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.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
9 of 19 cited sources checked · 5 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Most senescent cells express p16Ink4a.
“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.”
Quote in the paperSubstantial claim1 of 2 sources checked - Interpretationown data
Acquisition of the senescence-associated secretory phenotype contributes to age-related tissue dysfunction.
“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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [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
- Premisecitation
Rosiglitazone can induce senescence and p16Ink4a expression via PPARγ activation.
“rosiglitazone, a drug that can induce cellular senescence and p16Ink4a expression through activation of PPARγ16.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [16] Gan, Q. et al. PPARγ accelerates cellular senescence by inducing p16INK4α expression in human diploid fibroblasts. J. Cell Sci. 121, 2235–2245 (2008) source
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)
Experimental — accuracy not yet measured
- Premisecitation
Senescent cells accumulate in various tissues and organs with ageing.
“Senescent cells accumulate in various tissues and organs with ageing3”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [3] Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005) source
- Premisecitation
The 2,617-bp p16Ink4a promoter fragment is transcriptionally active in senescent but not non-senescent cells.
“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.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [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) source
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)
Experimental — accuracy not yet measured
- Findingown data
Skeletal muscle and eye of treated mice had a similar reduction in senescence indicators.
“Skeletal muscle and eye had a similar reduction in senescence indicators (Fig. 3c, d and Supplementary Fig. 6b, c).”
Quote in the paperNot a substantial claim - Findingown data
p16Ink4a-independent age-related phenotypes, such as cardiac arrhythmias and arterial wall stiffening, were not attenuated in AP20187-treated BubR1H/H;INK-ATTAC mice.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Matsumoto, T. et al. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke 38, 1050–1056 (2007) source
- Findingown data
Age-related phenotypes were not delayed by AP20187 in BubR1H/H mice lacking INK-ATTAC.
“The above age-related phenotypes were not delayed upon AP20187 treatment of BubR1H/H mice lacking INK-ATTAC (Fig. 2b and Supplementary Fig. 4).”
Quote in the paperSubstantial claim - Findingown data
Most cells from both transgenic lines were dead or dying 48 h after AP20187 addition.
“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).”
Quote in the paperSubstantial claim - Findingown data
IAT of AP20187-treated BubR1H/H;INK-ATTAC mice had a marked decrease in SA-β-Gal staining compared with untreated mice.
“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).”
Quote in the paperSubstantial claim - Findingown data
AP20187 treatment delayed onset of lordokyphosis and cataracts in both BubR1H/H;INK-ATTAC lines compared with untreated mice.
“Remarkably, treated mice of both BubR1H/H;INK-ATTAC lines had substantially delayed onset of lordokyphosis (a measure of sarcopenia onset in this model15) and cataracts compared to untreated mice (Fig. 2b, c).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature Cell Biol. 10, 825–836 (2008) source
- Findingown data
Late-life clearance of p16Ink4a-positive senescent cells slowed progression of already established age-related disorders.
“Furthermore, late-life clearance attenuated progression of already established age-related disorders.”
Quote in the paperSubstantial claim - Findingown data
AP20187 treatment prevented adipose tissue loss in BubR1H/H;INK-ATTAC mice.
“Dual-energy X-ray absorptiometry (DEXA) scans of BubR1H/H;INK-ATTAC mice confirmed that AP20187 treatment prevented loss of adipose tissue (Fig. 2f).”
Quote in the paperSubstantial claim - Findingown data
Activating FKBP-Casp8 efficiently eliminates p16Ink4a-positive senescent cells in vitro.
“These data show that FKBP–Casp8 activation efficiently eliminates p16Ink4a-positive senescent cells in vitro.”
Quote in the paperSubstantial claim - Findingown data
In BubR1 progeroid mice carrying the INK-ATTAC transgene, drug treatment removes p16Ink4a-positive senescent cells.
“Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16Ink4a-positive senescent cells upon drug treatment.”
Quote in the paperSubstantial claim - Findingown data
No overt side effects of senescent cell clearance were observed in the model.
“There were no overt side effects of senescent cell clearance in our model, even though it has been postulated that senescent cells enhance certain types of tissue repair23,24.”
- Also stated in: § Abstract · plain
“WT;INK-ATTAC mice were continuously treated with AP20187 until 8 months of age; however, no such effects were observed (data not shown).”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
GFP+ cells from IAT had higher p16Ink4a and other senescence markers than GFP− cells.
“GFP+ cells not only expressed much higher levels of p16Ink4a than GFP− cells but also had elevated levels of other key senescence markers (Fig. 1h and Supplementary Fig. 3d).”
Quote in the paperSubstantial claim - Findingown data
INK-ATTAC activity in founder lines 3 and 5 overlaps with endogenous p16Ink4a expression.
“Together, these data indicate that INK-ATTAC gene activity in founder lines 3 and 5 overlaps with endogenous p16Ink4a expression.”
Quote in the paperSubstantial claim - Findingown data
INK-ATTAC expression correlates with senescence marker expression in IAT.
“qRT–PCR analysis demonstrated that INK-ATTAC expression correlates with expression of senescence markers in IAT (Fig. 1f and Supplementary Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
INK-ATTAC is selectively expressed in p16Ink4a-positive senescent cells.
“Taken together, these results indicate that INK-ATTAC is selectively expressed in p16Ink4a-positive senescent cells.”
Quote in the paperSubstantial claim - Findingown data
BrdU incorporation was lower in IAT and muscle of untreated than treated animals.
“BrdU incorporation was lower in IAT and muscle tissue of untreated than treated animals (Fig. 3e), supporting the contention that senescence-associated replicative arrest is decreased upon administration of AP20187 in BubR1H/H;INK-ATTAC transgenic animals.”
Quote in the paperSubstantial claim - Findingown data
Late-life clearance of p16Ink4a-positive senescent cells attenuates progression of age-related decline in BubR1 hypomorphic mice.
