Cellular senescence and senolytics: the path to the clinic
Open accessAbstract
Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases. One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli. Senescent cells can arise throughout the lifespan and, if persistent, can have deleterious effects on tissue function due to the many proteins they secrete. In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders. In line with this, the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans. In this Review, we outline the rationale for senescent cells as a therapeutic target for disorders across the lifespan and discuss the most promising strategies—including recent and ongoing clinical trials—for translating small-molecule senolytics and other senescence-targeting interventions into clinical use. Cellular senescence has emerged as a promising therapeutic target for disorders across the lifespan; this Review highlights the most promising strategies for translating senescence-targeting interventions into clinical use in the near future.
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192 of 238 cited sources checked · 45 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Fundamental aging processes can act before conception, as with aged oocytes linked to Down syndrome.
“fundamental aging processes can operate even before conception, for example, in the context of aged oocytes linked to Down syndrome12,13.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [12] Igarashi, H., Takahashi, T. & Nagase, S. Oocyte aging underlies female reproductive aging: biological mechanisms and therapeutic strategies. Reprod. Med. Biol. 14, 159–169 (2015). source
- cites [13] Meharena, H. S. et al. Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell 29, 116–130 (2022). source
The Results section, “T21 induces NPC senescence” (page unavailable), reports senescence in Down-syndrome neural progenitor cells, supporting a link between Down syndrome and a process associated with aging. It does not examine aged oocytes or establish that the process operates before conception; searches for oocytes, maternal age, and preconception did not find support for that part of the claim. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Premisecitation
Chronological age is the main predictor of most diseases that cause most morbidity, mortality, and health costs in low-, middle-, and high-income countries.
“Chronological age is the major predictor for most of the diseases that account for the bulk of morbidity, mortality and health costs across low-, middle- and high-income countries2–7.”
Quote in the paperNot a substantial claim4 of 6 sources checked- cites [2] Niccoli, T. & Partridge, L. Ageing as a risk factor for disease. Curr. Biol. 22, R741–R752 (2012). source
- cites [3] Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014). source
The Introduction calls aging the predominant risk factor for most diseases that limit healthspan, and the Aging Research Initiative describes chronic diseases as the majority of global disease burden and the most common causes of mortality. The paper also calls chronic diseases of aging a major global healthcare burden, but our copy does not establish the claim separately for low-, middle-, and high-income countries or explicitly identify chronological age as the predictor. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [4] Scott, A. J., Ellison, M. & Sinclair, D. A. The economic value of targeting aging. Nat. Aging 1, 616–623 (2021). source
The Main section links rising age with frailty, disability and deaths, while the Results section models mortality risk and health deficits as increasing exponentially with age. But the paper uses US data and does not establish that chronological age is the major predictor of most diseases or associated health costs across low-, middle- and high-income countries. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [5] St Sauver, J. L. et al. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open 5, e006413 (2015). source
The Results (Description of the Olmsted County population; page unavailable) report that incidence of most of the 20 studied chronic conditions increased steeply with age. The paper does not establish that age is the major predictor of diseases accounting for most morbidity, mortality and costs, or extend that finding across low-, middle- and high-income countries. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [6] Tchkonia, T., Palmer, A. K. & Kirkland, J. L. New horizons: novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J. Clin. Endocrinol. Metab. 106, e1481–e1487 (2021). source
- cites [7] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). source
- Premisecitation
Interlinked fundamental aging processes appear to act as root causes of many disorders and diseases.
“Interlinked and fundamental aging processes appear to be a root-cause contributor to many disorders and diseases.”
Quote in the paperSubstantial claim5 of 5 sources checked- cites [3] Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014). source
- cites [15] Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). source
- cites [16] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science 373, eabe4832 (2021). source
The paper’s Abstract (page unavailable) identifies cellular senescence as a mechanism driving aging and age-related diseases, and says senescent cells play a causal role in preclinical models. It does not establish the broader claim that multiple interlinked aging processes are root-cause contributors to many disorders and diseases. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [17] Hadley, E. C., Kuchel, G. A., Newman, A. B. & Workshop Speakers and Participants. Report: NIA workshop on measures of physiologic resiliencies in human aging. J. Gerontol. A Biol. Sci. Med. Sci. 72, 980–990 (2017). source
The “Mechanistic Studies” section says basic aging mechanisms may act individually or collectively and influence a wide variety of aging-related outcomes. The “Influence of Biologic Aging Mechanisms on Resilience” section says they could contribute to declining clinical and physiologic resilience. Neither section establishes that these processes are root-cause contributors to many disorders and diseases; the paper frames their influence as a subject for further research. The supplied passages give no page numbers. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [18] Dungan, C. M. et al. Senolytic treatment rescues blunted muscle hypertrophy in old mice. Geroscience https://doi.org/10.1007/s11357-022-00542-2 (2022). source
The Introduction (page unavailable) links several aging-related mechanisms to anabolic resistance in skeletal muscle, and the Discussion reports that clearing senescent cells restores muscle growth in old mice. These passages support a contribution to one age-related condition, but not the broader claim that interlinked aging processes are root-cause contributors to many disorders and diseases. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Aging processes can be accentuated at etiologic sites of multiple acute and chronic diseases, including in children.
“Aging progresses throughout the lifespan can be accentuated at etiologic sites of multiple acute and chronic diseases, including in children6,8–12.”
Quote in the paperNot a substantial claim4 of 6 sources checked- cites [6] Tchkonia, T., Palmer, A. K. & Kirkland, J. L. New horizons: novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J. Clin. Endocrinol. Metab. 106, e1481–e1487 (2021). source
- cites [8] Wissler Gerdes, E. O. et al. Cellular senescence in aging and age-related diseases: implications for neurodegenerative diseases. Int. Rev. Neurobiol. 155, 203–234 (2020). source
The Introduction links cellular senescence to several chronic diseases, and the Brain tumors section says chemoradiation can induce senescence with damaging effects in pediatric patients (page numbers unavailable). The paper also discusses senescence after stroke. These passages support examples of disease- and treatment-associated senescence, but not the broader claim that aging processes are accentuated at the etiologic sites of multiple acute and chronic diseases, including in children. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [9] Ness, K. K. et al. Frailty in childhood cancer survivors. Cancer 121, 1540–1547 (2015). source
The Frailty section (page unavailable) says that age-related functional decline can accelerate after acute illness or injury, especially when organ systems are damaged. Potential biological markers of frail health (page unavailable) describes vulnerability in organs exposed to cancer-treatment toxins in children. The paper does not establish the broader claim that aging is accentuated at etiologic sites of multiple acute and chronic diseases generally, including in children outside the childhood-cancer context. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [10] Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014). source
- cites [11] Suvakov, S. et al. Epigenetic and senescence markers indicate an accelerated ageing-like state in women with preeclamptic pregnancies. EBioMedicine 70, 103536 (2021). source
The Discussion (page not provided) reports accelerated ageing-like changes and senescence in women with preeclampsia, including in placental and renal tissue. The Introduction links senescence more broadly to multiple chronic diseases. The paper does not establish the claim across multiple acute diseases or in children. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [12] Igarashi, H., Takahashi, T. & Nagase, S. Oocyte aging underlies female reproductive aging: biological mechanisms and therapeutic strategies. Reprod. Med. Biol. 14, 159–169 (2015). source
The ‘Contribution of oxidative stress to oocyte aging’ section (page not provided) links oxidative stress to aging and aging-related diseases, and the ‘Calorie restriction’ section names several such diseases. Neither section says that aging is accentuated at the etiologic sites of acute and chronic diseases or that this occurs in children. (LLM, conf=0.79)
Experimental — accuracy not yet measured
- Premisecitation
Many senescence triggers activate DNA damage response signaling and p53/p21, p16/RB or other pathways, producing cell cycle arrest and a SASP.
“Many such stressors activate DNA damage response signaling and activation of the p53/p21CIP1/WAF1, p16INK4a/retinoblastoma protein or other pathways, resulting in cell cycle arrest and the development of a senescence-associated secretory phenotype (SASP)24,40,48−53”
Quote in the paperNot a substantial claim6 of 8 sources checked- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Introduction (page unavailable) says that stresses including DNA damage can induce senescence, which involves proliferative arrest, and that senescent cells can develop a SASP. It does not say that those stressors activate DNA damage response signaling or the specified p53/p21 and p16/RB pathways to produce those outcomes. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [40] Hernandez-Segura, A., Nehme, J. & Demaria, M. Hallmarks of cellular senescence. Trends Cell Biol. 28, 436–453 (2018). source
- cites [48] Hickson, L. J. et al. Corrigendum to ‘Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease’ EBioMedicine 47 (2019) 446–456. EBioMedicine 52, 102595 (2020). source
- cites [49] Wang, B. et al. An inducible p21-Cre mouse model to monitor and manipulate p21-highly-expressing senescent cells in vivo. Nat. Aging 1, 962–973 (2021). source
The Introduction (page not available) says that stimuli including DNA damage can drive senescence through p16/Rb, p53/p21 and probably other pathways, with growth arrest and a SASP. It does not say that many of those stressors activate DNA damage response signaling, so that part of the attributed claim is not supported by our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [50] Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). source
The paper’s Abstract (page unavailable in our copy) supports a pathway from persistent DNA damage signalling to p53-dependent growth arrest and a senescence-associated inflammatory cytokine response. It does not support the sentence’s implication that the p53/p21 or p16/RB arrest pathways themselves produce that response: it reports that the cytokine response is p53-independent and that p16-induced senescence without DNA damage does not initiate it. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [51] Yousefzadeh, M. J. et al. Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice. Aging Cell 19, e13094 (2020). source
The Introduction (page not provided) says that several stressors induce senescence, describes entry through p53/p21, p16/pRB or GATA4 pathways, and defines senescence as proliferative arrest; it also says senescent cells can display a SASP. The paper does not establish the claim’s additional step that many of those stressors activate DNA damage response signaling. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [52] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). source
- cites [53] Sharpless, N. E. & Sherr, C. J. Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 (2015). source
- Premisecitation
Senescent cell fate can be triggered by many stressors, including DNA damage, oncogene activation, mitochondrial dysfunction, reactive metabolites, oxygen extremes, proteotoxic stress, extracellular signals, infections, mechanical or shear stress, resistance exercise, and factors secreted by other senescent cells.
“The senescent cell fate can be triggered by a number of stressors including DNA damage, cancerous mutations or oncogene activation, mitochondrial dysfunction, reactive metabolites, hyperoxia or hypoxia, proteotoxic stress, extracellular signals, infections, mechanical or shear stresses that deform cells, resistance exercise and factors secreted by other senescent cells18,38–47.”
Quote in the paperNot a substantial claim9 of 10 sources checked- cites [18] Dungan, C. M. et al. Senolytic treatment rescues blunted muscle hypertrophy in old mice. Geroscience https://doi.org/10.1007/s11357-022-00542-2 (2022). source
- cites [38] Yousefzadeh, M. J. et al. An aged immune system drives senescence and ageing of solid organs. Nature 594, 100–105 (2021). source
The Abstract (page unavailable) says stress can activate senescence, and the Rapamycin rejuvenates immune cells section specifically links unrepaired endogenous DNA damage to immune-cell senescence. The Cell autonomous mechanism section also suggests aged splenocytes can drive senescence in other tissues. The paper does not establish the rest of the listed triggers, including oxygen extremes, mechanical stress and resistance exercise. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [39] Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013). source
The Introduction and the section ‘Multiple components of the SASP mediate paracrine senescence’ support the claim that factors secreted by senescent cells can trigger senescence in other cells. The paper also studies oncogene-induced senescence and reports DNA and oxidative damage, but it does not establish the full list of triggers, including mitochondrial dysfunction, oxygen extremes, mechanical stress, infections, or resistance exercise. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [40] Hernandez-Segura, A., Nehme, J. & Demaria, M. Hallmarks of cellular senescence. Trends Cell Biol. 28, 436–453 (2018). source
Box 1 (page unavailable) identifies DNA damage, oncogene activation, oxidative products, mitochondrial dysfunction, and factors secreted by senescent cells as causes of senescence. The copy does not establish resistance exercise, mechanical or shear stress, or oxygen extremes as triggers. Its discussion of infections and protein accumulation concerns ER stress, not a direct finding that they trigger senescence. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [41] Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). source
The Discussion and Concluding Remark report that oncogenic ras provokes premature senescence and discuss several other potential routes to a senescence-like state. The Introduction mentions DNA damage and hypoxia as triggers of increased p53, not as demonstrated triggers of senescence. The paper does not support the sentence’s wider list, including mitochondrial dysfunction, infections, mechanical stress, resistance exercise, and factors secreted by senescent cells. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [42] Chaib, S., Tchkonia, T. & Kirkland, J. L. in Handbook of Experimental Pharmacology (eds Eckel, J. & Clément, K.) 165–180 (Springer, 2021). source
- cites [43] Wiley, C. D. & Campisi, J. From ancient pathways to aging cells—connecting metabolism and cellular senescence. Cell Metab. 23, 1013–1021 (2016). source
The Introduction says that diverse stresses and physiological signals induce senescence, and the sections on mitochondrial dysfunction and oncogene-induced senescence identify those specific triggers. The copy also discusses genotoxic stress and ROS, but the passages do not establish the full attributed list, particularly infections, mechanical or shear stress, resistance exercise, and hypoxia as triggers. No page numbers were supplied for these sections. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [44] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source
The Introduction (page unavailable) identifies damage signals, metabolic insults, mechanical or shear forces, hypoxia, reactive oxygen species, oncogenes, and telomere damage as drivers of senescence. It also says factors secreted by senescent cells can induce secondary senescence, and the paper addresses viral infection. The copy does not identify resistance exercise, proteotoxic stress, or mitochondrial dysfunction as triggers; it describes reactive metabolites as SASP products rather than explicitly as triggers. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [45] Lee, S. et al. Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature 599, 283–289 (2021). source
The Article section says that viral entry can trigger senescence and identifies activated oncogenes and DNA-damaging cancer therapy as other triggers. The Properties of VIS section also reports paracrine senescence induction. The paper does not support the full list attributed to it, including mitochondrial dysfunction, oxygen extremes, mechanical or shear stress, and resistance exercise (no page numbers provided). (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [46] Martini, H. & Passos, J. F. Cellular senescence: all roads lead to mitochondria. FEBS J. https://doi.org/10.1111/febs.16361 (2022). source
The Introduction (page not provided) names DNA-damaging agents, oncogene activation, and mitochondrial dysfunction as senescence triggers, and says the senescence-associated secretory phenotype can transmit senescence to healthy cells. The cited paper does not support the full list attributed to it: the passages do not establish oxygen extremes, infections, mechanical or shear stress, or resistance exercise as triggers. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Senescent cells are normally cleared within days to weeks by natural killer cells and other immune cells.
“Normally, senescent cells appear to be cleared within days to weeks after they develop by natural killer cells and other immune cell types62,66–69.”
Quote in the paperSubstantial claim5 of 5 sources checked- cites [62] Prata, L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin. Immunol. 40, 101275 (2018). source
The Introduction says senescent cells appear to be usually cleared by the immune system, and the NKs section describes natural killer cells clearing senescent-like cells in a liver-fibrosis model, with fibrosis resolving within 20 days. That example does not establish that senescent cells generally are cleared within days to weeks after developing; the Heterogeneous SC hypothesis section also notes that some persist for years. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [66] Pereira, B. I. et al. Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition. Nat. Commun. 10, 2387 (2019). source
The Introduction says senescent cells can be eliminated by the immune system and identifies NK cells and other immune cells as participants in their surveillance. The Results also show that NK cells can target senescent fibroblasts in vitro. Neither passage establishes that senescent cells are normally cleared within days to weeks after developing. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [67] Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). source
The indexed paper (section labeled Abstract; page unavailable) reports that natural killer cells, neutrophils and macrophages contributed to clearance of senescent murine liver tumours after p53 restoration; the tumours became nearly undetectable within 12 days of treatment. It does not establish that senescent cells are normally cleared within days to weeks after they develop. The paper explicitly says it is unclear whether such turnover is a general feature of senescence in vivo. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [68] Brighton, P. J. et al. Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium. Elife 6, e31274 (2017). source
The Results section (‘Immune clearance of senescent decidual cells’; page unavailable) reports that uterine natural killer cells selectively clear senescent decidual cells, and notes a broader role for immune cells, especially NK cells, in eliminating senescent cells. It does not establish that senescent cells generally are cleared within days to weeks after they develop, or demonstrate clearance by other immune-cell types in this setting. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [69] Stokes, K. L. et al. Natural killer cells limit the clearance of senescent lung adenocarcinoma cells. Oncogenesis 8, 24 (2019). source
The Discussion describes immune surveillance in which immune cells remove senescent cells, including examples involving NK cells and other immune cell types. The Results report substantial clearance within eight days after p53 reactivation. But the paper does not establish that senescent cells are normally cleared within days to weeks, and its lung adenocarcinoma findings show that NK cells dampen, rather than drive, clearance in that context. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
The proapoptotic SASP can harm locally and systemically when senescent cells accumulate and persist.
“This proapoptotic SASP can have detrimental effects both locally and systemically due to senescent cell accumulation and persistence24.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Introduction (page unavailable) says that the SASP contributes to local and systemic dysfunction as senescent-cell burden rises. It describes the SASP as pro-inflammatory, however, not proapoptotic; that characterization is unsupported by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Senescent cells with a proapoptotic SASP survive a cytotoxic environment by upregulating pro-survival and antiapoptotic pathways such as SRC kinases, PI3K-AKT, HSP, serpines, mitochondrial pathways, and BCL-2-related proteins.
“Through upregulation of pro-survival and antiapoptotic pathways such as SRC kinases, the PI3K-AKT signaling pathway, heat shock protein (HSP) pathways, serpines, mitochondrial pathways or apoptosis regulator BCL-2-related proteins, those senescent cells with a proapoptotic SASP can survive, despite the cytotoxic microenvironment they create6,7,14,34,35,54–58.”
