfunction, including cataract formation, lipodystrophy, and lordokyphosis (7).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [7]
In the citing paper
“Experiments in progeroid INK-ATTAC;BubR1H/H mice showed that senescent cell clearance could reverse age-related lipodystrophy.”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [7]
In the citing paper
“Current methods for assessing senescent cell burden in vivo are at the tissue level, either by quantification of senescent cells through methods such as immunohistochemistry for markers including heterochromatin foci, p16 expression, SA-βgal activity, or screening for transgenic labels such as the p16INK4A promoter-driven GFP in the INK-ATTAC mouse (7).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [7]
In the citing paper
“The development of transgenic mice from which senescent cells can be selectively cleared allowed the demonstration of senescent cells' causal role in disease (7).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [7]
In the citing paper
“Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Baker et al., 2011
In the citing paper
“selective elimination of senescent cells can prevent or delay age-related tissue dysfunction to extend life span and improve health span (Baker et al., 2011; Xu et al., 2015a; Baker et al., 2016; Hashimoto et al., 2016; Zhao et al., 2018).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Baker et al., 2011
In the citing paper
“Recently, attention has focused on the effect of senescence in vivo where purging p16-positive senescent cells in transgenic mice increased mean lifespan as well as aspects of healthspan65.”
From The central role of DNA damage in the ageing process (2021) · cites this paper as [65]
In the citing paper
“Another key feature of cellular senescence is the senescence-associated secretory phenotype (SASP), which is dependent on p38MAPK (p38 mitogen-activated protein kinases), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), cGAS(cyclic GMP-AMP synthase)/STING(stimulator of IFN genes), NOTCH and mTORmammalian target of rapamycin) signalling [38,39,40,41,42].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
In the citing paper
“Models of accelerated cellular senescence show premature ageing and increased incidence of age-related pathologies, suggesting that accumulating senescent cells contributes to ageing-related functional compromise and predisposes to age-related disease [38].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
In the citing paper
“Increased levels of p16INK4a have been documented in aged and stressed tissues, compared to younger, healthy tissues, whereas the removal of p16INK4a-expressing senescent cells in mice prevented or delayed tissue dysfunction and age-related disorders [38,80].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
In the citing paper
“progeroid models have provided in vivo experimental data of accelerated ageing-related degenerative pathologies.”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
In the citing paper
“In addition, experimental senolysis ameliorated ageing-related pathologies [38].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
In the citing paper
“Lifelong elimination of p16INK4A cells substantially delayed age-related disease, whereas late life elimination of p16INK4A cells attenuated these age-related pathologies [38]”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
In the citing paper
“robust in vivo proof of the causative involvement of senescent cells in aging and in particular age-related diseases10,11.”
From Identification and characterization of Cardiac Glycosides as senolytic compounds (2019) · cites this paper as [11]
In the citing paper
“clearing senescent cells from progeroid or naturally aging mice improves healthspan 10, increases lifespan 12 and benefits an array of pathologies”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [10]
In the citing paper
“Genetic and pharmacological strategies have demonstrated the benefits of eliminating senescent cells in the context of aging and disease 10,12,51.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [10]
In the citing paper
“To circumvent this problem, two similar yet unique mouse models have been developed to detect and eliminate senescent cells.”
From Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives (2018) · cites this paper as [29]
In the citing paper
“Using mouse models, elimination of these cells, through either genetic means or senolytic therapies, has largely shown beneficial impacts, irrespective of the disease or condition investigated (29-31, 99, 100).”
From Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives (2018) · cites this paper as [29]
In the citing paper
“In mice, the clearance of p16INK4A-positive cells extends lifespan and slows the emergence of ageing phenotypes and age-related functional deterioration of organs and tissues111,112.”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [111]
In the citing paper
“It is thus not surprising that senescent cell burden is a good predictor of animal lifespan.94,95”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [94]
In the citing paper
“the clearance of senescent cells by either genetic engineering or the administration of senolytic drugs has been associated with reduced circulating levels of pro-inflammatory markers, increased lifespan, and delayed frailty-related phenotypes in mice”
From Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty (2018) · cites this paper as [111]
In the citing paper
“A cohort of aged INK-ATTAC transgenic mice, in which cells with high INK4a promoter activity, which is indicative of senescence, can be forced to undergo apoptosis138,139, exhibited increased resilience to pathogens, including the mouse hepatitis virus (MHV, a mouse β-coronavirus), when p16INK4a-high senescent cells were subjected to ATTAC-dependent depletion27.”
From COVID-19 and cellular senescence (2023) · cites this paper as [138]
In the citing paper
“Elimination of senescent cells by suicide gene-mediated ablation of p16Ink4a-expressing senescent cells in INK-ATTAC mice has resulted in significant improvements in healthspan and lifespan”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Baker et al., 2011
In the citing paper
“suggesting that senescent cells are drivers of ageing (Baker et al., 2011, Baker et al., 2016).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Baker et al., 2011
In the citing paper
“Elimination of senescent cells may therefore allow better recovery of tissues, consistent with the finding that senescent cell elimination via transgenic techniques improves aging‐associated phenotypes”
From p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling (2017) · cites this paper as Baker et al, 2011
In the citing paper
“INK-ATTAC mice can be used as a reporter to track the dynamics of p16Ink4a-positive cells.”
From Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence (2024) · cites this paper as [25]
In the citing paper
“Indeed, sub-populations of senescent MuSCs marked by expression of p16Ink4a contribute to sarcopenic wasting and repair dysfunction characteristic of aged muscles in the accelerated-aging BubR1 hypomorphic mouse model59,60.”
From The central role of muscle stem cells in regenerative failure with aging (2015) · cites this paper as [60]
In the citing paper
“Conditional ablation of this p16Ink4a-expressing MuSC population and other senescent cells ameliorates muscle wasting, leading to improved performance in treadmill exercise tests60.”
From The central role of muscle stem cells in regenerative failure with aging (2015) · cites this paper as [60]
In the citing paper
“In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [3]
In the citing paper
“Senolytics have been used to prevent, delay, or alleviate a plethora of age-onset diseases and syndromes in pre-clinical models.”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [3]
In the citing paper
“While genetic models of senescent cell clearance provide proof-of-principle for the health and life span benefits of reducing the burden of old cells and the SASP”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [3]
In the citing paper
“Elimination of even a relatively small proportion of existing senescent cells (~30% reduction) using a “suicide” transgene, INK-ATTAC, that permits inducible elimination of p16Ink4a-expressing senescent cells upon administration of a drug (AP20187; Figure 2), extends healthspan and prevents the development of multiple age-related morbidities in both progeroid and normal chronologically-aged mice [”
From Reducing Senescent Cell Burden in Aging and Disease (2020) · cites this paper as [3]
In the citing paper
“Clearance of senescent cells only late in life did not improve age-related pathologies but did attenuate their progression170.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [170]
In the citing paper
“Using an inducible genetic model for senescent cell ablation, one study demonstrated that life-long clearance of senescent cells from progeroid mouse tissues, via ablation of p16Ink4a-expressing cells, delays the onset of pathologies in multiple aging tissues, including the fat, muscle and eye170.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [170]
In the citing paper
“selective killing of those p16-expressing cells in a premature ageing mouse model also delays ageing phenotypes 148”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [148]
In the citing paper
“Accordingly, removal of senescent cells by genetic or pharmacological “senolytic” approaches extends median lifespan in old mice and prevents the onset of age-associated disease (Baker et al., 2016; Baker et al., 2011; Xu et al., 2018; Zhu et al., 2015).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Baker et al., 2011
In the citing paper
“In support of this tenet, the genetic ablation of p16 + cells in a transgenic mouse model is sufficient to extend the lifespan of naturally aged mice and reduce the manifestation of age-associated pathologies, including cancer.177”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [177]
In the citing paper
“The whole-body elimination of p16 + senescent cells in middle-aged mice reduces the rate of spontaneous tumor formation.177”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [177]
In the citing paper
“The expression of p16Ink4a is essentially undetectable in young and healthy tissues, but p16Ink4a+ cells accumulate in many aged or diseased tissues.18,19,21,22,23,28”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [22]
In the citing paper
“The expression of p16Ink4a is essentially undetectable in young and healthy tissues, but p16Ink4a+ cells accumulate in many aged or diseased tissues.18,19,21,22,23,28”
From Identifying specific functional roles for senescence across cell types (2024) · cites this paper as [22]
In the citing paper
“Moreover, multiple p16-based mouse models [15,26–28] might not target the same p16high cells in vivo due to different transgene designs (such as different p16 promoters or transgene locations).”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [15]
In the citing paper
“Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing.”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [13]
In the citing paper
“However, excessive accumulation of senescent cells causally shortens the healthy lifespan [11] and drives organ ageing [12], age-related organ deterioration/disorders [13,14], tissue dysfunction and chronic diseases, including cardiovascular diseases (CVDs) [15,16], cancer [2], neurodegenerative diseases [17,18] and osteoarthritis [19].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [13]
In the citing paper
“Exposure to the drug AP20187 causes the caspase 8 fusion protein unique to p16INK4a-expressing cells to dimerize and initiate apoptosis (Baker et al., 2011; Xu et al., 2018).”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Baker et al., 2011
In the citing paper
“Encouragingly, initiation of p16INK4a-postive cell clearance in mid-life also benefitted the molecular and morphological phenotype of skeletal muscle and measures of physical function in progeroid mice.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Baker et al., 2011
In the citing paper
“Further, muscle fiber size and treadmill exercise time, distance, and total work to exhaustion were significantly greater in AP20187 treated BubR1 H/H;INK-ATTAC mice.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Baker et al., 2011
In the citing paper
“This model has enabled the study of how systemic removal of p16Ink4a-expressing cells, that are presumably senescent, affect the structure and function of multiple organ systems.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Baker et al., 2011
In the citing paper
“A major conceptual advance in the role of senescent cells in organismal aging was driven by the development and application of the INK-ATTAC mouse model (Baker et al., 2011).”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Baker et al., 2011
In the citing paper
“In contrast, deletion of senescent cells by a genetic approach attenuated age-related deterioration and extended the health-span in aged mice.8,9”
From Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice (2020) · cites this paper as [8]
In the citing paper
“Senescent cells can impair tissue function in ageing despite their relatively low abundance (< 15%) [3], [4].”
From Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis (2018) · cites this paper as [4]
In the citing paper
“Importantly, genetic or chemical ablation of senescent cells in mouse models delays the onset of age-related disorders, including cancer, leading to increased life-spans and promoting tissue rejuvenation in late life.36–38”
From Paracrine roles of cellular senescence in promoting tumourigenesis (2018) · cites this paper as [37]
In the citing paper
“Indeed, when senescent cells were removed from aged mice artificially, the animals lived longer and were healthier [96].”
From Evolution of the immune system in humans from infancy to old age (2015) · cites this paper as [96]
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“The progeric conditions were partly ameliorated by targeted elimination/reduction of p16INK4-positive cells (Baker et al., 2011), by enhancing Wnt signaling via loss of Dickkopf-1 (Seib et al., 2013) or via inhibition of secreted frizzled-related protein 3 (sFRP3) (Cho et al., 2019), both of which…”
BackgroundUntangling senescent and damage‐associated microglia in the aging and diseased brain
Ng, P. Y., McNeely, T. L., & Baker, D. J. (2023) · The FEBS Journal · doi:10.1111/febs.16315 · Cited by 68
Self-citationA coalition to heal—the impact of the cardiac microenvironment
Tzahor, E., & Dimmeler, S. (2022) · Science · doi:10.1126/science.abm4443 · Cited by 72
Hadri, K. E., Smith, R., Duplus, E., & Amri, C. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010077 · Cited by 71
Briot, A., Decaunes, P., Volat, F., Belles, C., Coupaye, M., Ledoux, S., & Bouloumié, A. (2018) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.310797 · Cited by 67
Elsallabi, O., Patruno, A., Pesce, M., Cataldi, A., Carradori, S., & Gallorini, M. (2022) · Molecules · doi:10.3390/molecules27030738 · Cited by 67
“This is a major finding that has paved the way for the creation of drugs and strategies that target SNC, particularly for the prevention and finding a cure for age-related diseases [67,70,71].”
BackgroundGeroconversion of aged muscle stem cells under regenerative pressure
Sousa-Victor, P., Perdiguero, E., & Muñoz-Cánoves, P. (2014) · Cell Cycle · doi:10.4161/15384101.2014.965072 · Cited by 68
“Furthermore, comparison with a comprehensive list of genes implicated in cellular senescence(57-59) showed specific up-regulation of several genes, including the master regulator of senescence Cdkn2a (p16).(15,17,49,60,61)”
Sasaki, M., Kajiya, H., Ozeki, S., Okabe, K., & Ikebe, T. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.08.123 · Cited by 67
Aging of Liver in Its Different Diseases
Radonjić, T., Dukić, M., Jovanović, I., Zdravkovic, M. D., Mandić, O., Popadić, V., Popović, M., Nikolić, N., Klašnja, S., Divac, A., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113085 · Cited by 77
“have shown in repeated research that by reducing the number of senescent cells, there is a reduction in SASP and the release of pro-inflammatory cytokines, thus, proving that SASP plays a role in “inflammaging” [73].”
BackgroundSystems approaches to investigate the role of NF-κB signaling in aging
Haga, M., & Okada, M. (2022) · Biochemical Journal · doi:10.1042/bcj20210547 · Cited by 67
Suda, M., Shimizu, I., Katsuumi, G., Hsiao, C. L., Yoshida, Y., Matsumoto, N., Yoshida, Y., Katayama, A., Wada, J., Seki, M., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-10522-3 · Cited by 70
IGF Binding Protein-5 Induces Cell Senescence
Sanada, F., Taniyama, Y., Muratsu, J., Otsu, R., Shimizu, H., Rakugi, H., & Morishita, R. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00053 · Cited by 70
Suzuki, K., Yamamoto, M., Hernández‐Benítez, R., Li, Z., Wei, C., Soligalla, R. D., Aizawa, E., Hatanaka, F., Kurita, M., Reddy, P., et al. (2019) · Cell Research · doi:10.1038/s41422-019-0213-0 · Cited by 69
Chronic stress exposure and daily stress appraisals relate to biological aging marker p16INK4a
Rentscher, K. E., Carroll, J., Repetti, R. L., Cole, S. W., Reynolds, B. M., & Robles, T. F. (2018) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2018.12.006 · Cited by 72
“Recent studies with mice demonstrated that removal of p16INK4apositive cells prevented or slowed the deterioration of several tissues and organs, and delayed tumor growth (Baker et al., 2011), and reduced metastasis in mice exposed to cytotoxic cancer treatments (Demaria et al.”