“Thus, late-life clearance of p16Ink4a-positive senescent cells attenuates progression of age-related decline in BubR1 hypomorphic mice.”
Quote in the paperSubstantial claim - Findingreasoning
Overall survival of AP20187-treated BubR1H/H;INK-ATTAC mice was not substantially extended.
“which could explain why the overall survival of AP20187-treated BubR1H/H;INK-ATTAC mice was not substantially extended (Supplementary Fig. 5d).”
Quote in the paperSubstantial claim- The authors state this as an assumption: Cardiac failure is the main cause of death in BubR1H/H mice.
- Findingown data
Senescence markers were substantially reduced in fat and skeletal muscle of AP20187-treated mice.
“Senescence markers were substantially reduced in both fat and skeletal muscle of AP20187-treated animals (Fig. 4f, g and Supplementary Fig. 7).”
Quote in the paperSubstantial claim - Findingown data
AP20187-treated BubR1H/H;INK-ATTAC mice had larger muscle fibre diameters than untreated mice.
“Consistent with decreased lordokyphosis, muscle fibre diameters of AP20187-treated BubR1H/H;INK-ATTAC animals were larger than those of untreated counterparts (Fig. 2d).”
Quote in the paperSubstantial claim - Findingown data
Continuous removal of p16Ink4a-expressing cells from BubR1H/H;INK-ATTAC mice selectively delays age-related phenotypes that depend on p16Ink4a induction.
“Taken together, these results indicate that continuous removal of p16Ink4a-expressing cells from BubR1H/H;INK-ATTAC mice selectively delays age-related phenotypes that depend on p16Ink4a induction.”
Quote in the paperSubstantial claim - Findingown data
Senescence markers were not elevated in 3-week-old BubR1H/H;INK-ATTAC mice.
“Senescence markers were not elevated in 3-week-old BubR1H/H;INK-ATTAC mice (Supplementary Fig. 3b, c).”
Quote in the paperSubstantial claim - Findingown data
In adipose tissue, skeletal muscle and eye, where p16Ink4a drives age-related pathology, life-long removal of p16Ink4a-expressing cells delayed the onset of those phenotypes.
“In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies, life-long removal of p16Ink4a-expressing cells delayed onset of these phenotypes.”
Quote in the paperSubstantial claim - Findingown data
Other senescence-associated markers decreased in IAT of treated mice, along with INK-ATTAC and GFP.
“Corresponding decreases in other senescence-associated markers were also observed, as well as expected reductions in INK-ATTAC and GFP (Fig. 3b and Supplementary Fig. 6a).”
Quote in the paperNot a substantial claim - Findingown data
Rosiglitazone treatment caused a high proportion of cells to express Flag-tagged FKBP-Casp8.
“Immunofluorescence microscopy revealed that a high proportion of cells expressed Flag-tagged FKBP–Casp8 in the presence of rosiglitazone, but not in its absence (Fig. 1d).”
Quote in the paperSubstantial claim - Findingreasoning
Lateral skin contained more subdermal adipose tissue in treated animals.
“Consistent with this generally increased adiposity, lateral skin contained significantly more subdermal adipose tissue (Fig. 2h).”
Quote in the paperNot a substantial claim - Findingown data
Lack of INK-ATTAC induction in heart and aorta correlated with lack of attenuation of p16Ink4a-independent phenotypes.
“This correlated with lack of INK-ATTAC induction in heart and aorta (Fig. 1c and Supplementary Fig. 5c).”
Quote in the paperSubstantial claim - Findingown data
Selective INK-ATTAC induction occurred in tissues of WT;INK-ATTAC-3 mice with elevated endogenous p16Ink4a during ageing.
“Furthermore, we observed selective INK-ATTAC transgene induction in tissues of WT;INK-ATTAC-3 mice showing elevated expression of endogenous p16Ink4a upon chronological ageing (Supplementary Fig. 2).”
Quote in the paperSubstantial claim - Findingown data
Fat tissue of aged BubR1H/H;INK-ATTAC mice stained strongly for SA-β-Gal.
“Fat tissue of aged BubR1H/H;INK-ATTAC mice stained strongly for senescence-associated-β-galactosidase (SA-β-Gal; Fig. 1e).”
Quote in the paperNot a substantial claim - Interpretationown data
Senescence-associated replicative arrest is decreased upon AP20187 administration in BubR1H/H;INK-ATTAC transgenic animals.
“supporting the contention that senescence-associated replicative arrest is decreased upon administration of AP20187 in BubR1H/H;INK-ATTAC transgenic animals.”
Quote in the paperSubstantial claim - Interpretationown data
Cellular senescence has a causal role in generating age-related phenotypes.
“These data indicate that cellular senescence is causally implicated in generating age-related phenotypes”
Quote in the paperSubstantial claim - Interpretationown data
Improvements in muscle and fat of late-life treated 10-month-old BubR1H/H;INK-ATTAC-5 mice reflect slowed progression of age-related decline, not reversal of ageing.
“Analysis of 5-month-old untreated BubR1H/H;INK-ATTAC-5 mice revealed that the observed improvements in skeletal muscle and fat of late-life treated 10-month-old BubR1H/H;INK-ATTAC-5 mice reflect attenuated progression of age-related declines rather than a reversal of ageing (Fig. 4a, c–e).”
Quote in the paperSubstantial claim - Premisecitation
p16Ink4a contributes to acquisition of age-related pathologies in adipose tissue, skeletal muscle, and eye.
“In tissues—such as adipose tissue, skeletal muscle and eye—in which p16Ink4a contributes to the acquisition of age-related pathologies”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature Cell Biol. 10, 825–836 (2008) source
- Premisecitation
BubR1H/H mice selectively accumulate p16Ink4a-positive cells in tissues where age-associated pathologies develop, including adipose, skeletal muscle, and eye.