Quote in the paperSubstantial claim8 of 10 sources checked- cites [6] Tchkonia, T., Palmer, A. K. & Kirkland, J. L. New horizons: novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J. Clin. Endocrinol. Metab. 106, e1481–e1487 (2021). source
- cites [7] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). source
Section 4 (‘The Achilles’ Heel of Senescent Cells’; page unavailable) says senescent cells may rely on upregulated antiapoptotic pathways to withstand their own pro-apoptotic SASP. It identifies BCL-2, PI3K/AKT, serpine and tyrosine-kinase pathways; its table also names Src kinase. The copy does not identify HSP or a mitochondrial pathway as one of these survival pathways: it discusses mitochondrial dysfunction only as a possible reason for their upregulation. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [14] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
The Introduction says senescent cells survive despite apoptosis-inducing SASP factors, and the Results (The senescent transcriptome and anti-apoptotic pathways; Senolytic siRNAs) report increased anti-apoptotic gene sets and survival roles for PI3KCD, PAI-2 and BCL-xL. The Discussion also discusses PI3K–AKT and serpines. Our copy does not establish that SRC kinases or HSP pathways are upregulated to protect these cells, or demonstrate upregulation of every pathway in the citing sentence. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [34] Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020). source
The Discovery of senolytic drugs section says that senescent cells with a pro-apoptotic SASP depend on anti-apoptotic SCAP networks to avoid self-destruction, and it identifies Src kinase and BCL-2 family members as relevant targets. Our copy does not establish PI3K-AKT, HSP, or mitochondrial pathways as parts of those survival networks. The Cellular senescence section lists serpines as SASP factors associated with clotting and fibrosis, not as anti-apoptotic pathways. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [35] Tchkonia, T. & Kirkland, J. L. Aging, cell senescence and chronic disease: emerging therapeutic strategies. J. Am. Med. Assoc. 320, 1319–1320 (2018). source
- cites [54] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). source
The Results section ('HSP90 inhibitors downregulate the anti-apoptotic PI3K/AKT pathway'; page unavailable) says senescent cells upregulate survival signaling that resists apoptosis, and the Introduction names PI3K/AKT, serpine and Bcl-2 pathways. The Discussion also links HSP90 to that resistance. The cited paper does not establish the claim's SRC-kinase or mitochondrial pathways, or that a proapoptotic SASP creates the cytotoxic environment these cells survive. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [55] Xu, Q. et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat. Metab. 3, 1706–1726 (2021). source
The Results section on mitochondrial dysfunction reports elevated BCL-xL in senescent cells and implicates AKT signalling in their response to PCC1. The Discussion also identifies HSP90 and BCL-2-family inhibitors as senolytics. These passages do not establish that senescent cells survive a SASP-created cytotoxic environment by upregulating the full list of pathways, including SRC kinases and serpines. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [56] Wissler Gerdes, E. O., Zhu, Y., Tchkonia, T. & Kirkland, J. L. Discovery, development, and future application of senolytics: theories and predictions. FEBS J. 287, 2418–2427 (2020). source
In “The discovery of senolytics” (page not provided), the paper proposes that senescent cells resist their proapoptotic SASP and identifies PI3K/Akt, BCL-2-family proteins, serpines, and HSP-90 among potential survival pathways. It does not identify SRC kinases or mitochondrial pathways as such defenses, and it describes the defenses as a hypothesis rather than establishing that all the listed pathways are upregulated in senescent cells. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [57] Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of antiapoptotic factors. Aging Cell 15, 428–435 (2016). source
The Introduction (page unavailable) says senescent cells resist apoptosis, potentially protecting them from their own inflammatory secretions, and reports upregulation of pro-survival pathways. The Results section on Bcl-2 family protein signatures (page unavailable) finds increased Bcl-xl and Bcl-2 in some, but not all, senescent cell types. Our copy does not establish upregulation of the other listed pathways—SRC, PI3K-AKT, HSP, and serpines—or show that every senescent cell with a proapoptotic SASP survives by these mechanisms. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [58] Gasek, N. S., Kuchel, G. A., Kirkland, J. L. & Xu, M. Strategies for targeting senescent cells in human disease. Nat. Aging 1, 870–879 (2021). source
The Cellular Senescence section says senescent cells avoid apoptosis by upregulating pro-survival pathways. The Modulating SCAPs section discusses Src kinase inhibition, PI3K/Akt, BCL-2-family proteins, mitochondrial apoptotic signaling and HSP90. The cited copy does not identify serpines as one of these pathways or specifically describe survival of cells with a proapoptotic SASP in a cytotoxic microenvironment; the SASP section instead discusses inflammatory effects and resistance to immune-mediated clearance. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
This sterile inflammatory state can impair neighboring and distant non-senescent cells, including progenitors, reducing tissue function and regenerative capacity.
“This sterile inflammatory state can provoke dysfunction of neighboring and distant non-senescent cells, such as progenitor cells, contributing to impaired tissue function and reduced regenerative capacity18,21,24,26,34.”
Quote in the paperSubstantial claim5 of 5 sources checked- cites [18] Dungan, C. M. et al. Senolytic treatment rescues blunted muscle hypertrophy in old mice. Geroscience https://doi.org/10.1007/s11357-022-00542-2 (2022). source
The Introduction (page unavailable) says senescent cells secrete pro-inflammatory factors that can disrupt muscle growth, and the Discussion links persistent senescent cells in old muscle with blunted growth. Our copy does not establish dysfunction of distant non-senescent cells or progenitor cells, or a resulting reduction in regenerative capacity. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [21] Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017). source
The paper’s Abstract says the inflammatory senescence-associated secretory phenotype has harmful paracrine and systemic effects and can cause tissue dysfunction. It also reports that senescent-cell-conditioned medium impaired osteoblast mineralization and altered osteoclast progenitor survival. It does not establish reduced regenerative capacity or show that progenitor cells themselves become dysfunctional. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Introduction describes a pro-inflammatory senescence-associated secretory phenotype that contributes to local and systemic dysfunction. The Results report senescence in recipients’ own cells and inflammatory markers in distant muscle after senescent-cell transplantation, alongside impaired physical function. Our copy does not show that the affected recipient cells were progenitors or that their regenerative capacity was reduced; the paper used progenitors as transplanted cells. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [26] Lewis-McDougall, F. C. et al. Aged-senescent cells contribute to impaired heart regeneration. Aging Cell 18, e12931 (2019). source
- cites [34] Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020). source
- Premisecitation
ABT-263 can cause thrombocytopenia and neutropenia even after brief exposure.
“N can cause thrombocytopenia and neutropenia, even after brief exposures57,88–91”
Quote in the paperSubstantial claim5 of 5 sources checked- cites [57] Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of antiapoptotic factors. Aging Cell 15, 428–435 (2016). source
The Discussion (page unavailable) says navitoclax can affect platelets, causing bleeding, and can cause neutropenia. It does not specifically identify thrombocytopenia or say these effects occur after brief exposure; the short exposures described in the Results concern senescent-cell experiments, not these adverse effects. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [88] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). source
The paper’s concluding discussion (indexed under Abstract; page unavailable) identifies thrombocytopenia and neutropenia as common, transient toxicities of ABT263 treatment in patients. It does not say that either occurs after brief exposure. The Online Methods describe short treatment cycles in mice but do not link those cycles to these toxicities. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [89] Wilson, W. H. et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 11, 1149–1159 (2010). source
The Results (Patients and Toxicity; page unavailable) report both thrombocytopenia and neutropenia during navitoclax treatment. The Results (Pharmacodynamic Effects; page unavailable) describe a platelet decline after a single dose, supporting the brief-exposure qualifier for thrombocytopenia. Neutropenia, however, tended to occur in later treatment cycles, so the paper does not support that qualifier for both toxicities. (LLM, conf=0.89)
Experimental — accuracy not yet measured - cites [90] Afreen, S. et al. BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells. Cell Death Dis. 11, 8 (2020). source
The Introduction (page not specified) identifies Navitoclax as ABT-263, reports rapid platelet loss, and lists neutropenia among side effects in some patients. It does not establish that both thrombocytopenia and neutropenia occur after brief exposure. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [91] Josefsson, E. C., Vainchenker, W. & James, C. Regulation of platelet production and lifespan: role of Bcl-xL and potential implications for human platelet diseases. Int. J. Mol. Sci. 21, 7591 (2020). source
Section 2 identifies navitoclax as ABT-263 and states that it can cause thrombocytopenia in mice and humans. The passages found do not establish that ABT-263 causes neutropenia or that either effect occurs after brief exposure. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Intracellular cues such as retrotransposable elements (e.g., LINE-1), cytosolic mitochondrial DNA, and circular DNA can activate cGAS-STING and trigger pro-inflammatory genes weeks or months after senescence induction.
“These include retrotransposable elements (for example, LINE-1), cytosolic mitochondrial DNA, or circular DNA—all of which can activate the cytosolic DNA-sensing (cGAS)-STING pathway, triggering the expression of pro-inflammatory genes79–81.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [79] De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). source
The Consequences of L1 activation section reports that suppressing cGAS or STING inhibited the interferon response and reduced pro-inflammatory SASP gene expression in late-senescent cells. The paper also mentions mitochondrial DNA as a possible source of cytoplasmic DNA, but does not establish the claimed pathway for mitochondrial DNA or address circular DNA. Its Extended Data examine cells at 12–16 weeks of senescence. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [80] Zhao, Y. et al. Transposon-triggered innate immune response confers cancer resistance to the blind mole rat. Nat. Immunol. 22, 1219–1230 (2021). source
The Results section (‘RTEs form Cytoplasmic RNA/DNA Hybrids and induce cGAS-STING’; page not provided) links LINE-1 and other retrotransposons to cGAS-STING activation and IFNB1/SASP gene expression in blind mole rat cells. The cited paper does not establish the same pathway for cytosolic mitochondrial DNA or circular DNA, or a weeks-to-months delay after senescence induction. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [81] Decout, A., Katz, J. D., Venkatraman, S. & Ablasser, A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21, 548–569 (2021). source
The sections on cell-intrinsic genomic and mitochondrial DNA describe LINE-1-derived DNA and cytosolic mitochondrial DNA activating cGAS–STING. The senescence and ageing section links cGAS–STING activity to inflammatory secretions from senescent cells. Our copy does not establish circular DNA as one of these triggers or specify that pro-inflammatory genes are induced weeks or months after senescence induction (pages unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
Persistent senescent cells are highly responsive to extracellular cues such as DAMPs and PAMPs, which can worsen the proapoptotic and pro-inflammatory SASP.
“Persistent senescent cells appear to be highly responsive to extracellular cues, such as damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), which can exacerbate the proapoptotic, pro-inflammatory qualities of the SASP16.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science 373, eabe4832 (2021). source
The Discussion (page unavailable) says senescent cells are primed to respond to PAMPs by producing more inflammatory SASP factors, supporting the PAMP and pro-inflammatory parts of the claim. The passages do not establish a response to DAMPs or describe the amplified SASP as proapoptotic. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Premisecitation
Certain HSP90 inhibitors, such as geldanamycin, are senolytic against particular senescent cell types.
“certain HSP90 inhibiting drugs, such as geldanamycin, are senolytic against particular senescent cell types.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [54] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). source
- Premisecitation
Senolytic compounds targeting a single SCAP node, such as BCL-2 inhibitors ABT-263, A1331852, or A1155463, tend to induce apoptosis in a restricted range of senescent cell types.
“In some cases, senolytic compounds that target a single SCAP node, such as the BCL-2 pathway inhibitors, N (ABT-263), A1331852 or A1155463, tend to induce apoptosis in a restricted range of senescent cell types57,86.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [57] Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of antiapoptotic factors. Aging Cell 15, 428–435 (2016). source
The Introduction and Results report that navitoclax (ABT-263) induces apoptosis in some senescent cell types but is not senolytic in human primary preadipocytes. Our copy does not address A1331852 or A1155463, so it does not establish the claim for those compounds. It also describes navitoclax as targeting several Bcl-2 family proteins, rather than a single protein. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [86] Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017). source
- Premisecitation
The intracellular and extracellular environment can modulate which SASP factors are produced and their abundance.
“The intracellular and extracellular environment can modulate which SASP factors are produced and their abundance.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science 373, eabe4832 (2021). source
- Premisecitation
Second-generation senolytics are being identified using high-throughput library screens and other approaches.
“Second-generation senolytics are now being identified using high-throughput library screens and other approaches54.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [54] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). source
- Findingcitation
Bioinformatic analyses identified 46 compounds targeting SCAP pathways as potentially senolytic.
“Bioinformatic analyses identified 46 compounds that target SCAP pathways as being potentially senolytic14.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [14] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
The Results (Senolytic siRNAs; page unavailable) describe network analysis of pro-survival targets, and the Discussion proposes that drugs acting on several of those targets may be senolytic. Our copy does not say that bioinformatic analyses identified 46 compounds; the reported count is 39 transcripts selected for siRNA knockdown, not compounds. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Modulating immune clearance of senescent cells is another strategy for reducing age-related senescent cell burden and pathologic conditions.
“Other strategies for decreasing age-related senescent cell burden and pathologic conditions involve modulating immune clearance of senescent cells62.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [62] Prata, L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin. Immunol. 40, 101275 (2018). source
- Premisecitation
Galacto-oligosaccharide-coated nanoparticles and β-galactosidase-activated prodrugs appear to eliminate at least some senescent cells, based on increased lysosomal mass and senescence-associated β-galactosidase activity.
“One approach stems from the increase in lysosomal mass and senescence-associated β-galactosidase activity in many senescent cells, whereby galacto-oligosaccharide-coated nanoparticles and β-galactosidase-activated prodrugs appear to eliminate at least some of these cells92,93.”
Quote in the paperNot a substantial claim2 of 2 sources checked - Premisecitation
In SARS-CoV-2 infection, some extracellular cues act through TLR3 and ACE-2 and contribute to COVID-19 morbidity.
“in the case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, some of these extracellular cues are mediated through Toll-like receptor 3 and angiotensin converting enzyme-2, contributing to coronavirus disease 2019 (COVID-19) morbidity44,82.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [44] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source
- cites [82] Kandhaya-Pillai, R. et al. TNF-α/IFN-γ synergy amplifies senescence-associated inflammation and SARS-CoV-2 receptor expression via hyper-activated JAK/STAT1. Aging Cell 21, e13646 (2022). source
The Introduction and Discussion (page numbers unavailable) describe ACE2 as a SARS-CoV-2 entry receptor and suggest that increased receptor expression may contribute to COVID-19 severity. Our copy does not describe extracellular cues acting through Toll-like receptor 3; searches for “TLR3” and “Toll-like receptor 3” found no supporting passage. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
SCAP pathways resemble pathways that protect some cancer cells, such as B cell lymphoma or chronic lymphocytic leukemia cells, which release tissue-destructive proapoptotic factors but avoid apoptosis.
“SCAP pathways are similar to those that protect certain types of cancer cells, such as B cell lymphoma or chronic lymphocytic leukemia cells, which also release tissue-destructive proapoptotic factors but evade undergoing apoptosis themselves84,85.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [84] Chen, L. S., Balakrishnan, K. & Gandhi, V. Inflammation and survival pathways: Chronic lymphocytic leukemia as a model system. Biochem. Pharmacol. 80, 1936–1945 (2010). source
The sections on CLL-cell survival and its microenvironment describe pathways that protect CLL cells from apoptosis and suppress apoptosis in B-lymphoma cells. The microenvironment section also discusses chemokine secretion, but it does not identify the secreted factors as tissue-destructive or proapoptotic. That part of the attributed claim is unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [85] Bessler, H. et al. Factor(s) released from irradiated B-CLL cells induce apoptosis in leukemic lymphocytes. Cancer Lett. 179, 103–108 (2002). source
- Premisecitation
SASP inhibitors can directly or indirectly attenuate the SASP by inhibiting NF-κB, JAK-STAT, mTOR, mitochondrial complex-1-related or 4-related targets, or other pathways involved in SASP induction and maintenance.
“SASP inhibitors (senomorphics) can directly or indirectly attenuate the SASP of senescent cells by inhibiting transcription factor nuclear factor (NF)-κB, the JAK-STAT signal transduction pathway, the serine/threonine protein kinase mTOR, mitochondrial complex-1-related or 4-related targets, or other pathways involved in the induction and maintenance of the SASP103–106.”
Quote in the paperSubstantial claim4 of 4 sources checked- cites [103] Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015). source
The paper’s Significance passage describes a capillary analog of muscle contraction driven by wetting affinity between silicone oil and a steel rod; its Keywords concern muscle contraction and force–velocity relations (page numbers unavailable). Searches for SASP inhibitors, senescent cells, NF-κB, JAK-STAT, mTOR, and mitochondrial targets found no passage addressing the attributed claim. (LLM, conf=0.79)
Experimental — accuracy not yet measured - cites [104] Tilstra, J. S. et al. NF-κB inhibition delays DNA damage-induced senescence and aging in mice. J. Clin. Invest. 122, 2601–2612 (2012). source
The Discussion (page not provided) reports that inhibiting IKK/NF-κB downregulated cytokines and other proinflammatory genes expressed by senescent cells, supporting the NF-κB part of the claim. It mentions mTOR as an activator of NF-κB, but does not show that inhibiting mTOR attenuates the SASP; the passages also do not support the JAK-STAT or mitochondrial-complex targets. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [105] Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980–989 (2013). source
The paper discusses compounds that inhibit mTORC1 (Abstract; page unavailable) and reports that rapamycin ameliorates premature senescence in progeria-derived cells (Abstract; page unavailable). Neither passage says that inhibiting mTOR—or the other listed pathways—attenuates the SASP. Searches for SASP and the named pathways found no passage addressing that relationship. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [106] Moiseeva, O. et al. Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation. Aging Cell 12, 489–498 (2013). source
The Discussion reports that metformin reduces inflammatory cytokine production in senescent cells by interfering with NF-κB, and the Effects of metformin on the NF-κB pathway section reports inhibition of IKK activation. The paper does not establish SASP attenuation through JAK-STAT, mTOR, or mitochondrial complex-1- or complex-4-related targets, so it supports only part of the cited list. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
D+Q alleviates transcriptional changes and cellular dysfunction in an in vitro human neural cell model of Down syndrome.
“D + Q alleviated transcriptional changes and cellular dysfunction in an in vitro human neural cell Down syndrome model.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Meharena, H. S. et al. Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell 29, 116–130 (2022). source
- Premisecitation
An RNA-mediated interference screen revealed that targeting alternative splicing in senescent cells may be a viable approach for inhibiting the SASP.
“an RNA-mediated interference screen revealed that targeting alternative splicing in senescent cells may be a viable approach for inhibiting the SASP107.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [107] Georgilis, A. et al. PTBP1-mediated alternative splicing regulates the inflammatory secretome and the pro-tumorigenic effects of senescent cells. Cancer Cell 34, 85–102 (2018). source
- Premisecitation
After resistance exercise, senescent cells accumulate in old mouse muscle alongside impaired exercise-induced hypertrophy compared with young mice.
“After resistance exercise, senescent cells develop in muscle of old mice in tandem with impaired exercise-induced muscle hypertrophy compared to young mice18.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [18] Dungan, C. M. et al. Senolytic treatment rescues blunted muscle hypertrophy in old mice. Geroscience https://doi.org/10.1007/s11357-022-00542-2 (2022). source
The Results (pages unavailable) show that senescent cells increased in old mouse muscle after mechanical overload and that hypertrophy was blunted compared with younger mice. The mouse intervention was surgically induced mechanical overload used to model resistance training, not resistance exercise itself; the paper reports resistance exercise separately in humans. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
In mice infected with murine coronavirus, D+Q or F reduced mortality.
“In mice infected with a murine coronavirus, the mortality rate was reduced following administration of D + Q or F16.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [16] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science 373, eabe4832 (2021). source
- Premisecitation
A third copy of chromosome 21 in neural progenitor cells causes transcriptional and nuclear organizational changes similar to those in senescent cells.
“A third copy of chromosome 21 in neural progenitor cells leads to transcriptional and nuclear organizational changes similar to those in senescent cells.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [13] Meharena, H. S. et al. Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell 29, 116–130 (2022). source
- Premisecitation
D+Q alleviates the negative effect of aging on muscle growth.