BackgroundRole of arterial telomere dysfunction in hypertension
Morgan, R. G., Ives, S. J., Walker, A. E., Cawthon, R., Andtbacka, R. H. I., Noyes, D. R., Lesniewski, L. A., Richardson, R. S., & Donato, A. J. (2014) · Journal of Hypertension · doi:10.1097/hjh.0000000000000157 · Cited by 69
“diseases [9,10], including cardiovascular diseases (CVDs) [11,12].”
Sohn, J. J., Schetter, A. J., Yfantis, H. G., Ridnour, L. A., Horikawa, I., Ma, K., Robles, A. I., Hussain, S. P., Goto, A., Bowman, E. D., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044156 · Cited by 67
NF-κB signaling as a driver of ageing
Osorio, F. G., Soria‐Valles, C., Santiago‐Fernández, O., Freije, J. M. P., & López-Otı́n, C. (2016) · International review of cytology · doi:10.1016/bs.ircmb.2016.04.003 · Cited by 67
Aneuploidy in Cancer and Aging
Naylor, R. M., & van Deursen, J. M. (2016) · Annual Review of Genetics · doi:10.1146/annurev-genet-120215-035303 · Cited by 66
Self-citationKiss, T., Nyúl-Tóth, Á., DelFavero, J., Balasubramanian, P., Tarantini, S., Faakye, J., Gulej, R., Ahire, C., Ungvari, A., Yabluchanskiy, A., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00521-7 · Cited by 66
Fang, C., Liu, B., & Wan, M. (2023) · Calcified Tissue International · doi:10.1007/s00223-023-01100-4 · Cited by 72
“mice, which have a markedly shortened lifespan, age-associated phenotypes in almost every organ system examined, and severe kyphosis [89].”
BackgroundIKKβ–NF-κB signaling in adult chondrocytes promotes the onset of age-related osteoarthritis in mice
Catheline, S. E., Bell, R. D., Oluoch, L. S., James, M., Escalera-Rivera, K., Maynard, R. D., Chang, M., Dean, C., Botto, E., Ketz, J. P., et al. (2021) · Science Signaling · doi:10.1126/scisignal.abf3535 · Cited by 67
Lipotoxicity, aging, and muscle contractility: does fiber type matter?
Carter, C. S., Justice, J. N., & Thompson, L. (2019) · GeroScience · doi:10.1007/s11357-019-00077-z · Cited by 66
Hallmarks and Biomarkers of Skin Senescence: An Updated Review of Skin Senotherapeutics
Bulbiankova, D., Díaz‐Puertas, R., Álvarez‐Martínez, F. J., Herranz‐López, M., Barrajón‐Catalán, E., & Micol, V. (2023) · Antioxidants · doi:10.3390/antiox12020444 · Cited by 72
Effect of peripheral cellular senescence on brain aging and cognitive decline
Budamagunta, V., Kumar, A., Rani, A., Bean, L. A., Manohar‐Sindhu, S., Yang, Y., Zhou, D., & Foster, T. C. (2023) · Aging Cell · doi:10.1111/acel.13817 · Cited by 68
“Cellular senescence is a hallmark of aging and plays a crucial role in aging and a wide variety of age- related diseases and disorders (Baker et al., 2011; Kirkland & Tchkonia, 2020).”
BackgroundAging: not all DNA damage is equal
Vermeij, W. P., Hoeijmakers, J. H. J., & Pothof, J. (2014) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2014.06.006 · Cited by 70
Kim, D. E., Dollé, M. E. T., Vermeij, W. P., Gyenis, Á., Vogel, K., Hoeijmakers, J. H. J., Wiley, C. D., Davalos, A. R., Hasty, P., Desprez, P., et al. (2019) · Aging Cell · doi:10.1111/acel.13072 · Cited by 66
“…transgenic mice in which senescent cells can be selectively eliminated, both lifelong and late-life clearance were shown to extend median lifespan and attenuate several deleterious age-associated phenotypes; these benefits were apparent in both progeric and naturally aged mice (Baker et al., 2011).”
BackgroundLongevity and anti-aging effects of curcumin supplementation
Izadi, M., Sadri, N., Abdi, A., Zadeh, M. M. R., Jalaei, D., Ghazimoradi, M. M., Shouri, S., & Tahmasebi, S. (2024) · GeroScience · doi:10.1007/s11357-024-01092-5 · Cited by 70
“Despite the fact that cellular senescence is a tumor-suppressing mechanism, SCs can also play a causal role in aging and diseases due to aging by accumulating over time [71–73].”
Therapeutic targeting of senescent cells in the CNS
Riessland, M., Ximerakis, M., Jarjour, A. A., Zhang, B., & Orr, M. E. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01033-z · Cited by 77
Cellular Senescence in Idiopathic Pulmonary Fibrosis
Kellogg, D. L., Kellogg, D. L., Musi, N., & Nambiar, A. M. (2021) · Current Molecular Biology Reports · doi:10.1007/s40610-021-00145-4 · Cited by 67
Ageing in the brain: mechanisms and rejuvenating strategies
Gaspar-Silva, F., Trigo, D., & Magalhães, J. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04832-6 · Cited by 88
“Removal of senescent cells was shown to increase life span in mouse models [97, 98].”