“BubR1H/H mice selectively accumulate p16Ink4a-positive cells in certain tissues in which age-associated pathologies develop, including adipose tissue, skeletal muscle and eye15.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature Cell Biol. 10, 825–836 (2008) source
- Premisecitation
Inactivating p16Ink4a in BubR1H/H mice delays onset of age-related phenotypes selectively in those tissues.
“Inactivation of p16Ink4a in these mice is known to delay the onset of age-related phenotypes selectively in these tissues15.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Baker, D. J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nature Cell Biol. 10, 825–836 (2008) source
- Classified as probably not a substantial claim. 4
- May combine two claims. 8
Classified as probably not a substantial claim.
Premisecitationp16Ink4a expression increases with ageing in several rodent and human tissues.
“Additionally, the expression of p16Ink4a is known to increase with ageing in several rodent and human tissues8.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004) source
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)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationSASP enables cells to secrete growth factors, cytokines, and proteases.
“senescence-associated secretory phenotype (SASP), which enables cells to secrete a variety of growth factors, cytokines and proteases4”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [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
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)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationCellular senescence halts proliferation of damaged or dysfunctional cells and constrains malignant progression of tumour cells.
“Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells1,2.”
Quote in the paperNot a substantial claim2 of 2 sources checkedMay combine two claims.
Findingown dataLate-life AP20187 treatment increased mean muscle fibre diameters and improved treadmill performance in BubR1H/H;INK-ATTAC mice.
“Importantly, late-life treated animals had increased mean muscle fibre diameters and showed improved performance in treadmill exercise tests (Fig. 4a, b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataSenescent cells were cleared from tissues, and this delays acquisition of age-related dysfunction in BubR1 hypomorphic mice.
“Together, these data indicate that senescent cells were cleared from tissues and that this delays acquisition of age-related dysfunction in BubR1 hypomorphic mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLate-life treated mice had enlarged fat depots and increased adipocyte size and subdermal adipose layer thickness.
“Furthermore, most fat depots of these animals were enlarged and adipocyte cell size and subdermal adipose layer thickness were significantly increased (Fig. 4c–e).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAP20187-treated mice showed increased treadmill exercise duration, distance, and work.
“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.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataGFP fluorescence was observed in two strains, BubR1H/H;INK-ATTAC-3 and -5.
“We observed GFP fluorescence in two of these strains, BubR1H/H;INK-ATTAC-3 and -5 (Fig. 1b and Supplementary Fig. 1a).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSkeletal muscle and lens tissue of aged BubR1H/H;INK-ATTAC mice are SA-β-Gal negative but express other senescence markers.
“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).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataRemoving senescent cells can prevent or delay tissue dysfunction and extend healthspan.
“and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationAP20187 induces dimerization of a membrane-bound myristoylated FKBP-Casp8 fusion protein.
“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.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [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
May combine two claims.
PremisecitationBubR1H/H mice have shortened lifespan and multiple age-related phenotypes.
“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.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [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
- cites [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
- cites [14] Matsumoto, T. et al. Aging-associated vascular phenotype in mutant mice with low levels of BubR1. Stroke 38, 1050–1056 (2007) source
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?
Killing p16-positive cells in transgenic mice reduces age-related disease and lengthens health span in two independent mouse strains, INK-ATTAC and p16-3MR.
“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]
The main text reports that clearing p16-positive cells delayed selected age-related deficits and preserved function in BubR1 progeroid mice carrying INK-ATTAC. Its two tested transgenic lines were INK-ATTAC-3 and INK-ATTAC-5, not INK-ATTAC and p16-3MR; our copy does not report a p16-3MR experiment. No page number is available in the indexed copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredThe BubR1H/H progeria model has accelerated and elevated superphysiologic cellular senescence due to chromosome missegregation and increasing aneuploidy.
“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]
The main text (page unavailable) describes BubR1H/H mice as progeroid and reports that they selectively accumulate p16Ink4a-positive senescent cells in adipose tissue, skeletal muscle and eye. It identifies BubR1 as part of the checkpoint for accurate chromosome segregation, but does not establish that missegregation or increasing aneuploidy causes the senescence, or quantify it as superphysiologic relative to normal ageing. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMany immune cell types and subtypes develop a senescence-like state with increased expression of p16, p21, and SASP factors.
“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]
The paper’s main text links senescence with p16 expression, and its concluding discussion describes the senescence-associated secretory phenotype (SASP). Its bone-marrow experiments do not identify multiple immune-cell types or subtypes, and the copy does not establish increased p21 expression in them. Page numbers are not supplied in the indexed copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredAdaptive immune function can be improved by short-term treatment with rapamycin, which reduces markers of senescence and SASP in PBMCs.
“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]
The main text (Fig. 3a–d) reports reduced senescence markers in the adipose tissue, skeletal muscle and eye of AP20187-treated transgenic mice. It does not show that rapamycin reduces senescence or SASP markers in PBMCs. The adaptive-immune-function statement is attached to a different citation (95), so it is not assessed here. (LLM, conf=0.84)
Experimental — accuracy not yet measuredKilling senescent cells using a transgenic suicide gene enhances healthspan in mice.
“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
The paper’s main text (Fig. 2–3 discussion) reports that drug-activated INK-ATTAC clearance of p16Ink4a-positive senescent cells delayed selected age-related deficits and preserved muscle function. This supports improved healthspan, but the benefit was demonstrated in BubR1 progeroid mice, not mice generally; some age-related conditions were unaffected. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Cell senescence is important for determination of ageing rate and lifespan in mammals.
“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]
In the intervention results (Fig. 2), clearing p16Ink4a-positive senescent cells delayed selected age-related phenotypes in progeroid mice, supporting a role in aspects of ageing. But the same section (Supplementary Fig. 5d) says overall survival was not substantially extended, so this study does not establish a role in determining lifespan. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDepletion of cells expressing the senescence marker p16INK4A in genetically modified mice prolongs median lifespan and improves overall health.