“D + Q alleviates this negative impact of aging on muscle growth.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Dungan, C. M. et al. Senolytic treatment rescues blunted muscle hypertrophy in old mice. Geroscience https://doi.org/10.1007/s11357-022-00542-2 (2022). source
- Premisecitation
Astronauts exposed to radiation, high G-forces, zero gravity, and cabin air quality show an accelerated aging-like phenotype.
“An accelerated aging-like phenotype has been observed in astronauts who are exposed to radiation, high G-forces, zero gravity and cabin air quality126.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [126] Garrett-Bakelman, F. E. et al. The NASA twins study: a multidimensional analysis of a year-long human spaceflight. Science 364, eaau8650 (2019). source
The Discussion section on persistent telomere loss reports postflight telomere shortening and identifies telomere length as a biomarker of aging. The paper also discusses physiological changes associated with weightlessness and radiation exposure, but it does not establish an overall accelerated aging-like phenotype in astronauts or link one to high G-forces or cabin air quality. Its year-long flight findings are principally from one astronaut. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Premisecitation
Intermittent senolytic administration appears as effective as continuous treatment for reducing senescent cell burden.
“With senolytics, intermittent administration appears to be as effective as continuous treatment for attenuating senescent cell burden21.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017). source
The treatment passage (indexed as Abstract; page unavailable) reports that once-monthly dasatinib plus quercetin reduced markers of senescent-cell burden in old mice. The Online Methods report similar effects with weekly and biweekly dosing, but the paper does not compare intermittent senolytic dosing with continuous senolytic treatment. The claimed equivalence to continuous treatment is therefore unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Premisecitation
In vitro and in vivo, NF-κB inhibitors can reduce pro-inflammatory SASP cytokines and chemokines.
“In vitro and in vivo, inhibitors of NF-κB (mediating the cell response to inflammation), can reduce pro-inflammatory SASP cytokines and chemokines104.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [104] Tilstra, J. S. et al. NF-κB inhibition delays DNA damage-induced senescence and aging in mice. J. Clin. Invest. 122, 2601–2612 (2012). source
The Discussion reports that 8K-NBD reduced expression of cytokine-related inflammatory genes and chemokines in treated mice. The Results report reduced senescence in cultured cells after genetic reduction of NF-κB, but do not report reduced SASP cytokines or chemokines in vitro. The source therefore supports the in vivo portion, not the full in vitro and in vivo claim. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Premisecitation
Transplanted senescent cells or organs from old mice spread senescence to distant sites in recipients, predisposing to poor transplantation outcomes.
“Transplanted senescent cells or organs from old mice have been shown to spread the senescent phenotype to distant sites in recipient mice, predisposing to detrimental outcomes after transplantation24,31.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Results section on senescent-cell transplantation reports markers consistent with senescence spreading to distant muscle tissue and impaired physical function in recipient mice (page not provided). But the transplanted cells were experimentally induced to become senescent; this paper does not report transplanting organs from old mice or assessing organ-transplant outcomes. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [31] Iske, J. et al. Senolytics prevent mtDNA-induced inflammation and promote the survival of aged organs following transplantation. Nat. Commun. 11, 4289 (2020). source
The Introduction reports that transplanting senescent cells into young recipients causes functional impairment, and the Discussion says the senescence-associated secretory phenotype induces senescence locally and systemically. The Results also show poorer survival of untreated old-donor heart grafts. However, the paper does not show that transplanted old organs spread senescence to distant sites in recipients or establish that such spread causes the poor graft outcomes. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Interpretationcitation
Intermittent hit-and-run senolytic dosing could reduce side effects of D that generally appear after weeks to months of continuous administration.
“This intermittent ‘hit-and-run’ strategy of senolytic administration could serve to reduce side effects of agents such as D, which generally appear after weeks to months of continuous administration118,119.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [118] Naqvi, K. et al. Long-term follow-up of lower dose dasatinib (50 mg daily) as frontline therapy in newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 126, 67–75 (2020). source
The Results (Safety; page unavailable) document adverse effects during daily dasatinib treatment, including pleural effusions and treatment interruptions. The paper does not establish that these effects generally begin after weeks to months, or test whether intermittent senolytic dosing reduces them; its regimen was daily dosing. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [119] Ottmann, O. et al. Long-term efficacy and safety of dasatinib in patients with chronic myeloid leukemia in accelerated phase who are resistant to or intolerant of imatinib. Blood Cancer J. 8, 88 (2018). source
The paper’s long-term safety discussion (page unavailable) reports dasatinib-related adverse events during ongoing treatment, including pulmonary hypertension diagnosed on study days 36, 463, 838, and 944. It does not establish that side effects generally begin after weeks to months of continuous use, and it does not test intermittent senolytic dosing. The proposed benefit of that strategy is the citing authors’ inference. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Premisecitation
Over 20 clinical trials of senolytic therapies are completed, ongoing, or planned.
“over 20 clinical trials of senolytic therapies are completed, ongoing or planned34 (Table 1).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [34] Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020). source
In ‘Strategies for translating agents targeting fundamental ageing processes into treatments’ (page unavailable), the paper says several senolytic trials are underway or planned. Its Table 3 also lists studies that are completed, recruiting, or planned. Neither passage establishes the claimed total of over 20 clinical trials. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Table 1
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
NAD+ or NAD precursors can increase healthspan in experimental animals.
“NAD+ or NAD precursors can increase healthspan in experimental animals141.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [141] Rajman, L., Chwalek, K. & Sinclair, D. A. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 27, 529–547 (2018). source
- Premisecitation
In a mouse osteoarthritis model, UBX0101 combined with N was necessary to restore aged joint structure.
“in a mouse model of osteoarthritis, a combination of UBX0101 with N was necessary to restore aged joint structure131.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [131] Faust, H. J. et al. IL-17 and immunologically induced senescence regulate response to injury in osteoarthritis. J. Clin. Invest. 130, 5493–5507 (2020). source
- Premisecitation
Results of that pilot suggested senolytics improved physical function in frail IPF patients.
“Results suggested that senolytics improved physical function in these frail patients.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [63] Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019). source
The Results (Functional and biological measures; page not provided) report improved walking distance, gait speed and chair-stand performance after senolytic treatment. The Introduction describes the participants as older adults with stable IPF, but the copy does not establish that they were frail. The Discussion also cautions that the open-label study lacked a control group, so the improvement cannot be attributed to treatment with certainty. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Interpretationcitation
Because senescent cells can spread via SASP, systemic intermittent senolytic administration is potentially more promising than local administration for senescence-associated diseases, except possibly for topical eye, skin, or dental applications.
“systemic, intermittent administration of senolytics for senescence-associated diseases is potentially more promising than local administration, with the exception of perhaps eye, skin or dental topical or other local applications34.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [34] Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
- Premisecitation
SASP factors, senescence markers, and markers of other aging processes such as α-Klotho can be assayed in body fluids including urine, saliva, blood, and cerebrospinal fluid.
“SASP factors, senescence markers and markers of other fundamental aging processes (for example, α-Klotho) can be assayed in body fluids such as urine, saliva, blood or cerebrospinal fluid7,19,48,59,61,64,132,133.”
Quote in the paperSubstantial claim6 of 8 sources checked- cites [7] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). source
Section 7, “Biomarkers of Senescent Cell Burden” (page unavailable), discusses possible blood and other body-fluid assays, SASP factors in plasma, and proposed assays of microvesicles shed into blood or urine. It does not mention α-Klotho, saliva, or cerebrospinal fluid, and says these assays still need development and validation rather than establishing that all the listed markers can be assayed in those fluids. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [19] Zhu, Y. et al. Orally active, clinically translatable senolytics restore α-Klotho in mice and humans. EBioMedicine 77, 103912 (2022). source
The Methods and Results describe assays of α-Klotho and SASP factors in urine, and the Discussion compares urinary α-Klotho assays with blood tests. The paper also mentions proposed testing of α-Klotho in cerebrospinal fluid, but our copy does not establish the full claim across all listed fluids and marker types, particularly saliva. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [48] Hickson, L. J. et al. Corrigendum to ‘Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease’ EBioMedicine 47 (2019) 446–456. EBioMedicine 52, 102595 (2020). source
- cites [59] Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020). source
The Results section reports that SASP factors overlap with aging markers measured in human plasma, and the Discussion proposes SASP-based biomarkers in plasma or other biofluids. The paper does not establish the claim for urine, saliva, or cerebrospinal fluid, and it does not address α-Klotho. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [61] Tripathi, U., Misra, A., Tchkonia, T. & Kirkland, J. L. Impact of senescent cell subtypes on tissue dysfunction and repair: importance and research questions. Mech. Ageing Dev. 198, 111548 (2021). source
The sections on SASP differences and endocrine effects (page unavailable) discuss SASP factors and senescence markers, but do not say they can be assayed in body fluids. Searches for urine, saliva, blood, cerebrospinal fluid, α-Klotho, and circulating biomarkers found no passage addressing the claimed assays. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [64] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source
The Research issues section (page unavailable) proposes blood biomarkers of senescent-cell burden based on detecting SASP products. It does not establish that such assays are available, or address α-Klotho or assays in urine, saliva, or cerebrospinal fluid. Searches for those fluids and α-Klotho found no supporting passage. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [132] Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 (2017). source
The Results and Discussion (page unavailable) discuss SASP factors and senescence markers, including genes used to identify senescent cells. They do not establish that these markers can be assayed in urine, saliva, blood, or cerebrospinal fluid, and the passages found do not address α-Klotho (searched: body fluids and α-Klotho). (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [133] Faget, D. V., Ren, Q. & Stewart, S. A. Unmasking senescence: context-dependent effects of SASP in cancer. Nat. Rev. Cancer 19, 439–453 (2019). source
- Premisecitation
In 20 IPF patients, post hoc analysis showed higher urine α-Klotho after oral D+Q than before treatment.
“post hoc analysis of a study involving 20 patients with IPF showed that urine levels of the ‘geroprotective’ factor α-Klotho were higher after oral D + Q than before treatment19.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Zhu, Y. et al. Orally active, clinically translatable senolytics restore α-Klotho in mice and humans. EBioMedicine 77, 103912 (2022). sourceExperimental — accuracy not yet measured
- Interpretationcitation
Immune clearance of remaining senescent cells could be especially important for older individuals or those with chronic diseases who already have high senescent cell burden.
“This could be especially important for older individuals or those with chronic diseases, who already have a high systemic senescent cell burden24,128.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Introduction (page not available) says senescent-cell burden increases in multiple tissues with aging and at sites of pathology in multiple chronic diseases. That supports the age and disease association, but not the stronger claim that people with chronic diseases already have a high systemic burden. The paper studies senolytic clearance, not the proposed importance of immune clearance in those people. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [128] Khosla, S., Farr, J. N., Tchkonia, T. & Kirkland, J. L. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol. 16, 263–275 (2020). source
The ‘Physiological relevance of cellular senescence’ section reports that senescent cells increase with age, and ‘Cellular senescence in ageing’ reports accelerated local or systemic accumulation across a broad range of human diseases. The paper also suggests that removing persistent senescent cells might reduce dysfunction. It does not establish that older people or people with chronic diseases generally have a high *systemic* burden, or specifically recommend immune clearance for them; ‘Markers of cellular senescence’ says it is unclear whether local measurements reflect overall burden. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
Dietary interventions such as caloric restriction and intermittent fasting might protect against age-related dysfunction and diseases based on animal studies.
“Dietary interventions, such as caloric restriction and intermittent fasting, might be protective against development of age-related dysfunction and diseases based on studies in animal models134,135.”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [134] Madeo, F., Carmona-Gutierrez, D., Hofer, S. J. & Kroemer, G. Caloric restriction mimetics against age-associated disease: targets, mechanisms and therapeutic potential. Cell Metab. 29, 592–610 (2019). source
- cites [135] Green, C. L., Lamming, D. W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat. Rev. Mol. Cell Biol. 23, 56–73 (2022). source
- Premisecitation
The first published senolytic clinical trial was an open-label pilot in 14 IPF patients treated with intermittent D+Q 3 days per week for 3 weeks.
“The first senolytic clinical trial published was an open-label pilot study in which 14 patients with IPF were treated with intermittent D + Q on 3 d per week for 3 weeks63.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [63] Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019). source
- Findingown data
Proteomic and transcriptomic analyses showed upregulation of one or more senescent cell antiapoptotic pathways (SCAPs) in senescent cells.
“Analysis of proteomic and transcriptomic datasets revealed there is indeed upregulation of one or more senescent cell antiapoptotic pathways (SCAPs) in senescent cells.”
Quote in the paperSubstantial claim - Findingown data
Unpublished work from the authors' laboratory suggests that targeting senescent cells in transgenic mice has different phenotypic effects (e.g., wound healing, healthspan) than senolytic agents in wild-type mice.
“Unpublished work from our own laboratory suggests that there may be differences in the phenotypic effects (such as those relating to wound healing and healthspan) of targeting senescent cells in transgenic mice compared to the effects of senolytic agents in wild-type mice.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites unpublished data
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
Small-molecule senolytic drugs that selectively clear senescent cells have opened promising ways to prevent or treat multiple human diseases and age-related conditions.
“the discovery of small-molecule senolytic drugs that selectively clear senescent cells has led to promising strategies for preventing or treating multiple diseases and age-related conditions in humans.”
Quote in the paperSubstantial claim- Rests on an assumption: Preclinical results in animal models predict human clinical outcomes for senolytic interventions.
- Premisenone given
In preclinical models, targeting persistent senescent cells that damage tissue delays, prevents, or alleviates multiple disorders.
“In preclinical models, interventions targeting those senescent cells that are persistent and cause tissue damage have been shown to delay, prevent or alleviate multiple disorders.”
Quote in the paperSubstantial claim - Premisenone given
If senescent cells persist, the proteins they secrete can damage tissue function.
“if persistent, can have deleterious effects on tissue function due to the many proteins they secrete.”
Quote in the paperSubstantial claim - Premisenone given
Most cells that become senescent develop a SASP.
“Most cells undergoing senescence develop a SASP (Fig. 1).”
Quote in the paperNot a substantial claim - Premisecitation
Accumulation and persistence of proapoptotic SASP senescent cells can induce a chronic low-grade pro-fibrotic inflammatory state called inflammaging.
“Although not every senescent cell develops a proapoptotic, inflammatory SASP, accumulation and persistence of such senescent cells can induce a chronic low-grade, pro-fibrotic inflammatory state (usually associated with aging and chronic diseases), known as ‘inflammaging’70.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [70] Franceschi, C. & Campisi, J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J. Gerontol. A Biol. Sci. Med. Sci. 69, S4–S9 (2014). source
- Premisecitation
Some senescent cells have high lysosomal activity that makes them sensitive to lysosomal ATPase inhibitors.
“Another approach is based on the high lysosomal activity of some senescent cells that renders them sensitive to lysosomal ATPase inhibitors94.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [94] Dorr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature 501, 421–425 (2013). source
- Premisereasoning
The first senolytic drugs were identified through hypothesis-driven, mechanism-based drug discovery.
“The first senolytic drugs were identified using a hypothesis-driven, mechanism-based drug discovery approach (Fig. 3).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Small-molecule senolytics may have an advantage over vaccines or transplanted CAR T cells because treatment can be stopped if senescent cells are needed, whereas vaccine- or CAR T-induced elimination may not be readily switched off.
“A possible advantage of small-molecule senolytics over vaccines or transplanted CAR T cells is that if a need for senescent cells occurs, for example, during wound healing, tissue remodeling or pregnancy, then treatment can be discontinued—whereas the continued elimination of senescent cells induced by vaccines or CAR T strategies may not readily be switched off.”
Quote in the paperSubstantial claim- Rests on an assumption: CAR T cell therapy is expensive, individually formulated, can cause graft-versus-host disease, and requires prolonged immunosuppression.
- Interpretationnone given
Suppressing the SASP without eliminating senescent cells is an alternative therapeutic approach for alleviating senescence-related phenotypes or diseases.
“Suppressing the SASP without eliminating senescent cells is an alternative therapeutic approach for alleviating cellular senescence-related phenotypes or diseases.”
Quote in the paperSubstantial claim - Interpretationreasoning
Interventions that predominantly target persistent tissue-destructive SASP-expressing senescent cells might have greater therapeutic potential and fewer off-target effects.
“interventions that predominantly target the persisting, tissue-destructive SASP-expressing senescent cells might have superior therapeutic potential and fewer off-target effects.”
Quote in the paperSubstantial claim - Interpretationreasoning
Eliminating all senescent cells or broadly inhibiting the SASP might be detrimental when senescent cells are beneficial.
“Elimination of all senescent cells or general inhibition of the SASP might be detrimental in some instances in which senescent cells are beneficial.”
Quote in the paperSubstantial claim - Premisereasoning
Fibrosis can be a senescence-driven progressive process that contributes to reduced organ function.
“Fibrosis can be a senescence-driven progressive process that contributes to reduced organ function”
Quote in the paperSubstantial claim - Premisenone given
Senescent cells have been implicated in worsening viral infections by amplifying SASP secretion, predisposing to cytokine storm and multi-organ failure.
“senescent cells have been implicated in accentuating the severity of viral infections due to amplification of SASP factor secretion, predisposing to cytokine storm and multi-organ failure.”
Quote in the paperNot a substantial claim - Premisenone given
SASP inhibitors can suppress both growth-promoting and proapoptotic, inflammatory, tissue-destructive SASP factors.
“Whereas SASP inhibitors potentially suppress both the growth-promoting as well as the proapoptotic, inflammatory, tissue-destructive sets of SASP factors”
Quote in the paperSubstantial claim - Premisecitation
First-generation senolytics such as D+Q have been tested in preclinical models of aging and diseases including type 2 diabetes and bone, heart, kidney, liver, lung, muscle, and neurological disorders.
“First-generation senolytics, such as D + Q, have been tested in several preclinical models of aging and diseases, including type 2 diabetes, and bone, heart, kidney, liver, lung, muscle and neurological disorders (Table 2).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Table 2
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
α-Klotho overexpression in mice increases healthspan and lifespan by up to 30%.
“α-Klotho overexpression in mice increases healthspan and lifespan by up to 30% (ref. 143).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [143] Kurosu, H. et al. Suppression of aging in mice by the hormone Klotho. Science 309, 1829–1833 (2005). source
- Premisecitation
A phase 2 randomized double-blind placebo-controlled trial (NCT04349956) of UBX0101 did not meet its primary endpoint of improving pain in knee osteoarthritis at 12 weeks.
“a phase 2, randomized, double-blind, placebo-controlled clinical trial (NCT04349956)—in which the senolytic agent was a p53-destabilizing protein MDM2 inhibitor, UBX0101 (also known as nutlin-3a)—did not achieve its primary endpoint of improving pain in patients with osteoarthritis of the knee in a 12-week follow-up.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites NCT04349956
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationnone given
Eliminating senescent cells has emerged as a plausible therapeutic strategy for preventing, delaying, or alleviating multiple diseases and age-related dysfunction.
“The elimination of senescent cells has emerged as a plausible therapeutic strategy for preventing, delaying or alleviating multiple diseases and age-related dysfunction.”
Quote in the paperNot a substantial claim - Premisecitation
The first gerodiagnostic score sensitive to senolytic administration in humans was a blood composite score published in 2019.