BackgroundEmerging roles of lnc RNA s in senescence
Montes, M., & Lund, A. H. (2016) · FEBS Journal · doi:10.1111/febs.13679 · Cited by 66
Understanding NK cell biology for harnessing NK cell therapies: targeting cancer and beyond
Shin, E., Bak, S. H., Park, T., Kim, J.-W., Yoon, S. R., Jung, H., & Noh, J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1192907 · Cited by 71
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“Ablation of p16INK4a-expressing cells in genetically engineered mice delays some age-related phenotypes such as cataracts and sarcopenia (Baker et al., 2011).”
BackgroundDefining the toxicology of aging
Sorrentino, J. A., Sanoff, H. K., & Sharpless, N. E. (2014) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.04.004 · Cited by 69
“For example, elimination of p16 INK4a -positive cells rescues some aspects of the aging phenotype in a progeroid strain of mice [42].”
BackgroundGiuliani, A., Prattichizzo, F., Micolucci, L., Ceriello, A., Procopio, A. D., & Rippo, M. R. (2017) · Mediators of Inflammation · doi:10.1155/2017/2309034 · Cited by 66
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Cormenier, J., Martin, N., Deslé, J., Salazar-Cardozo, C., Pourtier, A., Abbadie, C., & Pluquet, O. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2017.08.003 · Cited by 64
The Mechanism of Bone Remodeling After Bone Aging
Fang, H., Deng, Z., Liu, J., Chen, S., Deng, Z., & Li, W. (2022) · Clinical Interventions in Aging · doi:10.2147/cia.s349604 · Cited by 71
“age, senescent cells accumulate in various tissues and organs and the substances they secrete may destroy the structure and function of tissues.(3) As Berdasco reported, aging is a complex process that leads to complex biological changes in the body and increases an organism’s susceptibility to disease and death.”
BackgroundSharma, R., Kumar, R., Sharma, A., Goel, A., & Padwad, Y. S. (2022) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2022.109068 · Cited by 80
Ruggiero, A. D., Vemuri, R., Blawas, M., Long, M., DeStephanis, D., Williams, A. G., Chen, H., Justice, J. N., Macauley, S. L., Day, S. M., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00830-5 · Cited by 69
“A 30% reduction in senescent cells suffices to alleviate dysfunction in preclinical models [6].”
BackgroundTargeting aging and age-related diseases with vaccines
Wu, R., Sun, F., Zhang, W., Ren, J., & Liu, G.-H. (2024) · Nature Aging · doi:10.1038/s43587-024-00597-0 · Cited by 66
“Proof-of-concept study showing that elimination of senescent cells can ameliorate progeroid phenotypes in a mouse model 157 .”
Ras signaling in aging and metabolic regulation
Slack, C. (2017) · Nutrition and Healthy Aging · doi:10.3233/nha-160021 · Cited by 63
“[90] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs”
BackgroundInnate immunosensing of DNA in cellular senescence
Glück, S., & Ablasser, A. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.09.013 · Cited by 62
Soendenbroe, C., Andersen, J. L., & Mackey, A. L. (2021) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00174.2021 · Cited by 68
Fibroblast heterogeneity: Keystone of tissue homeostasis and pathology in inflammation and ageing
Gauthier, V., Kyriazi, M., Nefla, M., Pucino, V., Raza, K., Buckley, C. D., & Alsaleh, G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1137659 · Cited by 63
“Since then, senescence has been shown to be a complex phenomenon with beneficial functions in embryonic development (73, 75, 79), wound healing (80–82), tissue repair (83) and cancer prevention (84, 85), but also critical deleterious roles in organismal ageing (86, 87), age-related diseases (87), abnormal immune respo…”
BackgroundCDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease
Stenvinkel, P., Luttropp, K., McGuinness, D., Witasp, A., Qureshi, A. R., Wernerson, A. M., Nordfors, L., Schalling, M., Ripsweden, J., Wennberg, L. M., et al. (2017) · Aging · doi:10.18632/aging.101173 · Cited by 63
“Since senescent cells have been considered a target for antiaging therapies and removal of p16-positive cells in progeric mice led to an attenuation of the ageing phenotype [27], a functional involvement of p16 in ageing-associated disorders is likely.”
BackgroundDNA repair as a shared hallmark in cancer and ageing
Clarke, T. L., & Mostoslavsky, R. (2022) · Molecular Oncology · doi:10.1002/1878-0261.13285 · Cited by 74
Investigation of quercetin and hyperoside as senolytics in adult human endothelial cells
Hwang, H. V., Tran, D., Rebuffatti, M., Li, C., & Knowlton, A. A. (2018) · PLoS ONE · doi:10.1371/journal.pone.0190374 · Cited by 66
“The first study demonstrating the physiological benefits of selective removal of senescent cells utilized transgenic progeroid mice with a novel, inducible transgene, which would eliminate p16-positive, senescent cells [42].”