“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
In the main text (Fig. 2), clearing p16Ink4a-expressing cells in genetically modified BubR1 progeroid mice delayed several age-related deficits and preserved muscle function, supporting improved health. But the survival discussion (Supplementary Fig. 5d) says overall survival was not substantially extended; it does not support the claimed prolongation of median lifespan. (LLM, conf=0.90)
Experimental — accuracy not yet measuredTreatments to target and kill senescent cells, like senolytics, have shown promising results in extending lifespans and ameliorating various diseases.
“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]
The main text (Fig. 2 and Fig. 4; page not provided) reports that drug-triggered clearance of senescent cells in transgenic progeroid mice delayed or attenuated several age-related disorders. But the study did not test senolytic drugs as standalone treatments, and it explicitly says overall survival was not substantially extended (Supplementary Fig. 5d). Thus it supports the disease-related promise, not the claimed lifespan extension. (LLM, conf=0.91)
Experimental — accuracy not yet measuredInterference with senescent cell accumulation in BubR1 progeroid mice delays several aging-associated disorders.
“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]
In the INK-ATTAC model, drug-treated BubR1H/H;INK-ATTAC mice did not live longer but were remarkably protected from several other age-related pathologies, including cataracts, sarcopenia, and loss of subcutaneous fat.
“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]
This study provided the first direct evidence that senescent cells can, at least in a premature aging mouse model, drive degenerative age-related pathology.
“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 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.
“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]
In BubR1 hypomorphic mice carrying the INK-ATTAC transgene, removing p16-expressing cells from weaning onward reduced senescent cell buildup and premature ageing in skeletal muscle, eye, and adipose tissue.
“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]
Removal of senescent cells delays several pathologies and increases healthy lifespan.
“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 INK-ATTAC transgenic mouse model expresses FK506 binding protein-caspase-8 fusion protein under control of the p16INK4a promoter.
“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]
ATTAC ablates p16Ink4a-positive senescent cells upon administration of AP20187 in BubR1 progeroid mice.
“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]
Selective removal of p16 INK4A+ cells from BubR1 H/H INK-ATTAC mice delays kyphosis, cataracts, and muscle atrophy.
“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
Selective removal of p16 INK4A+ cells from BubR1 H/H INK-ATTAC mice does not delay cardiac arrhythmias and arterial wall stiffening nor does it extend lifespan.
“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
Ablation of p16 INK4A expressing cells slowed age-related declines in progeroid BubR1 H/H mice.
“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 demonstration that ablation of p16 INK4A expressing cells slowed age-related declines in progeroid BubR1 H/H mice provided the first evidence that senescent cells are causal for certain aging phenotypes.
“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
Clearance of p16-expressing cells improves parameters of physical health and function in progeroid mice.
“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]
Clearance of senescent cells is beneficial for age-associated disorders.
“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]
Longer term treatments (from 20 to 26 months of age) with 3TC were effective at opposing several known phenotypes of aging: macrophage infiltration of tissues, glomerulosclerosis of the kidney and skeletal muscle atrophy.
“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]
Citation 26 is attached to glomerulosclerosis of the kidney. Our copy’s account of late-life treatment reports effects in skeletal muscle and fat, but does not address glomerulosclerosis (main text, Fig. 4 discussion; page unavailable). Searches for glomerulosclerosis, kidney, 3TC, and treatment at 20–26 months found no supporting passage. (LLM, conf=0.75)
Experimental — accuracy not yet measuredCellular senescence is a major driver of aging, with age-associated accumulation of senescent cells.
“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
Removal of senescent cells attenuates age-related tissue dysfunction even late in life.
“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
Clearance of senescent cells in a mouse progeroid model in vivo can delay age-related tissue dysfunction, including cataract formation, lipodystrophy, and lordokyphosis.
“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 progeroid INK-ATTAC;BubR1H/H mice, senescent cell clearance could reverse age-related lipodystrophy.
“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]
Current in vivo assessment of senescent cell burden is done at the tissue level, by quantifying senescent cells with immunohistochemistry for markers such as heterochromatin foci, p16 expression or SA-beta-galactosidase activity, or by transgenic labels such as p16INK4A promoter-driven GFP in the INK-ATTAC mouse.
“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]
Transgenic mice that allow selective removal of senescent cells made it possible to show that senescent cells have a causal role in disease.
“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]
Removal of senescent cells can attenuate age-related tissue dysfunction and extend health span.
“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
Selective elimination of senescent cells can prevent or delay age-related tissue dysfunction to extend life span and improve health span.
“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
Purging p16-positive senescent cells in transgenic mice increased mean lifespan and aspects of healthspan.
“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]
The senescence-associated secretory phenotype is dependent on p38MAPK, NF-κB, cGAS/STING, NOTCH and mTOR signalling.
“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]
Accumulating senescent cells contributes to ageing-related functional compromise and predisposes to age-related disease.
“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]
Models of accelerated cellular senescence show premature ageing and increased incidence of age-related pathologies.
“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]
Increased levels of p16INK4a have been documented in aged and stressed tissues compared to younger, healthy tissues, and removal of p16INK4a-expressing senescent cells in mice prevented or delayed tissue dysfunction and age-related disorders.
“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]
Progeroid models have provided in vivo experimental data of accelerated ageing-related degenerative pathologies.
“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]
Experimental senolysis ameliorated ageing-related pathologies.
“In addition, experimental senolysis ameliorated ageing-related pathologies [38].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [38]
Lifelong elimination of p16INK4A cells substantially delayed age-related disease, whereas late life elimination attenuated these age-related pathologies in genetically modified BubR1 progeroid mice.
“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]
Robust in vivo evidence supports the causative involvement of senescent cells in aging and age-related diseases.
“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]
Clearing senescent cells from progeroid or naturally aging mice improves healthspan, increases lifespan, and benefits multiple pathologies.
“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]
Genetic and pharmacological strategies have demonstrated benefits of eliminating senescent cells in aging and disease.