“the first gerodiagnostic score sensitive to senolytic administration in humans was a blood composite score published in 2019 (ref. 48).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Hickson, L. J. et al. Corrigendum to ‘Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease’ EBioMedicine 47 (2019) 446–456. EBioMedicine 52, 102595 (2020). source
- Interpretationreasoning
Identifying and monitoring senescent cell burden in situ, especially in clinical trials, can be challenging if based solely on tissue biopsies because senescent cell fate is contextually and complexly regulated.
“Identification and monitoring of senescent cell burden in situ, especially during clinical trials to assess safety and efficacy, can be challenging if solely based on analysis of tissue biopsies given the contextual and complex regulation of the senescent cell fate.”
Quote in the paperSubstantial claim - Premisecitation
The first in-human senolytic trial (D+Q), the Hematopoietic Stem Cell Transplant Survivors Study, is still underway (NCT02652052; first patient dosed 1 April 2016).
“The first in-human trial of senolytics (D + Q), the Hematopoietic Stem Cell Transplant Survivors Study, is still underway (NCT02652052; first patient dosed on 1 April 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites NCT02652052
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- May combine two claims. 63
- The quote only partly states this claim. 1
- Classified as probably not a substantial claim. 15
May combine two claims.
PremisecitationThe Geroscience Hypothesis holds that the pillars of aging, including cellular senescence, tend to progress together and may be root-cause contributors to multiple diseases, age-related dysfunction, and loss of resilience.
“The Geroscience Hypothesis holds that these pillars of aging, including cellular senescence, tend to progress in concert and may be root-cause contributors to the pathophysiology of multiple diseases”
Quote in the paperSubstantial claim5 of 5 sources checked- cites [3] Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014). source
“The Pillars of Aging” section describes the seven pillars as highly intertwined processes that promote aging, and the introduction presents aging as a common driver of chronic disease. The paper also discusses cellular senescence and its potential adverse effects. It does not establish that the pillars progress together over time or that cellular senescence itself is a root-cause contributor to multiple diseases; no page numbers are available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [15] Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). source
- cites [16] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science 373, eabe4832 (2021). source
The Discussion (page unavailable) identifies cellular senescence as a pillar of aging and says that targeting fundamental aging mechanisms can improve health span and resilience. The Abstract (page unavailable) links senescent-cell accumulation to loss of resilience and predisposition to many diseases. Neither passage says that the pillars of aging progress in concert, so that part of the attributed claim is unsupported. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [17] Hadley, E. C., Kuchel, G. A., Newman, A. B. & Workshop Speakers and Participants. Report: NIA workshop on measures of physiologic resiliencies in human aging. J. Gerontol. A Biol. Sci. Med. Sci. 72, 980–990 (2017). source
The “Influence of Biologic Aging Mechanisms on Resilience” section identifies cellular senescence as a mechanism that could affect several types of resilience, and “Mechanistic Studies” says aging mechanisms may influence a wide variety of outcomes. Our copy does not say that the pillars of aging progress in concert or establish them as root-cause contributors to multiple diseases. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [18] Dungan, C. M. et al. Senolytic treatment rescues blunted muscle hypertrophy in old mice. Geroscience https://doi.org/10.1007/s11357-022-00542-2 (2022). source
The Introduction links cellular senescence to age-related anabolic resistance in skeletal muscle, and the Discussion reports that reducing senescent cells enhances muscle growth in old mice. The paper does not state the broader Geroscience Hypothesis that pillars of aging progress together or contribute to the pathophysiology of multiple diseases (searched: “Geroscience Hypothesis,” “pillars of aging,” and “multiple diseases”). (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationAfter the first senolytic drugs were reported in 2015, preclinical results enabled early-phase clinical trials of senolytics, some of which have been published.
“After the first reports of senolytic drugs (agents that selectively eliminate senescent cells) in 2015 (ref. 14), promising results from preclinical studies have facilitated progression to early-phase clinical trials evaluating the safety and efficacy of senolytics, some of which have now been published (Table 1).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
- Rests on an assumption: Preclinical results in animal models predict human clinical outcomes for senolytic interventions.
May combine two claims.
PremisecitationOnce the senescent cell burden passes a threshold, further increases in proapoptotic/pro-inflammatory senescent cells may cause tissue destruction, disease progression, immune dysregulation, and a feed-forward loop of accumulation.
“Once senescent cell burden surpasses this threshold, continuing increases in proapoptotic/pro-inflammatory senescent cell burden may contribute to tissue destruction and hence development or progression of multiple diseases and age-related disorders (Table 2) as well as immune dysregulation, further amplifying senescent cell accumulation in a feed-forward loop36,38,62.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [36] Lagnado, A. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 40, e106048 (2021). source
The Introduction links chronic exposure to the senescence-associated inflammatory response with age-associated tissue dysfunction. Results §5 proposes a vicious cycle in the liver: senescent cells recruit neutrophils, which may amplify senescence. The paper does not establish a burden threshold or support the broader claim of immune dysregulation and progression of multiple diseases through that loop; no page numbers are available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [38] Yousefzadeh, M. J. et al. An aged immune system drives senescence and ageing of solid organs. Nature 594, 100–105 (2021). source
The Abstract describes senescent cells as pro-inflammatory and tissue damaging and links them to age-related diseases. The “Rapamycin rejuvenates immune cells” section reports that immune-cell senescence impairs immunity and drives senescence in solid organs. Neither passage establishes a burden threshold, describes these cells as proapoptotic, or identifies the claimed feed-forward loop of accumulation; page numbers are not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [62] Prata, L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin. Immunol. 40, 101275 (2018). source
May combine two claims.
PremisecitationIn the other 30-70% of senescent cells, the SASP appears to contain growth and regenerative factors, may cause less apoptosis, tissue destruction, and fibrosis, and can contribute to tissue repair via factors such as VEGF-A and PDGF-AA.
“In the other 30–70% of senescent cells, the SASP appears to comprise growth and other regenerative factors, potentially causing less apoptosis, tissue destruction and fibrosis than proapoptotic, pro-inflammatory senescent cells and can even contribute to tissue repair (for example, through the growth factors VEGF-A and PDGF-AA)61,65.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [61] Tripathi, U., Misra, A., Tchkonia, T. & Kirkland, J. L. Impact of senescent cell subtypes on tissue dysfunction and repair: importance and research questions. Mech. Ageing Dev. 198, 111548 (2021). source
In “Anti-apoptotic defenses vary among senescent cells” (page unavailable), the paper estimates that deleterious cells may comprise 30–70% of senescent cells and says the remaining helper cells release fewer pro-apoptotic factors and might aid wound healing through PDGF-AA. “Type of inducers” (page unavailable) also describes VEGF secretion by senescent fibroblasts, but does not identify those fibroblasts as helper cells. The paper does not specifically say that helper cells cause less fibrosis than deleterious cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [65] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). source
The Discussion (page unavailable) reports that senescent cells accelerate cutaneous wound healing through PDGF-AA secretion and help restrain fibrosis. The Results (page unavailable) also report increased VEGF mRNA in wounds, but do not establish VEGF-A as a repair mechanism. The paper does not support the 30–70% estimate or the comparison involving less apoptosis and tissue destruction. (LLM, conf=0.89)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationTargeting cellular senescence and other aging pillars, rather than individual downstream diseases, could reduce multimorbidity and increase healthspan with societal and economic benefits.
“By understanding and targeting cellular senescence and the other pillars of aging, rather than targeting individual diseases that are downstream of fundamental aging processes, it is conceivable that multimorbidity could be reduced and healthspan increased, with realization of substantial societal and economic benefits4,6.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [4] Scott, A. J., Ellison, M. & Sinclair, D. A. The economic value of targeting aging. Nat. Aging 1, 616–623 (2021). source
The Conclusion says delaying aging could affect many diseases, improve health and longevity, and yield large economic gains compared with treating specific diseases. The Results section likewise links targeting aging to age-related comorbidities and longer healthy life. The paper takes an economic rather than biological perspective, however, and these passages do not establish the claim specifically about targeting cellular senescence and other aging pillars. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [6] Tchkonia, T., Palmer, A. K. & Kirkland, J. L. New horizons: novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J. Clin. Endocrinol. Metab. 106, e1481–e1487 (2021). source
- Rests on an assumption: Preclinical results in animal models predict human clinical outcomes for senolytic interventions.
May combine two claims.
PremisecitationTransient senescent cells can have beneficial functions: their SASPs can orchestrate tissue remodeling, induce immune responses during infection or injury, promote parturition via placental senescent cells, and attract immune cells to clear pro-inflammatory senescent cells.
“If senescent cells are present transiently, beneficial functions of both the proapoptotic and pro-growth types of SASP can orchestrate tissue remodeling”
Quote in the paperSubstantial claim5 of 6 sources checked- cites [10] Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014). source
- cites [11] Suvakov, S. et al. Epigenetic and senescence markers indicate an accelerated ageing-like state in women with preeclamptic pregnancies. EBioMedicine 70, 103536 (2021). source
The Introduction says physiological senescence prevents proliferation of damaged cells, and the Discussion says senescence is critical for embryogenesis. Neither passage addresses transient senescent cells, proapoptotic or pro-growth SASP, or SASP-driven tissue remodeling. Searches for tissue remodeling, parturition, and immune-cell clearance found no supporting passage in our copy; page numbers were unavailable. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [14] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [61] Tripathi, U., Misra, A., Tchkonia, T. & Kirkland, J. L. Impact of senescent cell subtypes on tissue dysfunction and repair: importance and research questions. Mech. Ageing Dev. 198, 111548 (2021). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [62] Prata, L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin. Immunol. 40, 101275 (2018). source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [65] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIf a threshold burden of senescent cells is exceeded, they can accumulate, possibly because proapoptotic SASP cells spread senescence by paracrine and endocrine mechanisms faster than immune clearance.
“However, if a threshold burden of senescent cells is exceeded, senescent cells can accumulate, perhaps because proapoptotic SASP-expressing senescent cells induce paracrine and endocrine spread of senescence at a rate exceeding immune clearance of preexisting and newly formed senescent cells24,62”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Results report increased senescence markers in recipients’ own cells after transplantation and findings consistent with spread to distant tissues; they also say the SASP may induce senescence spreading in vivo. The Introduction says senescent-cell burden increases with aging. Our copy does not establish a threshold burden, identify proapoptotic SASP-expressing cells as the cause, or compare the rate of spread with immune clearance. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [62] Prata, L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin. Immunol. 40, 101275 (2018). source
May combine two claims.
PremisecitationIn 30-70% of senescent cells, the SASP contains pro-inflammatory, proapoptotic, and pro-fibrotic factors, some of which can make previously non-senescent cells senescent locally and at a distance through endocrine action.
“In 30–70% of senescent cells, this SASP entails pro-inflammatory, proapoptotic and pro-fibrotic factors7,31,40,59–64, some of which can cause previously non-senescent cells to become senescent both locally and at a distance in an endocrine manner24,39,47.”
Quote in the paperSubstantial claim10 of 10 sources checked- cites [7] Kirkland, J. L. & Tchkonia, T. Cellular senescence: a translational perspective. EBioMedicine 21, 21–28 (2017). source
The Abstract describes the SASP as pro-inflammatory and tissue-destructive, section 4 calls it pro-apoptotic, and section 6 says it appears to contribute to pulmonary fibrosis. Our copy does not give the 30–70% figure or say that SASP factors induce senescence in previously non-senescent cells locally or at a distance through endocrine action. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [31] Iske, J. et al. Senolytics prevent mtDNA-induced inflammation and promote the survival of aged organs following transplantation. Nat. Commun. 11, 4289 (2020). source
The Introduction identifies pro-inflammatory cytokines as part of the SASP, and the Discussion says the SASP induces senescence locally and systemically. Neither passage establishes the 30–70% figure or describes SASP factors as proapoptotic or pro-fibrotic; the paper also does not specify an endocrine mechanism. The supplied copy gives no page numbers for these sections. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [40] Hernandez-Segura, A., Nehme, J. & Demaria, M. Hallmarks of cellular senescence. Trends Cell Biol. 28, 436–453 (2018). source
The paper defines paracrine senescence as senescence induced by a primary senescent cell’s SASP (Box 1; page unavailable), and describes inflammatory and tissue-remodeling SASP factors (DNA damage response; page unavailable). It does not give the 30–70% figure or establish that SASP factors induce senescence at a distance through endocrine action; its example of a distal effect concerns cancer-cell proliferation. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [59] Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020). source
The Introduction describes SASP cytokines, chemokines, growth factors, and proteases that initiate inflammation in nearby cells, and the Results identify inflammatory factors in the secretome. But the paper does not say that 30–70% of senescent cells have a SASP containing proapoptotic and pro-fibrotic factors. Its reported percentages concern other measures, such as the proportion of cells induced to senesce by a treatment. The endocrine-senescence clause carries separate citations in the citing sentence. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [60] Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010). source
The ‘Soluble Signaling Factors’ section (page not available) describes inflammatory SASP cytokines and a secreted factor that can induce senescence and apoptosis in neighboring cells. It does not establish that 30–70% of senescent cells have a SASP containing all three stated classes of factors, particularly pro-fibrotic factors. The local-and-distant endocrine claim has a separate citation group in the citing sentence and is not assessed against this source. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [61] Tripathi, U., Misra, A., Tchkonia, T. & Kirkland, J. L. Impact of senescent cell subtypes on tissue dysfunction and repair: importance and research questions. Mech. Ageing Dev. 198, 111548 (2021). source
The “Anti-apoptotic defenses vary among senescent cells” section says pro-inflammatory and pro-apoptotic D-senescent cells may comprise about 30–70% of senescent cells, based on unpublished observations; it does not include pro-fibrotic factors in that description. The “Endocrine and paracrine impact of the SASP” section says SASP factors can spread senescence to previously normal cells locally and in distant organs. The claim is therefore supported in part, but states the tentative percentage more firmly and adds an unsupported pro-fibrotic component. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [62] Prata, L., Ovsyannikova, I. G., Tchkonia, T. & Kirkland, J. L. Senescent cell clearance by the immune system: emerging therapeutic opportunities. Semin. Immunol. 40, 101275 (2018). source
The SASP section says senescent cells can affect nearby and distant cells through the SASP, including by spreading senescence, and describes inflammatory SASP factors. It does not give the 30–70% figure or characterize the factors as proapoptotic and pro-fibrotic. Although it mentions effects on endocrine function, it does not specify endocrine action as the mechanism by which senescence spreads at a distance. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [63] Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019). source
The Introduction (page not provided) describes the SASP as containing pro-fibrotic factors and contributing to a pro-inflammatory response; it also says senescent cells release pro-apoptotic factors as part of their SASP. Our copy does not support the cited clause’s 30–70% figure. The claim about inducing senescence locally and at a distance has separate citations in the citing sentence and is not attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [64] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). source
The SASP and Figure 2 passages describe inflammatory SASP factors and suggest that senescence can spread to neighboring cells. They do not establish the 30–70% figure, characterize SASP factors as proapoptotic or pro-fibrotic, or show that they induce senescence at a distance through endocrine action; the paper also frames spreading senescence as a possibility needing further investigation. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Results (page unavailable) report increased senescence markers in distant muscle after senescent-cell transplantation, and the Discussion proposes spread of senescence locally and to distant tissues. This supports the locally-and-at-a-distance part of the claim, but the paper presents spreading as a possible explanation rather than establishing that specific SASP factors cause it through endocrine action. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationActivated macrophages, which may not be classically senescent, can have high p16 expression but are not targeted by dasatinib plus quercetin.
“cell types such as activated macrophages, which may not be classically senescent, can have high p16INK4a expression100, but are not targeted by D + Q24.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [100] Hall, B. M. et al. p16Ink4a and senescence-associated beta-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging 9, 1867–1884 (2017). source
- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Results report that D+Q did not significantly reduce p16INK4A-positive macrophages in human adipose-tissue explants, and the Discussion describes little direct effect on macrophages. The paper does not specifically test activated macrophages, and its acute explant findings do not establish that D+Q never targets them. (LLM, conf=0.82)
Experimental — accuracy not yet measured
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PremisecitationIn commonly used preclinical models, senescence is abolished by p16- or p21-based genetic clearance, which acts through mechanisms distinct from first-generation SCAP-targeting small-molecule senolytics, leading to differences in targeted senescent cell types.
“in commonly used preclinical models, senescence is abolished by means of p16INK4a-based or p21CIP1/WAF1-based genetic clearance and this senescence-targeting approach acts through mechanisms that are distinct from first-generation, SCAP-targeting small-molecule senolytics; as a result, there appear to be differences in the types of senescent cells targeted.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [100] Hall, B. M. et al. p16Ink4a and senescence-associated beta-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging 9, 1867–1884 (2017). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured - cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
FindingcitationSenescent mesenchymal embryonic fibroblasts from Ercc1−/− mice and bone marrow mesenchymal progenitors from old mice are not eliminated by dasatinib or quercetin alone but are eliminated by their combination.
“senescent mesenchymal embryonic fibroblasts from Ercc1−/− mice and bone marrow mesenchymal progenitors from old mice are not eliminated by either D or Q alone, but are eliminated by the combination of these agents14.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
The Results section, “Dasatinib and quercetin reduce senescent cells in vivo” (page unavailable), reports that the combination significantly reduced senescent mouse embryonic fibroblasts compared with either drug alone. It also reports that quercetin alone significantly reduced senescent bone marrow-derived mesenchymal stem cells, contrary to the claim that neither drug alone eliminates them. (LLM, conf=0.90)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThese immune-targeting approaches eliminate senescent cells, but in some cases also affect activated macrophages and other non-senescent cell types.
“Each of these approaches eliminates senescent cells, although in some cases, activated macrophages and other non-senescent cell types are also affected96–99.”
Quote in the paperNot a substantial claim3 of 4 sources checked- cites [96] Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020). source
The paper reports that uPAR-directed CAR T cells eliminate senescent cells and that supratherapeutic doses cause macrophage accumulation and activation (Abstract, page unavailable). It also notes uPAR expression in monocytes, macrophages, neutrophils and bronchial epithelium, but does not show that those naturally occurring non-senescent cells were eliminated or otherwise affected by treatment. Its killing experiment used non-senescent leukemia cells engineered to express uPAR. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [97] Yoshida, S. et al. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat. Commun. 11, 2482 (2020). source
The Results (page unavailable) report reduced accumulation of senescent T cells in vaccinated mice and show that vaccine-induced antibodies killed LPS-stimulated macrophage cells in a complement-dependent assay. The paper does not establish effects on other non-senescent cell types, so it supports only part of the sentence attributed to this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [98] Suda, M. et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat. Aging 1, 1117–1126 (2021). source
- cites [99] Poblocka, M. et al. Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker. Sci. Rep. 11, 20358 (2021). source
The Introduction and Results report that the antibody–drug conjugate kills senescent cells. They do not report effects on activated macrophages or other non-senescent cell types; the Introduction instead says the tested treatment showed no toxicity to proliferating cells. The Discussion raises off-target effects as a possibility requiring further study, not an observed result. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationHSP90 prevents proteasomal degradation of AKT; inhibiting HSP90 disables pro-survival signaling through this SCAP node and eliminates some senescent cell types.