BackgroundSenescence in chronic wounds and potential targeted therapies
Wei, X., Li, M., Zheng, Z., Ma, J., Gao, Y., Chen, L., Peng, Y., Yu, S., & Yang, L. (2021) · Burns & Trauma · doi:10.1093/burnst/tkab045 · Cited by 70
“The transcriptional activity of p16 has been widely used to prove the presence of senescence in vivo [40].”
BackgroundEpigenetic Basis of Cellular Senescence and Its Implications in Aging
Nacarelli, T., Liu, P., & Zhang, R. (2017) · Genes · doi:10.3390/genes8120343 · Cited by 66
Senescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease
Schroth, J., Thiemermann, C., & Henson, S. M. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.564461 · Cited by 59
Abdelgawad, I. Y., Agostinucci, K. J., Sadaf, B., Grant, M. K. O., & Zordoky, B. N. M. (2023) · Frontiers in Aging · doi:10.3389/fragi.2023.1170434 · Cited by 71
“The hypothesis that senescent cells contribute to the pathogenesis of age-related diseases has led to the development of a new class of drugs called senotherapeutics (Baker et al., 2011).”
BackgroundNeuroferroptosis in health and diseases
Lei, P., Walker, T. L., & Ayton, S. (2025) · Nature reviews. Neuroscience · doi:10.1038/s41583-025-00930-5 · Cited by 77
“In the ageing brain, the accumulation of senescent cells is recognized as a contributing factor to many age-related diseases, with the clearance of these cells alleviating many pathologies associated with ageing 92,93 .”
Farr, J. N., Kaur, J., Doolittle, M. L., & Khosla, S. (2020) · Current Osteoporosis Reports · doi:10.1007/s11914-020-00619-x · Cited by 60
Chen, P., He, D. N., Zhang, Y., Yang, S., Chen, L., Wang, S., Zou, H.-X., Liao, Z., Zhang, X., & Wu, M. (2016) · Food & Function · doi:10.1039/c6fo00628k · Cited by 63
Senescent-like microglia limit remyelination through the senescence associated secretory phenotype
Gross, P. S., Durán-Laforet, V., Ho, L. T., Melchor, G. S., Zia, S., Manavi, Z., Barclay, W. E., Lee, S. H., Shults, N., Selva, S., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57632-w · Cited by 62
Methionine restriction slows down senescence in human diploid fibroblasts
Kozieł, R., Ruckenstuhl, C., Albertini, E., Neuhaus, M., Netzberger, C., Bust, M., Madeo, F., Wiesner, R. J., & Jansen‐Dürr, P. (2014) · Aging Cell · doi:10.1111/acel.12266 · Cited by 62
“There is increasing evidence that, besides serving as a model to study human aging in vitro, cellular senescence plays an important role in organismic aging in vivo (Baker et al., 2011; Campisi, 2011).”
BackgroundCellular senescence in Alzheimer’s disease: from physiology to pathology
Zhu, J., Wu, C., & Yang, L. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00447-4 · Cited by 74
Baraibar, M. A., Hyzewicz, J., Rogowska-Wrzesińska, A., Bulteau, A., Prip‐Buus, C., Butler-Browne, G. S., & Friguet, B. (2016) · Aging · doi:10.18632/aging.101126 · Cited by 64
“The metabolic changes we have identified during senescence have been shown to play a role in aging at the organismal level [47,48].”
BackgroundStorci, G., Carolis, S. D., Papi, A., Bacalini, M. G., Gensous, N., Marasco, E., Tesei, A., Fabbri, F., Arienti, C., Zanoni, M., et al. (2019) · Cell Death and Differentiation · doi:10.1038/s41418-018-0255-8 · Cited by 63
Guo, H., Liu, Z., Xu, B., Hu, H., Wei, Z., Liu, Q., Zhang, X., Ding, X., Wang, Y., Zhao, M., et al. (2013) · Aging Cell · doi:10.1111/acel.12138 · Cited by 63
“Cellular senescence may contribute to the decline in organ function and to the reduction in or loss of vitality of organisms (Wiemann et al., 2002; Baker et al., 2011).”
BackgroundSenolytic targets and new strategies for clearing senescent cells
Ge, M., Hu, L., Ao, H.-S., Zi, M., Kong, Q., & He, Y. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111468 · Cited by 64
Senescence and cancer: An evolving inflammatory paradox
Ruhland, M. K., Coussens, L. M., & Stewart, S. A. (2015) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2015.10.001 · Cited by 62
“Given recent evidence revealing elimination of p16+ cells from tissues in mice results in reversal of several age-related pathologies (87), it is possible that in humans, therapies targeting the deleterious functions of the SASP may prove beneficial not only for cancer, but for other diseases as well.”
Senescence and tissue fibrosis: opportunities for therapeutic targeting
O’Reilly, S., Tsou, P., & Varga, J. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.05.012 · Cited by 67
Pancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight
Cortesi, M., Zanoni, M., Pirini, F., Tumedei, M. M., Ravaioli, S., Rapposelli, I. G., Frassineti, G. L., & Bravaccini, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010254 · Cited by 62
“It is frequently considered a specific marker of senescence both in vitro and in vivo [109,110].”