“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]
Two related but distinct mouse models exist for detecting and clearing senescent cells.
“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 mice, removing senescent cells genetically or with senolytics has generally helped across many diseases and conditions.
“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 mice, clearance of p16INK4A-positive cells extends lifespan and slows emergence of ageing phenotypes and age-related functional deterioration of organs and tissues.
“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]
Senescent cell burden is a good predictor of animal lifespan.
“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]
Clearance of senescent cells by genetic engineering or senolytic drugs is associated with reduced circulating pro-inflammatory markers, increased lifespan, and delayed frailty-related phenotypes in mice.
“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 aged INK-ATTAC transgenic mice, depletion of p16INK4a-high senescent cells increased resilience to pathogens including mouse hepatitis virus.
“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]
Elimination of p16Ink4a-expressing senescent cells by suicide gene-mediated ablation in INK-ATTAC mice results in significant improvements in healthspan and lifespan.
“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
Senescent cells are drivers of ageing.
“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
Elimination of senescent cells may allow better recovery of tissues, consistent with the finding that senescent cell elimination via transgenic techniques improves aging-associated phenotypes.
“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
INK-ATTAC mice can be used as a reporter to track the dynamics of p16Ink4a-positive cells.
“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 BubR1 hypomorphic accelerated-aging mouse, p16Ink4a-marked senescent MuSC subpopulations contribute to sarcopenic wasting and repair dysfunction.
“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]
Ablating p16Ink4a-expressing MuSCs and other senescent cells reduces muscle wasting and improves treadmill performance.
“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 animals, genetic and pharmacologic reduction of senescent cell burden prevents, delays, or alleviates various aging-related diseases and sequelae.
“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 preclinical aging models, senescent cell accumulation is associated with chronic diseases, geriatric syndromes, multimorbidity, and accelerated aging phenotypes.
“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]
Senolytics have been used to prevent, delay, or alleviate many age-onset diseases and syndromes in preclinical models.
“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]
Genetic models of senescent cell clearance provide proof-of-principle for health and lifespan benefits of reducing old cell burden and the SASP.
“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]
Elimination of even a relatively small proportion of existing senescent cells (~30% reduction) using INK-ATTAC extends healthspan and prevents multiple age-related morbidities in progeroid and normal chronologically-aged mice.
“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]
Clearing senescent cells only in late life did not improve age-related pathologies, though it slowed their progression.
“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]
Removing p16Ink4a-expressing senescent cells throughout life in progeroid mice postpones pathology in several aging tissues, including fat, muscle and eye.
“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]
Selective killing of p16-expressing cells in a premature ageing mouse model delays ageing phenotypes.
“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]
Removal of senescent cells by genetic or pharmacological senolytic approaches extends median lifespan in old mice and prevents onset of age-associated disease.
“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
Senescence has also been implicated in promoting carcinogenesis and age-related pathologies through the senescence-associated secretory phenotype.
“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]
Genetic ablation of p16+ cells in a transgenic mouse model extends the lifespan of naturally aged mice and reduces age-associated pathologies including cancer.
“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]
Whole-body elimination of p16+ senescent cells in middle-aged mice reduces the rate of spontaneous tumor formation.
“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]
p16Ink4a expression is essentially undetectable in young and healthy tissues.
“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]
p16Ink4a+ cells accumulate in many aged or diseased tissues.
“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]
Multiple p16-based mouse models might not target the same p16high cells in vivo due to different transgene designs.
“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]
Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing.
“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]
Excessive accumulation of senescent cells causally shortens the healthy lifespan and drives organ ageing, age-related organ deterioration/disorders, tissue dysfunction and chronic diseases, including cardiovascular diseases, cancer, neurodegenerative diseases and osteoarthritis.
“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]
Mice that express low levels of 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.
“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
Exposure to the drug AP20187 causes the caspase 8 fusion protein unique to p16INK4a-expressing cells to dimerize and initiate apoptosis.
“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
Compared to vehicle-treated mice, skeletal muscle of life-long AP20187-treated BubR1 H/H;INK-ATTAC mice exhibited significantly lower expression of transgene elements (CASP8, EGFP) and senescence markers, including p16, p21, p19, Pai1, Il6, Mmp3, and Mmp13.
“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
Initiation of p16INK4a-positive cell clearance in mid-life also benefitted the molecular and morphological phenotype of skeletal muscle and measures of physical function in progeroid mice.
“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
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.
“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
The INK-ATTAC 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.
“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
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.
“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
Deletion of senescent cells by a genetic approach attenuates age-related deterioration and extends health-span in aged mice.
“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]
Sensitivity to senolytic methods is one of the strongest lines of evidence currently used in the literature.
“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]
Senescent cells can impair tissue function in ageing despite their relatively low abundance (<15%).
“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]
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.
“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]
When senescent cells were removed from aged mice artificially, the animals lived longer and were healthier.
“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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“Moreover, senescent cells accumulate with age in several vertebrate organisms (1), and their elimination can delay the onset of several age-associated disorders in mice (3, 4).”
BackgroundCellular Senescence: Aging, Cancer, and Injury
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“Other studies show that processes which eliminate senescent cells with p16(Ink4a)-positive markers, delay age-related pathologies in the mouse model of aging though side-effects can be problematical (126, 127).”
BackgroundAgeing and the pathogenesis of osteoarthritis
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Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline
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Self-citationSenescent cells: an emerging target for diseases of ageing
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“, first in progeroid BubR1 mice (Baker et al., 2011) and later in naturally aged mice (Baker et al.”
BackgroundMechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
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Targeting cellular senescence prevents age-related bone loss in mice
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Self-citationSenescent intimal foam cells are deleterious at all stages of atherosclerosis
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Self-citationSenescence is a developmental mechanism that contributes to embryonic growth and patterning
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“, 2007), premature aging (Baker et al., 2011; Keyes et al., 2005), fibrotic tissue (Jun and Lau, 2010; Krizhanovsky et al.”