“HSP90 prevents proteasomal degradation of AKT, hence inhibiting HSP90 disables pro-survival signaling through this SCAP node and results in elimination of some senescent cell types54.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [54] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). source
The Results section reports that HSP90 inhibition reduced active p-AKT and led to apoptosis in senescent cells; the Discussion says downregulating this survival pathway may contribute to senolytic activity. The paper does not establish that HSP90 prevents proteasomal degradation of AKT: it reports that total AKT was unchanged by the inhibitor. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationCertain cell surface proteins are more highly expressed by senescent cells than most other cell types, prompting development of CAR T cells, vaccines, and antibody-drug conjugates targeting these markers.
“Certain cell surface proteins tend to be more highly expressed by senescent cells than most other cell types, which prompted development of engineered chimeric antigen receptor (CAR) T cells, vaccines and antibody–drug conjugates targeting these cell surface markers.”
Quote in the paperSubstantial claim3 of 4 sources checked- cites [96] Amor, C. et al. Senolytic CAR T cells reverse senescence-associated pathologies. Nature 583, 127–132 (2020). source
The paper’s Abstract reports that surface proteins are upregulated in senescent cells and that the authors developed uPAR-targeting CAR T cells. It does not report the development of vaccines or antibody–drug conjugates targeting those markers, so those parts of the attributed claim are unsupported. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [97] Yoshida, S. et al. The CD153 vaccine is a senotherapeutic option for preventing the accumulation of senescent T cells in mice. Nat. Commun. 11, 2482 (2020). source
The Discussion (page unavailable) describes a vaccine targeting CD153 on senescent T cells, supporting the vaccine example. The paper does not report CAR T cells or antibody–drug conjugates, and it does not establish that senescent cells generally express these surface proteins more highly than most other cell types. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [98] Suda, M. et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nat. Aging 1, 1117–1126 (2021). source
- cites [99] Poblocka, M. et al. Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker. Sci. Rep. 11, 20358 (2021). source
The Introduction describes membrane proteins upregulated in senescent cells, and the Introduction and Discussion describe developing an antibody–drug conjugate targeting one of those markers. The cited paper does not support the claim that these markers prompted development of CAR T cells or vaccines; those approaches are not described in the passages retrieved for those terms. The paper also notes that senescent-cell markers are not specific and universal. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn some senescent cell types, SCAPs are redundant, so targeting one SCAP may not eliminate the cells, but targeting multiple SCAPs in combination may be effective.
“In some types of senescent cells, SCAPs can be redundant, so that targeting a single SCAP may not eliminate such cells—but combination treatment targeting multiple SCAPS may be effective.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
The Discussion (page unavailable) says dasatinib and quercetin generally work better together than individually and proposes drug combinations to target anti-apoptotic networks. The Results (page unavailable) report that the combination reduced senescent mouse embryonic fibroblasts more than either drug alone. The paper does not establish that redundancy among SCAPs is why targeting a single pathway may fail. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationWork to develop senolytics began before genetic models of senescent cell clearance were published and did not depend on those models.
“Indeed, work to develop senolytics began before genetic models of senescent cell clearance were published and did not depend on those models34,56.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [34] Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020). source
The “Discovery of senolytic drugs” section says the authors began trying to remove senescent cells in 2005, prompted by a 2004 study, and describes a later drug-discovery strategy based on apoptosis resistance. This supports an independent starting point, but the passages do not establish when genetic clearance models were published, so the claimed publication order is not verified by this source. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [56] Wissler Gerdes, E. O., Zhu, Y., Tchkonia, T. & Kirkland, J. L. Discovery, development, and future application of senolytics: theories and predictions. FEBS J. 287, 2418–2427 (2020). sourceExperimental — accuracy not yet measured
May combine two claims.
PremisecitationThe SASP is dynamic, changes over time, and varies with the type of senescent cell and how senescence was induced.
“The SASP of senescent cells is not static; it can change over time78–80 and varies depending on the type of cells that became senescent and how senescence was induced16,44,59,60,81.”
Quote in the paperNot a substantial claim8 of 8 sources checked- cites [78] Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016). sourceExperimental — accuracy not yet measured
- cites [79] De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). sourceExperimental — accuracy not yet measured
- cites [80] Zhao, Y. et al. Transposon-triggered innate immune response confers cancer resistance to the blind mole rat. Nat. Immunol. 22, 1219–1230 (2021). source
The citation is attached to the claim that SASP varies by senescent cell type and mode of induction. The Results section and Extended Data Fig. 1 report SASP activation in over-proliferating blind mole rat cells, but do not compare SASP across senescent cell types or induction methods. I searched the indexed copy for those comparisons; no passage establishes the attributed variation. (LLM, conf=0.70)
Experimental — accuracy not yet measured - cites [16] Camell, C. D. et al. Senolytics reduce coronavirus-related mortality in old mice. Science 373, eabe4832 (2021). sourceExperimental — accuracy not yet measured
- cites [44] Tripathi, U. et al. SARS-CoV-2 causes senescence in human cells and exacerbates the senescence-associated secretory phenotype through TLR-3. Aging 13, 21838–21854 (2021). source
The Results section shows that viral exposure and TLR-3 activation amplify SASP factors in senescent human cells, supporting the point that the SASP is not fixed. The cited paper does not establish the broader claim that SASP composition varies according to cell type or how senescence was induced. In the citing sentence, the separate claim about change over time is attached to other citations. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [59] Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020). sourceExperimental — accuracy not yet measured
- cites [60] Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010). sourceExperimental — accuracy not yet measured
- cites [81] Decout, A., Katz, J. D., Venkatraman, S. & Ablasser, A. The cGAS–STING pathway as a therapeutic target in inflammatory diseases. Nat. Rev. Immunol. 21, 548–569 (2021). source
The ‘cGAS–STING in senescence and ageing’ section describes SASP secretion and a role for cGAS–STING across multiple types of senescent cells. It does not say that the SASP changes over time or varies by cell type or how senescence was induced; searches for those distinctions found no supporting passage. (LLM, conf=0.74)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationA recent report shows that removing senescent cells expressing high p16 can lead to fibrosis in mice, whereas small-molecule senolytics appear to reduce fibrosis in several mouse tissues.
“This is in agreement with a recent report showing that the removal of senescent cells expressing high levels of p16INK4a can lead to fibrosis in mice101, whereas small-molecule senolytics appear to reduce fibrosis in several mouse tissues22,71,73,75,102.”
Quote in the paperSubstantial claim5 of 6 sources checked- cites [101] Grosse, L. et al. Defined p16high senescent cell types are indispensable for mouse healthspan. Cell Metab. 32, 87–99 (2020). source
- cites [22] Moncsek, A. et al. Targeting senescent cholangiocytes and activated fibroblasts with B cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/−) mice. Hepatology 67, 247–259 (2018). source
- cites [71] Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017). source
The Results section (‘Senescent cell clearance mitigates fibrotic lung disease’; page unavailable) reports that the small-molecule senolytic dasatinib plus quercetin improved lung function in bleomycin-injured mice. But reductions in lung fibrosis on histopathology did not reach statistical significance, and this paper does not establish reduced fibrosis across several mouse tissues. The separate claim that removing p16-expressing cells can cause fibrosis is attached to citation 101, not this source. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [73] Cavalcante, M. B. et al. Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice. Aging 12, 2711–2722 (2020). source
The Introduction and Discussion describe anti-fibrotic effects of dasatinib and quercetin in several tissues, supporting the general point attributed to this source. But this paper’s own mouse experiment found no significant reduction in uterine fibrosis with treatment (Results; treatment effect P = 0.503). This citation does not support the clause about removing p16INK4a-high cells, which is attached to a different reference. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [75] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source
Citation 102 is attached to the claim that small-molecule senolytics reduce fibrosis in several mouse tissues. The Results section, “Senescent cell clearance decreases liver fat accumulation” (page unavailable), reports that dasatinib plus quercetin reduced hepatic fat deposition, not fibrosis. Searches for fibrosis and fibrotic outcomes found no passage in our copy reporting the claimed reduction. (LLM, conf=0.78)
Experimental — accuracy not yet measured - cites [102] Kim, S. R. et al. Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin. Transl. Res. 213, 112–123 (2019). source
May combine two claims.
PremisecitationFOXO4 retains p53 in the nucleus, so peptides that interfere with this interaction can cause p53-mediated apoptosis in some senescent cells.
“forkhead box O4 (FOXO4) retains p53 in the nucleus, so peptides interfering with this interaction can lead to p53-mediated apoptosis in some types of senescent cells87.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [87] Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147 (2017). source
May combine two claims.
FindingcitationSenescent human fat cell progenitors are sensitive to dasatinib but not quercetin or fisetin, while senescent human umbilical vein endothelial cells are sensitive to quercetin or fisetin but not dasatinib.
“senescent human fat cell progenitors (preadipocytes or mesenchymal stromal cells) are sensitive to D but not Q or F, while senescent human umbilical vein endothelial cells are sensitive to Q or F but not D14.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [14] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015). source
In Results (‘Candidate senolytic drugs in vitro’; page unavailable), dasatinib preferentially killed senescent human preadipocytes and was much less effective on HUVECs, while quercetin preferentially killed senescent HUVECs and was less effective on preadipocytes. The paper does not support the claim about fisetin, and ‘less effective’ does not establish the categorical ‘not sensitive’ claims. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims. The quote only partly states this claim.
InterpretationcitationBecause genetic models cannot eliminate the naturally occurring heterogeneous senescent cell pool and also target non-senescent cells such as activated macrophages, they are of limited use for assessing translational potential of senolytic agents, though useful for mechanistic insights.
“these genetic models are of limited use to assess the translational potential of senolytic agents—but are useful for mechanistic insights nonetheless.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [100] Hall, B. M. et al. p16Ink4a and senescence-associated beta-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli. Aging 9, 1867–1884 (2017). source
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationCellular senescence is implicated in Down syndrome, and senolytics may have beneficial effects for it.
“A recent study implicated cellular senescence and the beneficial effects of senolytics for Down syndrome (trisomy 21)13.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Meharena, H. S. et al. Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors. Cell Stem Cell 29, 116–130 (2022). source
May combine two claims.
PremisecitationMetformin inhibits the SASP and alleviates several age-related conditions and chronic diseases.
“The antidiabetic drug metformin, which, among other activities, inhibits the SASP, alleviates several age-related conditions and chronic diseases110–114.”
Quote in the paperNot a substantial claim4 of 5 sources checked- cites [110] Novelle, M. G., Ali, A., Dieguez, C., Bernier, M. & de Cabo, R. Metformin: a hopeful promise in aging research. Cold Spring Harb. Perspect. Med. 6, a025932 (2016). source
- cites [111] Hansel, C. et al. Metformin protects against radiation-induced acute effects by limiting senescence of bronchial-epithelial cells. Int. J. Mol. Sci. 22, 7064 (2021). source
The Introduction (page not available) says metformin inhibits the SASP and has been shown to alleviate aging-associated cellular senescence. It describes alleviating aging-related diseased phenotypes as a potential benefit of SASP inhibitors, but does not establish that metformin alleviates several age-related conditions and chronic diseases. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [112] Deschenes-Simard, X. et al. Circumventing senescence is associated with stem cell properties and metformin sensitivity. Aging Cell 18, e12889 (2019). source
The Results section, ‘Metformin targets reprogrammed pancreatic cancer cells’ (page unavailable), reports reduced tumor-sphere formation after metformin treatment. The Discussion, ‘The transition from PanIN’ (page unavailable), reports delayed pancreatic tumorigenesis in mice. Neither passage shows that metformin inhibits the SASP or establishes that it alleviates several age-related conditions and chronic diseases. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [113] Kulkarni, A. S., Gubbi, S. & Barzilai, N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 32, 15–30 (2020). source
The section on cellular senescence reports that metformin suppresses SASP in several age-associated settings, but also says its effect is context-dependent and can increase SASP-related expression in some cancer settings. The Introduction reports clinical benefits for diabetes and cardiovascular disease, while evidence for several other age-related diseases is described largely as associations with lower incidence; the unqualified claim that metformin alleviates them overstates that evidence. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [114] Fang, J. et al. Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 17, e12765 (2018). source
The Introduction reports that metformin can alleviate various age-associated disorders, including cardiovascular disease, cancer, and cognitive decline. The Results and Discussion report reduced cellular senescence with metformin, but the passages found do not establish that it inhibits the SASP specifically. Page numbers were not available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationD, Q, and F have brief half-lives in humans (4, 11, and 3-4 hours) and rapid elimination, which are advantages over some other senolytics.
“the advantages of D, Q or F over some other senolytics are their brief half-lives (4, 11 or 3–4 h, respectively, in humans) and rapid elimination120–122.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [120] Christopher, L. J. et al. Metabolism and disposition of dasatinib after oral administration to humans. Drug Metab. Dispos. 36, 1357–1364 (2008). source
- cites [121] Graefe, E. U. et al. Pharmacokinetics and bioavailability of quercetin glycosides in humans. J. Clin. Pharm. 41, 492–499 (2001). source
- cites [122] Touil, Y. S. et al. Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. Biochem. Pharmacol. 82, 1731–1739 (2011). source
Section 3.1 (p. 13) reports a 3.12-hour terminal half-life for fisetin, but this was measured in mice after intraperitoneal dosing, not in humans. The Discussion (p. 18) emphasizes species differences in elimination. This paper does not establish a human half-life or show that rapid elimination is an advantage over other senolytics; the dasatinib and quercetin figures are not attributed to this source specifically. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationOral D+Q reduces neuroinflammation, increases neurogenesis markers, reduces gliosis, and alleviates anxiety in obese mice.
“Oral D + Q reduces this neuroinflammation, increases markers of neurogenesis, reduces gliosis and alleviates anxiety in obese mice33.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [33] Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1061–1077 (2019). source
The Methods report oral gavage of D+Q in obese db/db mice. The Results report improved anxiety-like behavior, increased neurogenesis markers, and reduced lipid-laden, senescent glial cells after D+Q. They also report reduced circulating inflammatory factors, but do not show that D+Q reduced neuroinflammation in the brain or gliosis generally. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn mouse models of diet-induced obesity, D+Q reduces adipose senescent cell burden, attenuates adipose inflammation, alleviates metabolic dysfunction, and restores preadipocyte differentiation into insulin-responsive fat cells.
“In mouse models of diet-induced obesity, reducing the burden of senescent cells in adipose tissue by administering D + Q attenuates adipose tissue inflammation, alleviates metabolic dysfunction, and restores the capacity of preadipocytes to differentiate into functional, mature, insulin-responsive fat cells25.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [25] Palmer, A. K. et al. Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18, e12950 (2019). source
The Results sections on senescent-cell clearance and adipogenic potential report reduced adipose senescence, improved glucose control and insulin sensitivity, and higher adipogenic gene expression after D + Q in diet-induced obese mice. The inflammation findings in diet-induced obese mice chiefly follow genetic senescent-cell clearance; the D + Q macrophage-homing experiment used db/db mice. The paper also suggests that progenitors can differentiate into insulin-responsive fat cells, but does not directly demonstrate that D + Q restores differentiation into functional, mature insulin-responsive cells. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationRapamycin and rapalogs suppress the SASP by inhibiting mTOR and appear to extend healthspan and lifespan in mice.
“Rapamycin and its analogs (so-called ‘rapalogs’) suppress the SASP by inhibiting mTOR and appear to extend healthspan and lifespan in mice105,108,109.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [105] Lamming, D. W., Ye, L., Sabatini, D. M. & Baur, J. A. Rapalogs and mTOR inhibitors as anti-aging therapeutics. J. Clin. Invest. 123, 980–989 (2013). source
The review’s “Effects of rapamycin on longevity” section (page unavailable) reports that rapamycin extends mouse lifespan, and it describes delays in several age-related changes in mice. But our copy does not report suppression of the SASP, nor does it establish that rapalogs extend mouse healthspan or lifespan; its conclusion calls for further testing of mTOR-targeting strategies. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [108] Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009). source
The Abstract (page unavailable) reports that rapamycin inhibits the mTOR pathway and extends median and maximal lifespan in genetically heterogeneous mice. It does not report SASP suppression, effects of rapalogs, or an extension of healthspan; it says that whether mTOR inhibition alters other aspects of ageing remains to be tested. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [109] Neff, F. et al. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 123, 3272–3291 (2013). source
The Results (p. 2) confirm that rapamycin extended lifespan in mice, and the Introduction (p. 1) identifies it as an mTOR inhibitor. But the paper does not establish SASP suppression or effects of rapalogs, and its Discussion (p. 13) reports that many aging phenotypes were not improved; it therefore does not support a broad healthspan benefit. (LLM, conf=0.90)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationD+Q treatment of old donor mice, harvested organs, or recipients reduces senescent cell burden and increases recipient survival, resembling young-donor transplant outcomes.
“D + Q treatment of either old donor mice, the organs harvested from the old donors before transplantation, or the recipients, led to decreased senescent cell burden and increased survival of recipient mice – so that outcomes resembled those observed in mice receiving a transplant from a young donor31.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [31] Iske, J. et al. Senolytics prevent mtDNA-induced inflammation and promote the survival of aged organs following transplantation. Nat. Commun. 11, 4289 (2020). source
The Results sections on senolytics report that D+Q reduced senescent-cell markers in old mice and that treating old donors prolonged cardiac graft survival; with recipient CTLA4-Ig treatment, graft survival was comparable to that of hearts from young donors (pages unavailable). The paper does not report D+Q treatment of harvested organs or transplant recipients, and the survival outcome measured was graft survival, not recipient-mouse survival. (LLM, conf=0.90)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationreasoningRapamycin's prolonged effect may result from inhibiting SASP-mediated spread of senescence, allowing the immune system to reduce senescent cell burden, consistent with the Unitary Theory.
“This may be a result of inhibiting SASP-mediated spread of senescence, thereby allowing the innate and adaptive immune system to further reduce senescent cell burden, consistent with the Unitary Theory (Fig. 2).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [116] Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018). source
- cites [117] Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife 5, e16351 (2016). source
The Results report that rapamycin-fed mice retained better grip strength and Rotarod performance 90 days after treatment ended, supporting a prolonged effect. The paper does not attribute that effect to inhibition of SASP-mediated senescence spread, immune clearance of senescent cells, or the Unitary Theory. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Classified as probably not a substantial claim.
PremisecitationApoptosis of transplanted mesenchymal stromal cells is required for their therapeutic effects, possibly through downstream immunosuppressive effects of apoptotic processes.
“The study suggested that apoptosis of mesenchymal stromal cells is required for their therapeutic effects, possibly by means of downstream immunosuppressive effects of apoptotic processes123.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [123] Pang, S. H. M. et al. Mesenchymal stromal cell apoptosis is required for their therapeutic function. Nat. Commun. 12, 6495 (2021). source
May combine two claims.
PremisecitationIn aged osteoporotic mice, D+Q reduces bone-resorbing osteoclasts, increases bone-forming osteoblasts, and restores bone mass.