Backgroundp53 plays a crucial role in endothelial dysfunction associated with hyperglycemia and ischemia
Yokoyama, M., Shimizu, I., Nagasawa, A., Yoshida, Y., Katsuumi, G., Wakasugi, T., Hayashi, Y., Ikegami, R., Suda, M., Ota, Y., et al. (2019) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2019.02.010 · Cited by 63
Cellular senescence in ionizing radiation (Review)
Chen, Z., Cao, K., Xia, Y., Li, Y., Hou, Y., Wang, L., Li, L., Chang, L., & Li, W. (2019) · Oncology Reports · doi:10.3892/or.2019.7209 · Cited by 69
“The application of senolytic agents that selectively kill senescent cells may improve organ function, including SNCs induced by IR (81,95).”
Positive and negative effects of cellular senescence during female reproductive aging and pregnancy
Velarde, M. C., & Menon, R. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0018 · Cited by 65
The Emerging Role of Senescence in Ocular Disease
Sreekumar, P. G., Hinton, D. R., & Kannan, R. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/2583601 · Cited by 67
“Therefore, removal of chronic senescent cells during both premature and normal aging is able to reduce the development and progression of many age-associated dysfunctions [9, 10].”
BackgroundReed, S., Taka, E., Darling‐Reed, S., & Soliman, K. F. A. (2025) · Cells · doi:10.3390/cells14141064 · Cited by 76
“This accumulation of senescent cells has been linked to several age-related diseases, including cardiovascular disease, osteoarthritis, and neurodegeneration [232].”
Primary sclerosing cholangitis: a review and update on therapeutic developments
Tabibian, J. H., & Lindor, K. D. (2013) · Expert Review of Gastroenterology & Hepatology · doi:10.1586/egh.12.80 · Cited by 61
Bientinesi, E., Lulli, M., Becatti, M., Ristori, S., Margheri, F., & Monti, D. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111689 · Cited by 61
Cellular Senescence and Senotherapies in the Kidney: Current Evidence and Future Directions
Docherty, M. H., Baird, D., Hughes, J., & Ferenbach, D. A. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.00755 · Cited by 66
“…2A gene (P16INK4A) to drive concomitant expression of a “suicide gene” activated upon administration of a drug or dietary compound, thus conferring selective vulnerability upon P16INK4A expressing cells to pharmacological clearance (Baker et al., 2011; Baker et al., 2016; Chang et al., 2016).”
BackgroundInfluentialRelationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging
Strickland, M., Yacoubi‐Loueslati, B., Bouhaouala‐Zahar, B., Pender, S. L. F., & Larbi, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00158 · Cited by 64
Fight to the bitter end: DNA repair and aging
Chen, Y., Geng, A., Zhang, W., Qian, Z. Y., Wan, X., Jiang, Y., & Mao, Z. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101154 · Cited by 63
Khalil, R., Diab‐Assaf, M., & Lemaître, J.-M. (2023) · Cells · doi:10.3390/cells12060915 · Cited by 68
“Targeting senescence seems to be a promising approach for treatment and prevention of aging to further promote an increased health longevity [17,18].”
BackgroundDeath by transposition – the enemy within?
Sedivy, J. M., Kreiling, J. A., Neretti, N., Cecco, M. D., Criscione, S. W., Hofmann, J. W., Zhao, X., Ito, T., & Peterson, A. L. (2013) · BioEssays · doi:10.1002/bies.201300097 · Cited by 62
Bartke, A. (2020) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-020-09593-2 · Cited by 63
Tackling the glial scar in spinal cord regeneration: new discoveries and future directions
Shafqat, A., Albalkhi, I., Magableh, H. M., Saleh, T., AlKattan, K. M., & Yaqinuddin, A. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1180825 · Cited by 71
LncRNA-OIS1 regulates DPP4 activation to modulate senescence induced by RAS
Li, L., Breugel, P. C. V., Loayza‐Puch, F., Ugalde, A. P., Korkmaz, G., Messika-Gold, N., Han, R., Lopes, R., Barberà, E. P., Teunissen, H., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky087 · Cited by 58
Kidney Aging and Chronic Kidney Disease
Zhang, Y., Chen, Y., & Li, X. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126585 · Cited by 72
“The p16 INK-ATTAC mice, in which apoptosis of highly p16 INK-ATTAC -expression cells can be induced upon administration of the drug AP20187 (AP), have been utilized to investigate the presence of p16 positive cells in kidneys during aging and renal fibrosis [51].”