BackgroundMolecular regulation of stem cell quiescence
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Senescence and the SASP: many therapeutic avenues
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“Eliminating senescent cells reduces the levels of proinflammatory cytokines in old mice (Baker et al. 2011, 2016), suggesting that the SASP may also contribute to inflammaging.”
BackgroundResultInfluentialLaberge, R.-M., Sun, Y., Orjalo, A. V., Patil, C. K., Freund, A., Zhou, L., Curran, S. C., Davalos, A. R., Wilson-Edell, K. A., Liu, S., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3195 · Cited by 1,160 · see citing works
Zhu, Y., Tchkonia, T., Fuhrmann‐Stroissnigg, H., Dai, H. M., Ling, Y. Y., Stout, M. B., Pirtskhalava, T., Giorgadze, N., Johnson, K. O., Giles, C. B., et al. (2016) · Aging Cell · doi:10.1111/acel.12445 · Cited by 1,148 · see citing works
“AP20187 eliminated senescent cells and alleviated age-related dysfunction in progeroid mice producing ATTAC only in p16Ink4a-expressing cells (Baker et al., 2011).”
BackgroundSelf-citationAntioxidant and Oxidative Stress: A Mutual Interplay in Age-Related Diseases
Tan, B. L., Norhaizan, M. E., Liew, W.-P.-P., & Rahman, H. S. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01162 · Cited by 1,182 · see citing works
“Persistent senescent cells have been associated with aging or age-related diseases via secretion of proinflammatory cytokines that alter the tissue microenvironment or modify the function of normal cells (Baker et al., 2011).”
BackgroundForging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
Cellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,105 · see citing works
Self-citationSenolytic CAR T cells reverse senescence-associated pathologies
Amor, C., Feucht, J., Leibold, J., Ho, Y.-J., Zhu, C., Alonso-Curbelo, D., Mansilla-Soto, J., Boyer, J. A., Li, X., Giavridis, T., et al. (2020) · Nature · doi:10.1038/s41586-020-2403-9 · Cited by 1,098 · see citing works
ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age‐Related Diseases
Davalli, P., Mitic, T., Caporali, A., Lauriola, A., & D’Arca, D. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3565127 · Cited by 1,059 · see citing works
“While the sequence of proliferative arrest (senescence), recruitment of immune phagocytic cells (clearance), and promotion of tissue renewal (regeneration) results in being beneficial upon a damaged tissue, for instance, the sequence is inefficiently completed in aging tissues, causing senescent cells to undergo chron…”
BackgroundCellular senescence drives age-dependent hepatic steatosis
Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., Day, C. P., Burt, A., Palmer, A., Anstee, Q. M., et al. (2017) · Nature Communications · doi:10.1038/ncomms15691 · Cited by 1,044 · see citing works
Self-citationMitochondrial dysfunction in cell senescence and aging
Miwa, S., Kashyap, S., Chini, E., & von Zglinicki, T. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158447 · Cited by 1,061 · see citing works
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL
Yosef, R., Pilpel, N., Tokarsky-Amiel, R., Biran, A., Ovadya, Y., Cohen, S., Vadai, E., Dassa, L., Shahar, E., Condiotti, R., et al. (2016) · Nature Communications · doi:10.1038/ncomms11190 · Cited by 1,032 · see citing works
“Overall, these findings suggest that the clearance of senescent cells can lead to tissue renewal and improved fitness, a possibility consistent with the recent finding that elimination of senescent cells via transgenic techniques and combinatorial treatments improves aging-associated phenotypes 14,43 .”
Fisetin is a senotherapeutic that extends health and lifespan
Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., Ling, Y. Y., Melos, K. I., Pirtskhalava, T., Inman, C. L., et al. (2018) · EBioMedicine · doi:10.1016/j.ebiom.2018.09.015 · Cited by 1,032 · see citing works
Self-citationCellular senescence: a translational perspective
Kirkland, J. L., & Tchkonia, T. (2017) · EBioMedicine · doi:10.1016/j.ebiom.2017.04.013 · Cited by 1,013 · see citing works
“In a later study, an increase in median lifespan was suggested in INKATTAC mice in which p16Ink4a+ cells had been targeted by repeated intraperitoneal (ip) injections of AP20187 beginning in mid-adulthood at the equivalent of 40 years of human age, compared to vehicle-treated controls (Baker et al., 2016).”
BackgroundInfluentialSelf-citationGeriatric muscle stem cells switch reversible quiescence into senescence
Sousa-Victor, P., Gutarra, S., García-Prat, L., Rodriguez-Ubreva, J., Ortet, L., Ruiz-Bonilla, V., Jardí, M., Ballestar, E., González, S., Serrano, A. L., et al. (2014) · Nature · doi:10.1038/nature13013 · Cited by 1,010 · see citing works
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., Lu, T., Yankner, B. A., Campisi, J., & Elledge, S. J. (2015) · Science · doi:10.1126/science.aaa5612 · Cited by 982 · see citing works
Zhang, P., Kishimoto, Y., Grammatikakis, I., Gottimukkala, K., Cutler, R. G., Zhang, S., Abdelmohsen, K., Bohr, V. A., Misra Sen, J., Gorospe, M., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0372-9 · Cited by 977 · see citing works
Epigenetic mechanisms of longevity and aging
Sen, P., Shah, P. P., Nativio, R., & Berger, S. L. (2016) · Cell · doi:10.1016/j.cell.2016.07.050 · Cited by 956 · see citing works
Immunosenescence: molecular mechanisms and diseases
Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y., & Han, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01451-2 · Cited by 1,023 · see citing works
The central role of DNA damage in the ageing process
Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. J. (2021) · Nature · doi:10.1038/s41586-021-03307-7 · Cited by 907 · see citing works
Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White, T. A., Johnson, K. O., Stout, M. B., Mezera, V., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1515386112 · Cited by 915 · see citing works
“(iii) p16positive senescent cells were the main cause of increased IL-6 expression in the stromal vascular fraction of adipose tissue digests from older progeroid mice (21).”