“In age-related osteoporosis linked to senescent-like osteocytes and bone marrow cells in mice, D + Q reduced development of bone-resorbing osteoclasts, while increasing differentiated bone-forming osteoblasts, with restoration of bone mass21.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [21] Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017). source
The D+Q results (Abstract; page unavailable in our copy) report improved bone microarchitecture and fewer osteoclasts in aged mice. Osteoblast numbers increased on the endocortical surface, but did not change in trabecular bone. The reported osteoclast counts do not establish that D+Q reduced osteoclast development. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationTransplanting senescent cells reduces healthspan and lifespan in preclinical models, while eliminating transplanted or endogenous senescent cells increases healthspan, satisfying Koch's postulates for causality.
“Whereas transplanting senescent cells decreases healthspan and lifespan in preclinical models, eliminating transplanted or endogenous senescent cells increases healthspan, thereby fulfilling Koch’s postulates for causality24,124.”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Results report that senescent-cell transplantation caused physical dysfunction and increased mortality in mice. The Discussion reports that senolytics alleviated transplantation-induced dysfunction and that clearing senescent cells improved physical function and remaining lifespan in old mice. It describes this evidence as satisfying a *modified set* of Koch’s postulates, rather than Koch’s postulates without qualification. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [124] Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018). source
The Introduction (page unavailable) reports that injecting senescent cells causes frailty and decreased survival in mice, while clearing senescent cells from aging mice has therapeutic benefits. The Results (page unavailable) report improved age-related pathology and longer lifespan after fisetin treatment. Our copy does not state that eliminating transplanted cells improves healthspan or that these findings fulfill Koch’s postulates. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn a mouse model of idiopathic pulmonary fibrosis, D+Q improves lung compliance and reduces frailty.
“in a mouse model of idiopathic pulmonary fibrosis (IPF), D + Q treatment improved lung compliance and reduced frailty71.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [71] Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017). source
The Results section, “Senescent cell clearance mitigates fibrotic lung disease” (page unavailable), reports that D+Q limited the bleomycin-induced reduction in mouse lung compliance and improved weight retention and treadmill performance. These physical-health measures are consistent with reduced frailty, but the paper does not report a direct frailty assessment. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationSome SASP inhibitors have agent-specific off-target effects; rapamycin can cause nephrotoxicity, metabolic impairment, and infection susceptibility at higher doses in mice.
“some SASP inhibitors can have agent-specific off-target effects, for example, rapamycin, which can cause nephrotoxicity, metabolic impairment and susceptibility to infections, at least at higher doses in mice109.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [109] Neff, F. et al. Rapamycin extends murine lifespan but has limited effects on aging. J. Clin. Invest. 123, 3272–3291 (2013). source
The Figure 8 text (p. 12) reports considerable nephrotoxicity, impaired glucose tolerance, and hypercholesterolemia in rapamycin-treated mice. The paper does not establish increased susceptibility to infections from rapamycin or show that these adverse effects occur specifically at higher doses; its mention of infection concerns age-related immune dysfunction (p. 10). (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationIn HFD-fed mice, oral D+Q reduces senescent hepatocyte burden and hepatic steatosis.
“In livers of HFD-fed mice, oral D + Q reduces the burden of senescent hepatocytes and hepatic steatosis75.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [75] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source
The Results (section “Senescent cell clearance decreases liver fat accumulation”; page unavailable) report that D+Q reduced senescence markers and liver fat in aged and db/db mice. In the high-fat-diet experiment, however, the treatment reported to reduce senescent hepatocyte markers and hepatic fat was AP, not D+Q. The Methods (Animals; page unavailable) specify oral gavage of D+Q for the db/db mice, so the claimed combination of oral D+Q and high-fat-fed mice is not supported. (LLM, conf=0.90)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationContinuous treatment with SASP inhibitors is needed to maintain SASP suppression, although rapamycin can have prolonged effects after a brief course.
“In the case of SASP inhibitors, continuous treatment is needed to maintain suppression of the SASP, although some agents, such as rapamycin, can have prolonged effects after a brief course of administration116,117.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [116] Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, eaaq1564 (2018). source
- cites [117] Bitto, A. et al. Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice. Elife 5, e16351 (2016). source
The Results report that healthspan benefits in middle-aged mice persisted 90 days after a three-month rapamycin course, supporting the claim that brief treatment can have prolonged effects. The paper does not establish that continuous treatment is needed to maintain SASP suppression, or that the persistent effects measured were SASP suppression. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationSenolytics can increase α-Klotho, which is geroprotective, neuroprotective, and linked to healthspan in mice.
“senolytics can increase α-Klotho, which is geroprotective, neuroprotective and linked to healthspan in mice19.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Zhu, Y. et al. Orally active, clinically translatable senolytics restore α-Klotho in mice and humans. EBioMedicine 77, 103912 (2022). source
May combine two claims.
PremisecitationFirst clinical trials of senolytics are being conducted in patients with serious conditions such as diabetic kidney disease, Alzheimer's disease, frailty, and IPF because human side effects are not fully known and to maximize benefit-risk.
“Because side effects of senolytics in humans are not yet fully known, and to maximize benefit–risk ratios, the first clinical trials are underway in patients with serious health conditions, such as diabetic kidney disease, Alzheimer’s disease, frailty and IPF34.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [34] Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020). source
May combine two claims.
Premisecitation17α-estradiol declines with aging in both sexes, and treatment extends healthspan and alleviates age-related metabolic dysfunction and inflammation in mice.
“The non-feminizing estrogen, 17α-estradiol, declines with aging in females and males and 17α-estradiol treatment extends healthspan and alleviates age-related metabolic dysfunction and inflammation in mice142.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [142] Stout, M. B. et al. 17α-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. J. Gerontol. A Biol. Sci. Med. Sci. 72, 3–15 (2017). source
The Abstract and Discussion (page numbers unavailable) report improved metabolic and inflammatory measures in aged male mice and describe 17α-estradiol as a potential way to improve healthspan. They do not report that endogenous 17α-estradiol declines with age in either sex, or establish that treatment extends healthspan; the reported lifespan extension is limited to male mice. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationSenescent cells can decrease NAD+ via SASP activation of CD38 on macrophages, and senolytics partially restore tissue NAD+ levels.
“Senescent cells can decrease NAD+ through SASP activation of the NAD-degrading enzyme CD38 on the surface of macrophages and, remarkably, senolytics partially restore tissue NAD+ levels139,140.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [139] Chini, C. C. S. et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels. Nat. Metab. 2, 1284–1304 (2020). source
The Results section on SASP-induced CD38 reports that secretions from senescent cells increased CD38 activity in macrophages and lowered NAD+ in mouse white adipose tissue. The Results section on cellular senescence reports that clearing senescent cells partly restored NAD+ in that tissue, but the experiment used genetic ablation in INK-ATTAC mice, not a senolytic treatment. The Discussion also notes that NAD+ recovery was much greater in the liver. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [140] Schultz, M. B. & Sinclair, D. A. Why NAD+ declines during aging: it’s destroyed. Cell Metab. 23, 965–966 (2016). source
The paper’s Abstract links rising CD38 activity during aging to declining NAD+ levels and reports that mice lacking CD38 retain higher NAD+ levels. It does not describe SASP activation of CD38 on macrophages or report that senolytics restore tissue NAD+; its discussion of inflammation as a possible trigger is speculative. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
InterpretationcitationTiming, choice of senolytic, and individual age, sex, and other characteristics may affect senolytic effectiveness.
“The timing, the particular senolytic agent used, and the age, sex, and other characteristics of the individual may impact effectiveness of senolytics24.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [24] Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018). source
The Results section reports that D+Q was beneficial when given immediately or five weeks after senescent-cell transplantation, with comparable effects at both times. The Discussion considers optimized agents and says efficacy in tissues from older humans needs study. The paper does not establish that timing, choice of agent, age, sex, or other individual characteristics change senolytic effectiveness; in particular, it reports benefits in both male and female mice. (LLM, conf=0.82)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationExercise may delay senescent cell formation and reduce inflammation, frailty, and chronic disease onset in mice.
“Exercise may delay senescent cell formation and reduce inflammation, frailty and chronic disease onset in mice136,137.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [136] Duggal, N. A., Niemiro, G., Harridge, S. D. R., Simpson, R. J. & Lord, J. M. Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? Nat. Rev. Immunol. 19, 563–572 (2019). source
In “Physical activity as a therapy” (page not specified), the review reports that exercise prevented senescent-cell accumulation in the adipose tissue of mice with diet-induced obesity. It links senescent cells to inflammation, but attributes prevention of age-related disease in mice to removal of those cells, not to exercise. The cited passage does not establish that exercise reduces frailty or chronic disease onset in mice. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [137] Schafer, M. J. et al. Exercise prevents diet-induced cellular senescence in adipose tissue. Diabetes 65, 1606–1615 (2016). source
The Results and Discussion (page numbers unavailable) report that exercise reduced diet-induced senescence markers and inflammatory signaling in the visceral fat of mice, while improving physical and metabolic measures. The paper does not show that exercise reduced frailty or delayed the onset of chronic diseases in these mice; those effects extend beyond the outcomes studied. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataTransiently disabling SCAP pathways causes apoptosis of senescent cells with a tissue-destructive SASP, while non-senescent cells and senescent cells with a pro-growth non-apoptotic SASP remain viable.
“Transiently disabling SCAP pathways results in apoptosis of the senescent cells with a tissue-destructive SASP, while non-senescent cells or those senescent cells with a pro-growth, non-apoptotic SASP remain viable (U. Tripathi, S.C., L.G.P.L. Prata, T.T. and J.L.K., unpublished data).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites U. Tripathi, S.C., L.G.P.L. Prata, T.T. and J.L.K., unpublished data
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Premisenone givenSenescent cells accumulate during aging and at pathogenic sites of multiple disorders and diseases.
“Senescent cells accumulate during aging and at pathogenic sites of multiple disorders and diseases.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Premisenone givenSenescent cells can appear at any point in life.
“Senescent cells can arise throughout the lifespan”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Premisenone givenCellular senescence is a cell-cycle arrest state caused by damaging stimuli.
“One such process is cellular senescence, which entails a state of cell cycle arrest in response to damaging stimuli.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe Unitary Theory of Fundamental Aging Mechanisms proposes that interventions targeting any one fundamental aging mechanism may also affect the others.
“The Unitary Theory of Fundamental Aging Mechanisms builds on the Geroscience Hypothesis by positing that interventions targeting any one fundamental mechanism may target the others6.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Tchkonia, T., Palmer, A. K. & Kirkland, J. L. New horizons: novel approaches to enhance healthspan through targeting cellular senescence and related aging mechanisms. J. Clin. Endocrinol. Metab. 106, e1481–e1487 (2021). source
May combine two claims.
Premisenone givenSenescent cells are essentially irreversibly arrested in the cell cycle but remain viable.
“Senescent cells, which are in a state of essentially irreversible cell cycle arrest but remain viable”
Quote in the paperSubstantial claimMay combine two claims.
Premisenone givenSenescent cells can accumulate with aging, especially in frail individuals, and at pathogenic sites of multiple diseases in animals and humans across the lifespan.
“can accumulate with aging, especially in more frail individuals, and at pathogenic sites of multiple disorders and diseases in experimental animals and humans across the lifespan.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAt least some senescent cells depend on glutamine metabolism as a pH-buffering system due to ruptured lysosomal membranes, and inhibiting this makes them vulnerable to apoptosis.
“Due to ruptured lysosomal membranes, at least some senescent cells depend on glutamine metabolism as a pH-buffering system, inhibition of which renders them vulnerable to apoptosis95.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [95] Johmura, Y. et al. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science 371, 265–270 (2021). source
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationEx vivo perfusion of organs from older donors with senolytics may be a new application to reduce organ failure or rejection and offset organ shortages.
“a potential new application of senolytics may entail ex vivo perfusion of organs from older donors that are currently being discarded because of increased risk of organ failure or allograft rejection, potentially offsetting shortages of organs for transplantation125.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [125] Tullius, S. G. & Rabb, H. Improving the supply and quality of deceased-donor organs for transplantation. N. Engl. J. Med. 378, 1920–1929 (2018). source
May combine two claims.
PremisecitationObesity causes senescent cell accumulation near the third ventricle of mouse brain and neuropsychiatric dysfunction, particularly anxiety, through altered limbic function.
“Obesity also leads to accumulation of senescent cells near the third ventricles of the murine brain, together with development of neuropsychiatric dysfunction, particularly anxiety, which results from altered function of the limbic system situated near the third ventricles.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningFirst-generation senolytics eliminate senescent cells that release proapoptotic factors, thereby targeting the source of detrimental SASP factor production.
“the first-generation senolytics target the underlying cause of detrimental SASP factor production by eliminating those senescent cells that release proapoptotic factors.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenSenolytics cause SASP-expressing senescent cells to undergo apoptosis, and such cells are present at sites of dysfunction.
“Senolytics cause SASP-expressing senescent cells to undergo apoptosis, and such senescent cells are present at sites of dysfunction.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn HFD-fed mice, Q reduces senescent cell burden and SASP markers, alleviates renal fibrosis, and improves kidney function.
“HFD-induced senescent mouse kidney cells are linked to renal fibrosis and functional impairment; Q treatment reduces senescent cell burden and SASP marker expression, alleviates renal fibrosis and improves kidney function102.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [102] Kim, S. R. et al. Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin. Transl. Res. 213, 112–123 (2019). source
May combine two claims.
PremisecitationGenetic models have been useful for pinpointing cells expressing particular senescence-linked markers and as complementary tools in senolytic proof-of-concept studies.
“These genetic models have been useful in pinpointing those cells expressing particular senescence-linked markers (for example, p16INK4a or p21CIP1/WAF1) and as complementary tools in senolytic proof-of-concept studies (Table 2).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Table 2
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisereasoningHigh-fat diets and obesity cause senescent cell accumulation and impair multiple organs.
“High-fat diets (HFDs) and obesity result in senescent cell accumulation and lead to impaired function of multiple organs.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S4 (based).
InterpretationreasoningAfter systemic senolytic treatment lowers senescent cell burden below a threshold, the immune system might clear remaining senescent cells, including those resistant to that senolytic.
“once systemic senolytic treatment has reduced overall senescent cell burden to below a threshold, the immune system might clear remaining senescent cells, including those resistant to that particular senolytic.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.
Interpretationnone givenICD codes for these conditions would facilitate regulatory approvals, recording in hospital and insurance records, epidemiological studies, reimbursement, and pharmaceutical industry engagement.
“Such ICD codes would facilitate regulatory approvals, recording of conditions linked to fundamental aging processes in hospital and insurance records, epidemiological studies, physician and hospital reimbursement and engagement of the pharmaceutical industry.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn an open-label phase 1 pilot of 9 diabetic kidney disease patients, a 3-day course of oral D+Q decreased adipose senescent cell burden, inflammation, fibrosis, and circulating SASP factors for at least 11 days after the last dose, indicating target engagement and suggesting intermittent dosing may be effective in humans.
“In an open-label phase 1 pilot study in 9 patients with diabetic kidney disease, a 3-d course of oral D + Q was sufficient to decrease adipose tissue senescent cell burden, inflammation, fibrosis and circulating SASP factors for at least 11 d after the last dose of senolytics, indicating target engagement and suggesting that an intermittent dosing regimen may be effective in humans48.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [48] Hickson, L. J. et al. Corrigendum to ‘Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease’ EBioMedicine 47 (2019) 446–456. EBioMedicine 52, 102595 (2020). source
Classified as probably not a substantial claim.
InterpretationreasoningIf the Unitary hypothesis is correct, combining interventions may yield less-than-additive effects because fundamental aging mechanisms are tightly interconnected.
“if the Unitary hypothesis is correct, they may contribute less-than-additive effects because fundamental aging mechanisms are tightly interconnected.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The Unitary Theory/hypothesis that fundamental aging mechanisms are tightly interconnected is correct.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenEfforts are underway to identify and define biomarkers of senescent cell accumulation and senolysis that meet regulatory requirements.
“ongoing efforts are underway to identify and define biomarkers of senescent cell accumulation (senescence biomarkers) and destruction of senescent cells during senolytic treatment (senolysis biomarkers) that meet requirements of regulatory authorities.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S2 (checkable).
InterpretationreasoningCombining geroscience with disease-specific interventions may be a more promising strategy.
“A more promising strategy could be to combine geroscience with disease-specific interventions.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationTAME will test whether metformin delays a second age-related disorder in patients who already have one, not in completely healthy older adults.
“TAME will test if metformin delays the appearance of a second age-related disorder in patients who already have one such disorder; it will not be a trial including completely healthy older adults115.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [115] American Federation for Aging Research. Targeting the biology of aging. Ushering a new era of interventions. https://www.afar.org/tame-trial (2022).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
PremisecitationNutlin-3a shows no or weak senolytic activity and can induce cellular senescence.
“In our hands and others, nutlin-3a does not show or shows only weak senolytic activity and, in some cases, can even induce cellular senescence95,130.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [95] Johmura, Y. et al. Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science 371, 265–270 (2021). source
- cites [130] Efeyan, A. et al. Induction of p53-dependent senescence by the MDM2 antagonist nutlin-3a in mouse cells of fibroblast origin. Cancer Res. 67, 7350–7357 (2007). source
Probably not a substantial claim: may not pass S4 (based).
Premisenone givenLack of WHO ICD codes for multimorbidity, sarcopenia, healthspan, or geriatric syndromes is a barrier to clinical development.
“The lack of WHO International Classification of Disease (ICD) codes for multimorbidity, sarcopenia, healthspan or the geriatric syndromes represents a barrier to clinical development.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningGerodiagnostic ratios could enhance sensitivity and reduce denominator effects; for example, using creatinine as a denominator for urine analytes introduces confounding by muscle mass.
“This approach could both enhance sensitivity and reduce ‘denominator effects’; for example, creatinine is often used as a dominator for urine analytes, introducing the confounding variable of muscle mass, upon which creatinine levels depend.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationF may be beneficial while D may be detrimental in healthy young female mice that have not accumulated many senescent cells.
“F may be beneficial but D detrimental in healthy young female mice that have not yet accumulated many senescent cells129.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [129] Fang, Y. et al. Sexual dimorphic responses of C57BL/6 mice to fisetin or dasatinib and quercetin cocktail oral treatment. Preprint at bioRxiv https://doi.org/10.1101/2021.11.08.467509 (2021). source
May combine two claims.
InterpretationreasoningConsistent with the Unitary Theory, interventions targeting different fundamental aging mechanisms appear to alleviate aging phenotypes, delay, prevent, or treat multiple diseases, and extend healthspan in preclinical models.
“consistent with the Unitary Theory, interventions targeting the different fundamental aging mechanisms appear to alleviate aging phenotypes, delay, prevent or treat multiple diseases, and extend healthspan in preclinical models.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationMetformin, resveratrol, and rapalogs are SASP inhibitors and appear to affect some of the same basic processes as caloric restriction or exercise.
“Metformin, resveratrol and rapalogs (agents related to rapamycin) are SASP inhibitors and appear to impact some of the same basic processes as caloric restriction or exercise110,138.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [110] Novelle, M. G., Ali, A., Dieguez, C., Bernier, M. & de Cabo, R. Metformin: a hopeful promise in aging research. Cold Spring Harb. Perspect. Med. 6, a025932 (2016). source
- cites [138] Baur, J. A. et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444, 337–342 (2006). source
May combine two claims.