BackgroundMethodThe somatotropic axis and aging: Benefits of endocrine defects
Bartke, A., List, E. O., & Kopchick, J. J. (2016) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2016.02.002 · Cited by 60
Molecular pathology endpoints useful for aging studies
Niedernhofer, L. J., Kirkland, J. L., & Ladiges, W. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.012 · Cited by 59
Self-citationFBP1 controls liver cancer evolution from senescent MASH hepatocytes
Gu, L., Zhu, Y., Nandi, S. P., Lee, M., Watari, K., Bareng, B., Ohira, M., Liu, Y., Sakane, S., Carlessi, R., et al. (2025) · Nature · doi:10.1038/s41586-024-08317-9 · Cited by 63
CIN and Aneuploidy: Different Concepts, Different Consequences
Schukken, K. M., & Foijer, F. (2017) · BioEssays · doi:10.1002/bies.201700147 · Cited by 63
Sahu, S. K., Reddy, P., Lu, J. Y., Shao, Y., Wang, C., Tsuji, M., Núñez‐Delicado, E., Esteban, C. R., & Belmonte, J. C. I. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adg1777 · Cited by 66
Doolittle, M. L., Saul, D., Kaur, J., Rowsey, J. L., Vos, S. J., Pavelko, K. D., Farr, J. N., Monroe, D. G., & Khosla, S. (2023) · Nature Communications · doi:10.1038/s41467-023-40393-9 · Cited by 57
“To do so, we leveraged the INK-ATTAC transgene (FLAG-tagged caspase 8 driven by an endogenous p16 promoter fragment) to monitor p16 INK4a transcriptional activation 12,13 .”
Senescence under appraisal: hopes and challenges revisited
Davan-Wetton, C. S. A., Pessolano, E., Perretti, M., & Montero‐Melendez, T. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03746-x · Cited by 61
Mbara, K. C., Devnarain, N., & Owira, P. M. O. (2022) · Pharmaceutical Medicine · doi:10.1007/s40290-022-00444-w · Cited by 47
“SCs are reduced by targeting networks of anti-apoptotic factors that promote their survival, suppressing the inflammatory SASP, and genetic modification using transgenic animals in activating apoptotic signals mediated by p16Ink4a or p21Cip1 promoter elements [20, 21].”
BackgroundToll-like receptor 4 (TLR4) deficient mice are protected from adipose tissue inflammation in aging
Ghosh, A. K., O’Brien, M., Mau, T., & Yung, R. L. (2017) · Aging · doi:10.18632/aging.101288 · Cited by 58
“Recent studies have also indicated that with aging there is increased accumulation of senescent cells in many organs including fat depots, which contributes to aging pathologies [9].”
BackgroundResultReduced Life- and Healthspan in Mice Carrying a Mono-Allelic BubR1 MVA Mutation
Wijshake, T., Malureanu, L. A., Baker, D. J., Jeganathan, K. B., van de Sluis, B., & van Deursen, J. M. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1003138 · Cited by 61
“1 denotes previous published results [21]; 2 [38]; and 3 [42].”
BackgroundMethodResultInfluentialSelf-citationExtending human healthspan and longevity: a symposium report
DeVito, L. M., Barzilai, N., Cuervo, A. M., Niedernhofer, L. J., Milman, S., Levine, M. E., Promislow, D., Ferrucci, L., Kuchel, G. A., Mannick, J. B., et al. (2021) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14681 · Cited by 58
Self-citationSenescent T cells: Beneficial and detrimental roles
Laphanuwat, P., Gomes, D. C. O., & Akbar, A. N. (2023) · Immunological Reviews · doi:10.1111/imr.13206 · Cited by 64
Multiple facets of p53 in senescence induction and maintenance
Johmura, Y., & Nakanishi, M. (2016) · Cancer Science · doi:10.1111/cas.13060 · Cited by 59
Metadata
- Authors
- Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Venue
- Nature
- Published
- 2011-11
- Volume
- 479
- Issue
- 7372
- Pages
- 232-236
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3468323
- OpenAlex
- W2069519394
- Cited by
- 3,670
- References
- 32
- Citations by year
- 2026: 221 · 2025: 284 · 2024: 347 · 2023: 316 · 2022: 333 · 2021: 333 · 2020: 324 · 2019: 299 · 2018: 250 · 2017: 190 · 2016: 203 · 2015: 157 · 2014: 159 · 2013: 127 · 2012: 119
- FWCI
- 89.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- National Institute on Aging (P01AG041122, AG 13925, R01AG013925, R37AG013925)
- National Cancer Institute (CA-96985, R01CA096985)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050456)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, senolytics, senolytic therapy, p16INK4a, senescent cell clearance, aging, age-related diseases, healthspan extension, adipose tissue, skeletal muscle, eye, tissue dysfunction
- MeSH terms
- Adipose Tissue, Aging, Animals, Bone Marrow Cells, Cell Count, Cells, Cultured, Eye, Female, Genotype, Longevity, Male, Mice, Transgenic, Phenotype, Progeria, Time Factors, Weaning, Gene Expression, Tacrolimus, Cellular Senescence, Protein Serine-Threonine Kinases, Muscle, Skeletal, Cell Cycle Proteins, Cyclin-Dependent Kinase Inhibitor p16, Mice
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 2026-09-28, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-09-28 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
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.
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