BackgroundMethodInfluentialSelf-citationSenescence and apoptosis: dueling or complementary cell fates?
Childs, B. G., Baker, D. J., Kirkland, J. L., Campisi, J., & van Deursen, J. M. (2014) · The EMBO Reports · doi:10.15252/embr.201439245 · Cited by 915 · see citing works
“The lack of any overt downside to senescent cell clearance in the BubR1; INK-ATTAC model suggests that apoptosis of senescent cells might be safe [119].”
Self-citationExploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
Unmasking senescence: context-dependent effects of SASP in cancer
Faget, D. V., Ren, Q., & Stewart, S. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0156-2 · Cited by 863 · see citing works
Kalinkovich, A., & Livshits, G. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2016.09.008 · Cited by 882 · see citing works
How the ageing microenvironment influences tumour progression
Fane, M., & Weeraratna, A. T. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0222-9 · Cited by 849 · see citing works
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence
Rajman, L., Chwalek, K., & Sinclair, D. A. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.02.011 · Cited by 865 · see citing works
“In the case of the BubR1 mouse, median lifespan was extended by 58% percent and maximum by 21% (North et al., 2014), which is more than twice the effect of senolytics in this model (Baker et al., 2011).”
Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD
Ferenbach, D. A., & Bonventre, J. V. (2015) · Nature Reviews Nephrology · doi:10.1038/nrneph.2015.3 · Cited by 880 · see citing works
Cellular senescence and its effector programs
Salama, R., Sadaie, M., Hoare, M., & Narita, M. (2014) · Genes & Development · doi:10.1101/gad.235184.113 · Cited by 855 · see citing works
“Of note, Baker et al. (2008, 2011) showed that, in contrast to the case of p16 ablation, which accelerates lung tumor development in the BubR1 hypomorphic background, clearance of p16-expressing senescent cells does not appear to show obvious side effects.”
BackgroundResultTelomeric DNA damage is irreparable and causes persistent DNA-damage-response activation
Fumagalli, M., Rossiello, F., Clerici, M., Barozzi, S., Cittaro, D., Kaplunov, J. M., Bucci, G., Dobreva, M., Matti, V., Beausejour, C. M., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2466 · Cited by 851 · see citing works
Stem cell aging: mechanisms, regulators and therapeutic opportunities
Oh, J., Lee, Y. D., & Wagers, A. J. (2014) · Nature Medicine · doi:10.1038/nm.3651 · Cited by 796 · see citing works
The Critical Role of Metabolic Pathways in Aging
Barzilai, N., Huffman, D. M., Muzumdar, R. H., & Bartke, A. (2012) · Diabetes · doi:10.2337/db11-1300 · Cited by 803 · see citing works
Chronic inflammation induces telomere dysfunction and accelerates ageing in mice
Jurk, D., Wilson, C., Passos, J. F., Oakley, F., Correia-Melo, C., Greaves, L., Saretzki, G., Fox, C., Lawless, C., Anderson, R., et al. (2014) · Nature Communications · doi:10.1038/ncomms5172 · Cited by 814 · see citing works
Self-citationMechanisms and therapeutic implications of cellular senescence in osteoarthritis
Coryell, P. R., Diekman, B. O., & Loeser, R. F. (2021) · Nature Reviews Rheumatology · doi:10.1038/s41584-020-00533-7 · Cited by 761 · see citing works
Senescence and aging: the critical roles of p53
Rufini, A., Tucci, P., Celardo, I., & Melino, G. (2013) · Oncogene · doi:10.1038/onc.2012.640 · Cited by 798 · see citing works
Mitochondria are required for pro-ageing features of the senescent phenotype
Correia‐Melo, C., Marques, F. D., Anderson, R., Hewitt, G., Hewitt, R., Cole, J., Carroll, B. M., Miwa, S., Birch, J., Merz, A., et al. (2016) · The EMBO Journal · doi:10.15252/embj.201592862 · Cited by 796 · see citing works
“Cellular senescence, the irreversible loss of proliferative potential in somatic cells, has been shown to not only play a major role in tumour suppression, but also to contribute to age-related tissue degeneration (Baker et al , 2011).”
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype
Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3225 · Cited by 788 · see citing works
“As rapamycin extends the lifespan of mice 21 , and the ablation of senescent cells improves age-related diseases 26,27 , downregulating the SASP could contribute to the benefits observed in rapamycin-treated old mice.”
A senescent cell bystander effect: senescence‐induced senescence
Nelson, G., Wordsworth, J., Wang, C., Jurk, D., Lawless, C., Martin‐Ruiz, C., & von Zglinicki, T. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00795.x · Cited by 755 · see citing works
“This could explain how senescent cells might drive the aging process in vivo as proposed (Tchkonia et al., 2010; Baker et al., 2011).”
BackgroundBenefits of Metformin in Attenuating the Hallmarks of Aging
Kulkarni, A. S., Gubbi, S., & Barzilai, N. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.04.001 · Cited by 766 · see citing works
“…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, and attenuation of age-related tissue dysfunction after their removal, even late in life (Hayflick and Moorhead 1961, Baker et al. 2011).”
BackgroundBiomarkers, oxidative stress and autophagy in skin aging
Gu, Y., Han, J., Jiang, C., & Zhang, Y. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101036 · Cited by 768 · see citing works
Zhu, Y., Doornebal, E. J., Pirtskhalava, T., Giorgadze, N., Wentworth, M., Fuhrmann-Stroissnigg, H., Niedernhofer, L. J., Robbins, P. D., Tchkonia, T., & Kirkland, J. L. (2017) · Aging · doi:10.18632/aging.101202 · Cited by 757 · see citing works
Self-citationRoos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., Hagler, M., Jurk, D., Smith, L. A., Casaclang‐Verzosa, G., et al. (2016) · Aging Cell · doi:10.1111/acel.12458 · Cited by 738 · see citing works
“973 Aging Cell (2016) 15, pp973–977 Doi: 10.1111/acel.12458 Ag in g Ce ll mechanism (Baker et al., 2011)], thus confirming the effectiveness and phenotypic consequences of senescent cell clearance (Figs S2–S4).”