PremisecitationAccording to the threshold theory, senescent cells can exist without clinical manifestations, but when their abundance exceeds a threshold, burden can increase and contribute to local and systemic dysfunction and multiple diseases.
“According to the threshold theory of cellular senescence, senescent cells can be present without clinical manifestations but, if their abundance exceeds a threshold, senescent cell burden can increase further and contribute to development of local and systemic dysfunction and multiple diseases (Fig. 2).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fig. 2
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
InterpretationreasoningPromising preclinical senolytic results suggest therapeutic and preventive opportunities for delaying multimorbidity and increasing healthspan.
“Promising results of senolytics in preclinical models suggest therapeutic and preventive opportunities for delaying multimorbidity and increasing healthspan.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe failure of the UBX0101 trial seems related to the particular agent, which may not have been a fully effective senolytic.
“Thus, the failure of this clinical trial seems related to the particular agent administered, which may not have been a fully effective senolytic.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenClinical studies of geroscience interventions targeting other pillars of aging are underway or planned.
“Clinical studies of geroscience interventions targeting the other pillars of aging are currently underway or being planned.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenSirtuins facilitate DNA damage repair, partly relying on oxidized NAD+.
“Sirtuins facilitate DNA damage repair, partially relying on oxidized NAD+ to do so.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Preclinical results in animal models predict human clinical outcomes for senolytic interventions.
“promising results from preclinical studies have facilitated progression to early-phase clinical trials evaluating the safety and efficacy of senolytics”
The paper relies on this without support.
CAR T cell therapy is expensive, individually formulated, can cause graft-versus-host disease, and requires prolonged immunosuppression.
“Furthermore, CAR T cell therapy is expensive, generally has to be specifically formulated for each individual being treated, and can lead to graft versus host disease, necessitating prolonged immunosuppressive therapy with all its attendant risks.”
The authors state this as an assumption.
The Unitary Theory/hypothesis that fundamental aging mechanisms are tightly interconnected is correct.
“if the Unitary hypothesis is correct, they may contribute less-than-additive effects because fundamental aging mechanisms are tightly interconnected.”
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?
Genetic or pharmacological clearance of p16 positive cells in different tissues has shown efficacy in more than forty disease models, including models of neurodegenerative diseases.
“Genetic or pharmacological clearance of p16 positive cells in different tissues has shown efficacy in more than forty disease models, including models of neurodegenerative diseases.1”
From A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease (2025) · cites this paper as [1]
The ‘Senolytics in preclinical models’ section reports beneficial effects of senolytic treatment across several disease models, including neurological disorders. The ‘Discovery and development of senolytic drugs’ section also describes genetic clearance of p16INK4a-expressing cells, but distinguishes its targets from those of small-molecule senolytics. Our copy does not substantiate the count of more than forty models or establish that the pharmacological results specifically reflect clearance of p16-positive cells; it says ‘neurological,’ not specifically ‘neurodegenerative,’ disorders. No page numbers are available in the indexed passages. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe target specificity and toxicity to non-senescent cells is still a big hurdle for clinical applications of current senolytic treatments.
“The target specificity and toxicity to non-senescent cells is still a big hurdle for clinical applications of the current senolyitc treatments.14,15”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [15]
The “Discovery and development of senolytic drugs” section reports toxicity from one senolytic and says some strategies also affect non-senescent cells. But the paper frames off-target toxicity as a possible risk for particular agents, not an established major hurdle for current senolytic treatments generally; it also suggests strict cell-type specificity may not be necessary. Page numbers were not available in our copy. (LLM, conf=0.83)
Experimental — accuracy not yet measuredElimination of senescent cells mitigates ageing associated events, such as inflammation, stem cell exhaustion, and mitochondrial dysfunction.
“The elimination of senescent cells has been observed to mitigate ageing associated events, such as inflammation, stem cell exhaustion, and mitochondrial dysfunction.537”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [537]
Around 20 clinical trials of senotherapies are ongoing, two of which are evaluating therapeutic efficacy of D+Q in individuals with MCI or AD.
“Currently, around 20 clinical trials of senotherapies are ongoing, two of which (NCT04785300 and NCT04685590) are evaluating the therapeutic efficacy of D+Q in individuals with MCI or AD.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [186]
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Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
Cites a retracted work: 10.1038/s43587-021-00063-1
InfoThe cited work was retracted on 2024-10-31 (notice 10.1038/s43587-024-00749-2), not before this paper was published (2022-08).
Cited work 10.1038/s43587-021-00063-1 · retracted 2024-10-31 · notice 10.1038/s43587-024-00749-2 · this paper published 2022-08
“Zhang, B. et al. KDM4 orchestrates epigenomic remodeling of senescent cells and potentiates the senescence-associated secretory phenotype. Nat. Aging 1, 454–472 (2021).”
Cites a retracted work: 10.1101/2020.08.03.235465
InfoThe cited work was retracted; the date of the notice is not on record.
Cited work 10.1101/2020.08.03.235465 · retraction date not known · this paper published 2022-08
Cites
2 retracted
(2021) · doi:10.1038/s43587-021-00063-1 · Cited by 66 · see citing works
Self-citationRetracted(2020) · doi:10.1101/2020.08.03.235465 · Cited by 66 · see citing works
Self-citationRetractedLópez-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
The serial cultivation of human diploid cell strains
Hayflick, L., & Moorhead, P. S. (1961) · Experimental Cell Research · doi:10.1016/0014-4827(61)90192-6 · Cited by 8,508 · see citing works
The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · see citing works
Resveratrol improves health and survival of mice on a high-calorie diet
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., et al. (2006) · Nature · doi:10.1038/nature05354 · Cited by 4,290 · see citing works
Chronic Inflammation (Inflammaging) and Its Potential Contribution to Age-Associated Diseases
Franceschi, C., & Campisi, J. (2014) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glu057 · Cited by 3,891 · see citing works
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766 · see citing works
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · see citing works
Self-citationCellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · see citing works
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
Geroscience: Linking Aging to Chronic Disease
Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S., Franceschi, C., Lithgow, G. J., Morimoto, R. I., Pessin, J. E., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.039 · Cited by 2,764 · see citing works
Hallmarks of Cellular Senescence
Hernandez-Segura, A., Nehme, J., & Demaria, M. (2018) · Trends in Cell Biology · doi:10.1016/j.tcb.2018.02.001 · Cited by 2,605 · see citing works
The Achilles' heel of senescent cells: from transcriptome to senolytic drugs
Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., Palmer, A. K., Ikeno, Y., Hubbard, G. B., Lenburg, M., et al. (2015) · Aging Cell · doi:10.1111/acel.12344 · Cited by 2,562 · see citing works
Self-citationSenescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas
Xue, W., Zender, L., Miething, C., Dickins, R. A., Hernando, E., Krizhanovsky, V., Cordon-Cardo, C., & Lowe, S. W. (2007) · Nature · doi:10.1038/nature05529 · Cited by 2,473 · see citing works
The cGAS–STING pathway as a therapeutic target in inflammatory diseases
Decout, A., Katz, J. D., Venkatraman, S., & Ablasser, A. (2021) · Nature Reviews Immunology · doi:10.1038/s41577-021-00524-z · Cited by 2,309 · see citing works
Senolytics improve physical function and increase lifespan in old age
Xu, M., Pirtskhalava, T., Farr, J. N., Weigand, B. M., Palmer, A. K., Weivoda, M. M., Inman, C. L., Ogrodnik, M. B., Hachfeld, C. M., Fraser, D. G., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0092-9 · Cited by 2,287 · see citing works
Self-citationA complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · see citing works
Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion
Rodier, F., Coppé, J.-P., Patil, C. K., Hoeijmakers, W. A. M., Muñoz, D. P., Raza, S. R., Freund, A., Campeau, E., Davalos, A. R., & Campisi, J. (2009) · Nature Cell Biology · doi:10.1038/ncb1909 · Cited by 2,232 · see citing works
An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
Demaria, M., Ohtani, N., Youssef, S. A., Rodier, F., Toussaint, W., Mitchell, J. R., Laberge, R.-M., Vijg, J., Van Steeg, H., Dollé, M. E. T., et al. (2014) · Developmental Cell · doi:10.1016/j.devcel.2014.11.012 · Cited by 2,045 · see citing works
Suppression of Aging in Mice by the Hormone Klotho
Kurosu, H., Yamamoto, M., Clark, J. D., Pastor, J. V., Nandi, A., Gurnani, P., McGuinness, O. P., Chikuda, H., Yamaguchi, M., Kawaguchi, H., et al. (2005) · Science · doi:10.1126/science.1112766 · Cited by 1,935 · see citing works
Ageing as a Risk Factor for Disease
Niccoli, T., & Partridge, L. (2012) · Current Biology · doi:10.1016/j.cub.2012.07.024 · Cited by 1,831 · see citing works
Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice
Chang, J., Wang, Y., Shao, L., Laberge, R.-M., Demaria, M., Campisi, J., Janakiraman, K., Sharpless, N. E., Ding, S., Feng, W., et al. (2016) · Nature Medicine · doi:10.1038/nm.4010 · Cited by 1,819 · see citing works
Sarcopenia: Aging-Related Loss of Muscle Mass and Function
Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797 · see citing works
Self-citationCellular senescence and the senescent secretory phenotype: therapeutic opportunities
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64098 · Cited by 1,774 · see citing works
Self-citationKrtolica, A., Parrinello, S., Lockett, S., Desprez, P.-Y., & Campisi, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.211053698 · Cited by 1,730 · see citing works
Cellular senescence mediates fibrotic pulmonary disease
Schafer, M. J., White, T. A., Iijima, K., Haak, A. J., Ligresti, G., Atkinson, E. J., Oberg, A. L., Birch, J., Salmonowicz, H., Zhu, Y., et al. (2017) · Nature Communications · doi:10.1038/ncomms14532 · Cited by 1,613 · see citing works
Self-citationEstimation of clinical trial success rates and related parameters
Wong, C. H., Siah, K. W., & Lo, A. W. (2019) · Biostatistics · doi:10.1093/biostatistics/kxx069 · Cited by 1,585 · see citing works
Jeon, O. H., Kim, C., Laberge, R.-M., Demaria, M., Rathod, S., Vasserot, A. P., Chung, J. W., Kim, D. H., Poon, Y., David, N., et al. (2017) · Nature Medicine · doi:10.1038/nm.4324 · Cited by 1,515 · see citing works
Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.02.031 · Cited by 1,454 · see citing works
Hickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.08.069 · Cited by 1,383 · see citing works
Self-citationA proteomic atlas of senescence-associated secretomes for aging biomarker development
Basisty, N., Kale, A., Jeon, O. H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., Ferrucci, L., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000599 · Cited by 1,348 · see citing works
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse
Demaria, M., O'Leary, M. N., Chang, J., Shao, L., Liu, S., Alimirah, F., Koenig, K., Le, C., Mitin, N., Deal, A. M., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0241 · Cited by 1,338 · see citing works
Cytoplasmic chromatin triggers inflammation in senescence and cancer
Dou, Z., Ghosh, K., Vizioli, M. G., Zhu, J., Sen, P., Wangensteen, K. J., Simithy, J., Lan, Y., Lin, Y., Zhou, Z., et al. (2017) · Nature · doi:10.1038/nature24050 · Cited by 1,335 · see citing works
Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline
Bussian, T. J., Aziz, A., Meyer, C. F., Swenson, B. L., van Deursen, J. M., & Baker, D. J. (2018) · Nature · doi:10.1038/s41586-018-0543-y · Cited by 1,289 · see citing works
Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study
Justice, J. N., Nambiar, A. M., Tchkonia, T., LeBrasseur, N. K., Pascual, R., Hashmi, S. K., Prata, L., Masternak, M. M., Kritchevsky, S. B., Musi, N., et al. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2018.12.052 · Cited by 1,261 · see citing works
Self-citationL1 drives IFN in senescent cells and promotes age-associated inflammation
De Cecco, M., Ito, T., Petrashen, A. P., Elias, A. E., Skvir, N. J., Criscione, S. W., Caligiana, A., Brocculi, G., Adney, E. M., Boeke, J. D., et al. (2019) · Nature · doi:10.1038/s41586-018-0784-9 · Cited by 1,255 · see citing works
Senolytic drugs: from discovery to translation
Kirkland, J. L., & Tchkonia, T. (2020) · Journal of Internal Medicine · doi:10.1111/joim.13141 · Cited by 1,227 · see citing works
Self-citationSenescent intimal foam cells are deleterious at all stages of atherosclerosis
Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016) · Science · doi:10.1126/science.aaf6659 · Cited by 1,195 · see citing works
Targeting cellular senescence prevents age-related bone loss in mice
Farr, J. N., Xu, M., Weivoda, M. M., Monroe, D. G., Fraser, D. G., Onken, J. L., Negley, B. A., Sfeir, J. G., Ogrodnik, M. B., Hachfeld, C. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4385 · Cited by 1,182 · see citing works
Self-citationZhu, 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
Self-citationThe NASA Twins Study: A multidimensional analysis of a year-long human spaceflight
Garrett-Bakelman, F. E., Darshi, M., Green, S. J., Gur, R. C., Lin, L., Macias, B. R., McKenna, M. J., Meydan, C., Mishra, T., Nasrini, J., et al. (2019) · Science · doi:10.1126/science.aau8650 · Cited by 1,128 · see citing works
Forging 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
Senolytic 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
Chien, Y., Scuoppo, C., Wang, X., Fang, X., Balgley, B., Bolden, J. E., Premsrirut, P., Luo, W., Chicas, A., Lee, C. S., et al. (2011) · Genes & Development · doi:10.1101/gad.17276711 · Cited by 1,046 · see citing works
Cellular 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-citationFisetin 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
Self-citationThe 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
An aged immune system drives senescence and ageing of solid organs
Yousefzadeh, M. J., Flores, R. R., Zhu, Y., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., Cui, Y., Angelini, L., Lee, K.-A., McGowan, S. J., et al. (2021) · Nature · doi:10.1038/s41586-021-03547-7 · Cited by 972 · see citing works
Unmasking Transcriptional Heterogeneity in Senescent Cells
Hernandez-Segura, A., de Jong, T. V., Melov, S., Guryev, V., Campisi, J., & Demaria, M. (2017) · Current Biology · doi:10.1016/j.cub.2017.07.033 · Cited by 972 · 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
Self-citationA crucial role for adipose tissue p53 in the regulation of insulin resistance
Minamino, T., Orimo, M., Shimizu, I., Kunieda, T., Yokoyama, M., Ito, T., Nojima, A., Nabetani, A., Oike, Y., Matsubara, H., et al. (2009) · Nature Medicine · doi:10.1038/nm.2014 · Cited by 891 · see citing works
Wilson, W. H., O'Connor, O. A., Czuczman, M. S., LaCasce, A. S., Gerecitano, J. F., Leonard, J. P., Tulpule, A., Dunleavy, K., Xiong, H., Chiu, Y.-L., et al. (2010) · The Lancet Oncology · doi:10.1016/s1470-2045(10)70261-8 · Cited by 876 · 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
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
Benefits 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
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
Self-citationMolecular mechanisms of dietary restriction promoting health and longevity
Green, C. L., Lamming, D. W., & Fontana, L. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00411-4 · Cited by 714 · see citing works
Identification 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
Self-citationMoiseeva, 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
Pharmacokinetics and bioavailability of quercetin glycosides in humans
Graefe, E. U., Wittig, J., Mueller, S., Riethling, A., Uehleke, B., Drewelow, B., Pforte, H., Jacobasch, G., Derendorf, H., & Veit, M. (2001) · The Journal of Clinical Pharmacology · doi:10.1177/00912700122010366 · Cited by 649 · see citing works
Madeo, F., Carmona-Gutierrez, D., Hofer, S. J., & Kroemer, G. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.018 · Cited by 630 · see citing works
Targeting senescent cells enhances adipogenesis and metabolic function in old age
Xu, M., Palmer, A. K., Ding, H., Weivoda, M. M., Pirtskhalava, T., White, T. A., Sepe, A., Johnson, K. O., Stout, M. B., Giorgadze, N., et al. (2015) · eLife · doi:10.7554/elife.12997 · Cited by 604 · see citing works
Self-citationTau 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
Identification of senescent cells in the bone microenvironment
Farr, J. N., Fraser, D. G., Wang, H., Jaehn, K., Ogrodnik, M. B., Weivoda, M. M., Drake, M. T., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., et al. (2016) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.2892 · Cited by 562 · see citing works
Self-citationCellular Senescence as a Mechanism and Target in Chronic Lung Diseases
Barnes, P. J., Baker, J. R., & Donnelly, L. (2019) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201810-1975tr · Cited by 560 · see citing works
Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition
Pereira, B. I., Devine, O. P., Vukmanovic-Stejic, M., Chambers, E. S., Subramanian, P., Patel, N., Virasami, A., Sebire, N. J., Kinsler, V., Valdovinos, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10335-5 · Cited by 556 · see citing works
Synthetic lethal metabolic targeting of cellular senescence in cancer therapy
Dörr, J. R., Yu, Y., Milanovic, M., Beuster, G., Zasada, C., Däbritz, J. H. M., Lisec, J., Lenze, D., Gerhardt, A., Schleicher, K., et al. (2013) · Nature · doi:10.1038/nature12437 · Cited by 541 · see citing works
Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis
Ogrodnik, M., Zhu, Y., Langhi, L. G. P., Tchkonia, T., Krüger, P., Fielder, E., Victorelli, S., Ruswhandi, R. A., Giorgadze, N., Pirtskhalava, T., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2018.12.008 · Cited by 536 · see citing works
Self-citationLength-independent telomere damage drives post-mitotic cardiomyocyte senescence
Anderson, R., Lagnado, A., Maggiorani, D., Walaszczyk, A., Dookun, E., Chapman, J., Birch, J., Salmonowicz, H., Ogrodnik, M., Jurk, D., et al. (2019) · The EMBO Journal · doi:10.15252/embj.2018100492 · Cited by 532 · see citing works
Self-citationRapalogs and mTOR inhibitors as anti-aging therapeutics
Lamming, D. W., Ye, L., Sabatini, D. M., & Baur, J. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64099 · Cited by 531 · see citing works
Chinta, S. J., Woods, G., Demaria, M., Rane, A., Zou, Y., McQuade, A., Rajagopalan, S., Limbad, C., Madden, D. T., Campisi, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2017.12.092 · Cited by 530 · see citing works
The role of cellular senescence in ageing and endocrine disease
Khosla, S., Farr, J. N., Tchkonia, T., & Kirkland, J. L. (2020) · Nature Reviews Endocrinology · doi:10.1038/s41574-020-0335-y · Cited by 523 · see citing works
Self-citationNOTCH1 mediates a switch between two distinct secretomes during senescence
Hoare, M., Ito, Y., Kang, T.-W., Weekes, M. P., Matheson, N. J., Patten, D. A., Shetty, S., Parry, A. J., Menon, S., Salama, R., et al. (2016) · Nature Cell Biology · doi:10.1038/ncb3397 · Cited by 522 · see citing works
Strategies for targeting senescent cells in human disease
Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M. (2021) · Nature Aging · doi:10.1038/s43587-021-00121-8 · Cited by 501 · see citing works
Self-citationSenescent cell clearance by the immune system: Emerging therapeutic opportunities
Prata, L. G. P. L., Ovsyannikova, I. G., Tchkonia, T., & Kirkland, J. L. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2019.04.003 · Cited by 497 · see citing works
Self-citationTORC1 inhibition enhances immune function and reduces infections in the elderly
Mannick, J. B., Morris, M., Hockey, H.-U. P., Roma, G., Beibel, M., Kulmatycki, K., Watkins, M., Shavlakadze, T., Zhou, W., Quinn, D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aaq1564 · Cited by 496 · see citing works
(1995) · PubMed · Cited by 496 · see citing works
Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice
Bitto, A., Ito, T. K., Pineda, V. V., LeTexier, N. J., Huang, H. Z., Sutlief, E., Tung, H., Vizzini, N., Chen, B., Smith, K., et al. (2016) · eLife · doi:10.7554/elife.16351 · Cited by 474 · see citing works
Acceleration of β Cell Aging Determines Diabetes and Senolysis Improves Disease Outcomes
Aguayo-Mazzucato, C., Andle, J., Lee, T. B., Midha, A., Talemal, L., Chipashvili, V., Hollister-Lock, J., van Deursen, J., Weir, G., & Bonner-Weir, S. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.05.006 · Cited by 469 · see citing works
NF-κB inhibition delays DNA damage–induced senescence and aging in mice
Tilstra, J. S., Robinson, A. R., Wang, J., Gregg, S. Q., Clauson, C. L., Reay, D. P., Nasto, L. A., St Croix, C. M., Usas, A., Vo, N., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci45785 · Cited by 462 · see citing works
Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan
Grosse, L., Wagner, N., Emelyanov, A., Molina, C., Lacas-Gervais, S., Wagner, K.-D., & Bulavin, D. V. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.05.002 · Cited by 460 · see citing works
From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence
Wiley, C. D., & Campisi, J. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.010 · Cited by 440 · see citing works
Novais, E. J., Tran, V. A., Johnston, S. N., Darris, K. R., Roupas, A. J., Sessions, G. A., Shapiro, I. M., Diekman, B. O., & Risbud, M. V. (2021) · Nature Communications · doi:10.1038/s41467-021-25453-2 · Cited by 440 · see citing works
Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders
Johmura, Y., Yamanaka, T., Omori, S., Wang, T.-W., Sugiura, Y., Matsumoto, M., Suzuki, N., Kumamoto, S., Yamaguchi, K., Hatakeyama, S., et al. (2021) · Science · doi:10.1126/science.abb5916 · Cited by 440 · see citing works
Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity?