BackgroundResultInfluentialSelf-citationMechanisms and Metabolic Implications of Regional Differences among Fat Depots
Tchkonia, T., Thomou, T., Zhu, Y. Z., Karagiannides, I., Pothoulakis, C., Jensen, M. D., & Kirkland, J. L. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.03.008 · Cited by 728 · see citing works
Self-citationIdentification of HSP90 inhibitors as a novel class of senolytics
Fuhrmann-Stroissnigg, H., Ling, Y. Y., Zhao, J., McGowan, S. J., Zhu, Y., Brooks, R. W., Grassi, D., Gregg, S. Q., Stripay, J. L., Dorronsoro, A., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00314-z · Cited by 701 · see citing works
Self-citationTargeting senescent cells alleviates obesity-induced metabolic dysfunction
Palmer, A. K., Xu, M., Zhu, Y., Pirtskhalava, T., Weivoda, M. M., Hachfeld, C. M., Prata, L. G., van Dijk, T. H., Verkade, E., Casaclang‐Verzosa, G., et al. (2019) · Aging Cell · doi:10.1111/acel.12950 · Cited by 658 · see citing works
“…by whole‐body lumines‐ cence (Demaria et al., 2014) and (b) INK‐ATTAC mice, in which a truncated p16Ink4a‐promoter sequence drives expression of a vFKBP‐caspase‐8‐FLAG fusion protein that can be activated by AP20187, a vFKBP dimerizer, to cause senescent cell apoptosis (Baker et al., 2011).”
BackgroundInfluentialSelf-citationThe senescence-associated secretory phenotype induces cellular plasticity and tissue regeneration.
Ritschka, B., Storer, M., Mas, A., Heinzmann, F., Ortells, M. C., Morton, J. P., Sansom, O. J., Zender, L., & Keyes, W. M. (2017) · Genes & Development · doi:10.1101/gad.290635.116 · Cited by 650 · see citing works
“Indeed, when the clearance of senescent cells is perturbed, pronounced SASP exposure leads to tumor formation and progression (Krtolica et al. 2001; Kang et al. 2011; Rodier and Campisi 2011; Yoshimoto et al. 2013) or paracrine senescence and aging (Baker et al. 2011; Acosta et al. 2013).”
BackgroundMoiseeva, O., Deschênes‐Simard, X., St‐Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N., & Ferbeyre, G. (2013) · Aging Cell · doi:10.1111/acel.12075 · Cited by 654 · see citing works
“Remarkably, elimination of senescent cells attenuates signs of accelerated aging in mice (Baker et al., 2011).”
BackgroundA guide to assessing cellular senescence <i>in vitro</i> and <i>in vivo</i>
González‐Gualda, E., Baker, A. G., Fruk, L., & Muñoz‐Espín, D. (2021) · The FEBS Journal · doi:10.1111/febs.15570 · Cited by 645 · see citing works
Telomeres: history, health, and hallmarks of aging
Chakravarti, D., LaBella, K. A., & DePinho, R. A. (2021) · Cell · doi:10.1016/j.cell.2020.12.028 · Cited by 637 · see citing works
“Similarly, removal of senescent cells from the BubR1 progeroid mouse model leads to an extended health span (Baker et al., 2011).”
BackgroundThe effects of aging in the hippocampus and cognitive decline
Bettio, L. E. B., Rajendran, L., & Gil‐Mohapel, J. (2017) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2017.04.030 · Cited by 654 · see citing works
“…that SC removal leads to rejuvenation of several tissues in aged mice, including an improvement in vascular phenotype (Roos et al., 2016), rejuvenation of hematopoietic stem cells (Chang et al., 2016), and attenuation of cataracts, sarcopenia, and lipodystrophy development (Baker et al., 2011).”
Microglial dysfunction in brain aging and Alzheimer's disease
Mosher, K. I., & Wyss-Coray, T. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.008 · Cited by 618 · see citing works
“This has already been accomplished by clearing p16-positive cells [58], but has not been assessed in the nervous system.”
BackgroundAging and age‐related diseases: from mechanisms to therapeutic strategies
Li, Z., Zhang, Z., Ren, Y., Wang, Y., Fang, J., Yue, H., Ma, S., & Guan, F. (2021) · Biogerontology · doi:10.1007/s10522-021-09910-5 · Cited by 668 · see citing works
Cellular senescence: a key therapeutic target in aging and diseases
Zhang, L., Pitcher, L. E., Yousefzadeh, M. J., Niedernhofer, L. J., Robbins, P. D., & Zhu, Y. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158450 · Cited by 631 · see citing works
“This genetic clearance strategy was first applied in Bub1bH/H-progeroid mice, in which it blunted age-related pathologies including sarcopenia, cataracts, and lipodystrophy (51).”
MethodTau protein aggregation is associated with cellular senescence in the brain
Musi, N., Valentine, J. M., Sickora, K. R., Baeuerle, E., Thompson, C. S., Shen, Q., & Orr, M. E. (2018) · Aging Cell · doi:10.1111/acel.12840 · Cited by 595 · see citing works
HIV-1 infection accelerates age according to the epigenetic clock
Horvath, S., & Levine, A. J. (2015) · Journal of Infectious Diseases · doi:10.1093/infdis/jiv277 · Cited by 556 · see citing works
“[56] demonstrated that removal of senescent cells expressing p16 from a murine model of Progeria delayed the onset of aging-related diseases in several tissue and organ systems.”
Background
- 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
- Health Sciences › Medicine › Physiology › 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
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