Duggal, N. A., Niemiro, G., Harridge, S. D. R., Simpson, R. J., & Lord, J. M. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0177-9 · Cited by 436 · see citing works
Hall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., Rydkina, E., Vujcic, S., Balan, K., Gitlin, I. I., et al. (2017) · Aging · doi:10.18632/aging.101268 · Cited by 407 · see citing works
Ogrodnik, M., Evans, S. A., Fielder, E., Victorelli, S., Kruger, P., Salmonowicz, H., Weigand, B. M., Patel, A. D., Pirtskhalava, T., Inman, C. L., et al. (2021) · Aging Cell · doi:10.1111/acel.13296 · Cited by 405 · see citing works
Self-citationDNA damage-how and why we age?
Yousefzadeh, M., Henpita, C., Vyas, R., Soto-Palma, C., Robbins, P., & Niedernhofer, L. (2021) · eLife · doi:10.7554/elife.62852 · Cited by 399 · see citing works
Identification and characterization of Cardiac Glycosides as senolytic compounds
Triana-Martínez, F., Picallos-Rabina, P., Da Silva-Álvarez, S., Pietrocola, F., Llanos, S., Rodilla, V., Soprano, E., Pedrosa, P., Ferreirós, A., Barradas, M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12888-x · Cited by 384 · see citing works
Rapamycin extends murine lifespan but has limited effects on aging
Neff, F., Flores-Dominguez, D., Ryan, D. P., Horsch, M., Schröder, S., Adler, T., Afonso, L. C., Aguilar-Pimentel, J. A., Becker, L., Garrett, L., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67674 · Cited by 374 · see citing works
Cardiac glycosides are broad-spectrum senolytics
Guerrero, A., Herranz, N., Sun, B., Wagner, V., Gallage, S., Guiho, R., Wolter, K., Pombo, J., Irvine, E. E., Innes, A. J., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0122-z · Cited by 359 · see citing works
Vizioli, M. G., Liu, T., Miller, K. N., Robertson, N. A., Gilroy, K., Lagnado, A. B., Perez-Garcia, A., Kiourtis, C., Dasgupta, N., Lei, X., et al. (2020) · Genes & Development · doi:10.1101/gad.331272.119 · Cited by 359 · see citing works
Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice
Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., Curran, G. L., Ogrodnik, M., Jurk, D., Johnson, K. O., et al. (2016) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glw154 · Cited by 352 · see citing works
Self-citationTherapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
Prasanna, P. G. S., Citrin, D. E., Hildesheim, J., Ahmed, M. M., Venkatachalam, S., Riscuta, G., Xi, D., Zheng, G., van Deursen, J., Goronzy, J. J., et al. (2021) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djab064 · Cited by 351 · see citing works
Self-citationVirus-induced senescence is a driver and therapeutic target in COVID-19
Lee, S., Yu, Y., Trimpert, J., Benthani, F., Mairhofer, M., Richter-Pechanska, P., Wyler, E., Belenki, D., Kaltenbrunner, S., Pammer, M., et al. (2021) · Nature · doi:10.1038/s41586-021-03995-1 · Cited by 350 · see citing works
CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD+ and NMN levels
Chini, C. C. S., Peclat, T. R., Warner, G. M., Kashyap, S., Espindola-Netto, J. M., de Oliveira, G. C., Gomez, L. S., Hogan, K. A., Tarragó, M. G., Puranik, A. S., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-00298-z · Cited by 349 · see citing works
Self-citationThe flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice
Xu, Q., Fu, Q., Li, Z., Liu, H., Wang, Y., Lin, X., He, R., Zhang, X., Ju, Z., Campisi, J., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00491-8 · Cited by 341 · see citing works
Self-citationA versatile drug delivery system targeting senescent cells
Muñoz‐Espín, D., Rovira, M., Galiana, I., Giménez, C., Lozano‐Torres, B., Paez‐Ribes, M., Llanos, S., Chaib, S., Muñoz‐Martín, M., Ucero, A. C., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809355 · Cited by 339 · see citing works
Self-citationCellular senescence: at the nexus between ageing and diabetes
Palmer, A. K., Gustafson, B., Kirkland, J. L., & Smith, U. (2019) · Diabetologia · doi:10.1007/s00125-019-4934-x · Cited by 337 · see citing works
Self-citationCellular senescence: all roads lead to mitochondria
Martini, H., & Passos, J. F. (2023) · The FEBS Journal · doi:10.1111/febs.16361 · Cited by 334 · see citing works
Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice
Yousefzadeh, M. J., Zhao, J., Bukata, C., Wade, E. A., McGowan, S. J., Angelini, L. A., Bank, M. P., Gurkar, A. U., McGuckian, C. A., Calubag, M. F., et al. (2020) · Aging Cell · doi:10.1111/acel.13094 · Cited by 331 · see citing works
Clearance of senescent decidual cells by uterine natural killer cells in cycling human endometrium
Brighton, P. J., Maruyama, Y., Fishwick, K., Vrljicak, P., Tewary, S., Fujihara, R., Muter, J., Lucas, E. S., Yamada, T., Woods, L., et al. (2017) · eLife · doi:10.7554/elife.31274 · Cited by 323 · see citing works
Senolytics reduce coronavirus-related mortality in old mice
Camell, C. D., Yousefzadeh, M. J., Zhu, Y., Prata, L. G. P. L., Huggins, M. A., Pierson, M., Zhang, L., O’Kelly, R. D., Pirtskhalava, T., Xun, P., et al. (2021) · Science · doi:10.1126/science.abe4832 · Cited by 320 · see citing works
Self-citationAged-senescent cells contribute to impaired heart regeneration
Lewis‐McDougall, F. C., Ruchaya, P. J., Domenjo‐Vila, E., Shin Teoh, T., Prata, L., Cottle, B. J., Clark, J. E., Punjabi, P. P., Awad, W., Torella, D., et al. (2019) · Aging Cell · doi:10.1111/acel.12931 · Cited by 317 · see citing works
Self-citationCigarette smoke induces cellular senescence
Nyunoya, T., Monick, M. M., Klingelhutz, A., Yarovinsky, T. O., Cagley, J. R., & Hunninghake, G. W. (2006) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2006-0169oc · Cited by 306 · see citing works
González‐Gualda, E., Pàez‐Ribes, M., Lozano‐Torres, B., Macias, D., Wilson, J. R., González‐López, C., Ou, H., Mirón‐Barroso, S., Zhang, Z., Lérida‐Viso, A., et al. (2020) · Aging Cell · doi:10.1111/acel.13142 · Cited by 303 · see citing works
Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies
Tchkonia, T., & Kirkland, J. L. (2018) · JAMA · doi:10.1001/jama.2018.12440 · Cited by 302 · see citing works
Self-citationSuda, M., Shimizu, I., Katsuumi, G., Yoshida, Y., Hayashi, Y., Ikegami, R., Matsumoto, N., Yoshida, Y., Mikawa, R., Katayama, A., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00151-2 · Cited by 290 · see citing works
The economic value of targeting aging
Scott, A. J., Ellison, M., & Sinclair, D. A. (2021) · Nature Aging · doi:10.1038/s43587-021-00080-0 · Cited by 267 · see citing works
Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue
Schafer, M. J., White, T. A., Evans, G., Tonne, J. M., Verzosa, G. C., Stout, M. B., Mazula, D. L., Palmer, A. K., Baker, D. J., Jensen, M. D., et al. (2016) · Diabetes · doi:10.2337/db15-0291 · Cited by 267 · see citing works
Self-citationIL-17 and immunologically induced senescence regulate response to injury in osteoarthritis
Faust, H. J., Zhang, H., Han, J., Wolf, M. T., Jeon, O. H., Sadtler, K., Peña, A. N., Chung, L., Maestas, D. R., Tam, A. J., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci134091 · Cited by 260 · see citing works
St Sauver, J. L., Boyd, C. M., Grossardt, B. R., Bobo, W. V., Finney Rutten, L. J., Roger, V. L., Ebbert, J. O., Therneau, T. M., Yawn, B. P., & Rocca, W. A. (2015) · BMJ Open · doi:10.1136/bmjopen-2014-006413 · Cited by 257 · see citing works
Walaszczyk, A., Dookun, E., Redgrave, R., Tual‐Chalot, S., Victorelli, S., Spyridopoulos, I., Owens, A., Arthur, H. M., Passos, J. F., & Richardson, G. D. (2019) · Aging Cell · doi:10.1111/acel.12945 · Cited by 250 · see citing works
Saccon, T. D., Nagpal, R., Yadav, H., Cavalcante, M. B., Nunes, A. D. D. C., Schneider, A., Gesing, A., Hughes, B., Yousefzadeh, M., Tchkonia, T., et al. (2021) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glab002 · Cited by 247 · see citing works
Self-citationMesenchymal stromal cell apoptosis is required for their therapeutic function
Pang, S. H. M., D’Rozario, J., Mendonca, S., Bhuvan, T., Payne, N. L., Zheng, D., Hisana, A., Wallis, G., Barugahare, A., Powell, D., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26834-3 · Cited by 245 · see citing works
Jin Bing, P. A. N., Li, D., Xu, Y., Zhang, J., Wang, Y., Chen, M., Lin, S., Huang, L., Chung, E. J., Citrin, D. E., et al. (2017) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2017.02.216 · Cited by 244 · see citing works
Tabibian, J. H., O'Hara, S. P., Splinter, P. L., Trussoni, C. E., & LaRusso, N. F. (2014) · Hepatology · doi:10.1002/hep.26993 · Cited by 241 · see citing works
Georgilis, A., Klotz, S., Hanley, C. J., Herranz, N., Weirich, B., Morancho, B., Leote, A. C., D'Artista, L., Gallage, S., Seehawer, M., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.06.007 · Cited by 237 · see citing works
Caron, M., Auclair, M., Donadille, B., Béréziat, V, Guerci, B., Laville, M., Narbonne, H., Bodemer, C., Lascols, O., Capeau, J., et al. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402197 · Cited by 226 · see citing works
mTOR pathway activation drives lung cell senescence and emphysema
Houssaini, A., Breau, M., Kebe, K., Abid, S., Marcos, É., Lipskaia, L., Rideau, D., Parpaleix, A., Huang, J. L., Amsellem, V., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.93203 · Cited by 219 · see citing works
Mylonas, K. J., O'Sullivan, E. D., Humphries, D. C., Baird, D., Docherty, M.-H., Neely, S. A., Krimpenfort, P., Melk, A., Schmitt, R., Ferreira-González, S., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abb0203 · Cited by 216 · see citing works
Biology of premature ageing in survivors of cancer
Cupit-Link, M. C., Kirkland, J. L., Ness, K. K., Armstrong, G. T., Tchkonia, T., LeBrasseur, N. K., Armenian, S. H., Ruddy, K. J., & Hashmi, S. K. (2017) · ESMO Open · doi:10.1136/esmoopen-2017-000250 · Cited by 214 · see citing works
Self-citationNeutrophils induce paracrine telomere dysfunction and senescence in ROS‐dependent manner
Lagnado, A., Leslie, J., Ruchaud‐Sparagano, M., Victorelli, S., Hirsova, P., Ogrodnik, M., Collins, A. L., Vizioli, M. G., Habiballa, L., Saretzki, G., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020106048 · Cited by 211 · see citing works
Self-citationIske, J., Seyda, M., Heinbokel, T., Maenosono, R., Minami, K., Nian, Y., Quante, M., Falk, C. S., Azuma, H., Martin, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18039-x · Cited by 211 · see citing works
Self-citationMetabolism and disposition of dasatinib after oral administration to humans
Christopher, L. J., Cui, D., Wu, C., Luo, R., Manning, J. A., Bonacorsi, S. J., Lago, M., Allentoff, A., Lee, F. Y. F., McCann, B., et al. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.107.018267 · Cited by 202 · see citing works
Cellular senescence in the glaucomatous outflow pathway
Liton, P. B., Challa, P., Stinnett, S. S., Luna, C., Epstein, D. L., & González, P. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.06.005 · Cited by 195 · see citing works
Frailty in childhood cancer survivors
Ness, K. K., Armstrong, G. T., Kundu, M., Wilson, C. L., Tchkonia, T., & Kirkland, J. L. (2015) · Cancer · doi:10.1002/cncr.29211 · Cited by 188 · see citing works
Self-citationSenescence in the pathogenesis of age-related macular degeneration
Blasiak, J. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03420-x · Cited by 183 · see citing works
Crespo-Garcia, S., Tsuruda, P. R., Dejda, A., Ryan, R. D., Fournier, F., Chaney, S. Y., Pilon, F., Dogan, T., Cagnone, G., Patel, P., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.01.011 · Cited by 182 · see citing works
Fang, J., Yang, J., Wu, X., Zhang, G., Li, T., Wang, X., Zhang, H., Wang, C., Liu, G., & Wang, L. (2018) · Aging Cell · doi:10.1111/acel.12765 · Cited by 179 · see citing works
Metformin: A Hopeful Promise in Aging Research
Novelle, M. G., Ali, A., Diéguez, C., Bernier, M., & de Cabo, R. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025932 · Cited by 178 · see citing works
Report: NIA Workshop on Measures of Physiologic Resiliencies in Human Aging
Hadley, E. C., Kuchel, G. A., Newman, A. B., Allore, H. G., Bartley, J. M., Bergeman, C. S., Blinov, M. L., Colon-Emeric, C. S., Dabhar, F. S., Dugan, L. L., et al. (2017) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glx015 · Cited by 173 · see citing works
Self-citationClearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery
Dookun, E., Walaszczyk, A., Redgrave, R., Palmowski, P., Tual‐Chalot, S., Suwana, A., Chapman, J., Jirkovsky, E., Donastorg Sosa, L., Gill, E., et al. (2020) · Aging Cell · doi:10.1111/acel.13249 · Cited by 173 · see citing works
Improving the Supply and Quality of Deceased-Donor Organs for Transplantation
Tullius, S. G., & Rabb, H. (2018) · New England Journal of Medicine · doi:10.1056/nejmra1507080 · Cited by 173 · see citing works
Galactose‐modified duocarmycin prodrugs as senolytics
Guerrero, A., Guiho, R., Herranz, N., Uren, A., Withers, D. J., Martínez‐Barbera, J. P., Tietze, L. F., & Gil, J. (2020) · Aging Cell · doi:10.1111/acel.13133 · Cited by 172 · see citing works
Galactose-modified duocarmycin prodrugs as senolytics
(2019) · doi:10.1101/746669 · Cited by 172 · see citing works
Patil, P. R., Dong, Q. D., Wang, D., Chang, J., Wiley, C. D., Demaria, M., Lee, J., Kang, J. D., Niedernhofer, L. J., Robbins, P. D., et al. (2019) · Aging Cell · doi:10.1111/acel.12927 · Cited by 169 · see citing works
Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity
Wang, L., Wang, B., Gasek, N. S., Zhou, Y., Cohn, R. L., Martin, D. E., Zuo, W., Flynn, W. F., Guo, C., Jellison, E. R., et al. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2021.11.002 · Cited by 163 · see citing works
Self-citationYoshida, S., Nakagami, H., Hayashi, H., Ikeda, Y., Sun, J., Tenma, A., Tomioka, H., Kawano, T., Shimamura, M., Morishita, R., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16347-w · Cited by 161 · see citing works
Conley, S. M., Hickson, L. J., Kellogg, T. A., McKenzie, T. J., Heimbach, J. K., Taner, T., Tang, H. J., Jordan, K. L., Saadiq, I. M., Woollard, J. R., et al. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00197 · Cited by 160 · see citing works
Self-citationDiscovery, development, and future application of senolytics: theories and predictions
Wissler Gerdes, E. O., Zhu, Y., Tchkonia, T., & Kirkland, J. L. (2020) · The FEBS Journal · doi:10.1111/febs.15264 · Cited by 160 · see citing works
Self-citationSenescent cell turnover slows with age providing an explanation for the Gompertz law
Karin, O., Agrawal, A., Porat, Z., Krizhanovsky, V., & Alon, U. (2019) · Nature Communications · doi:10.1038/s41467-019-13192-4 · Cited by 151 · see citing works
Cellular senescence impairs the reversibility of pulmonary arterial hypertension
van der Feen, D. E., Bossers, G. P. L., Hagdorn, Q. A. J., Moonen, J.-R., Kurakula, K., Szulcek, R., Chappell, J., Vallania, F., Donato, M., Kok, K., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aaw4974 · Cited by 150 · see citing works
Wang, B., Wang, L., Gasek, N. S., Zhou, Y., Kim, T., Guo, C., Jellison, E. R., Haynes, L., Yadav, S., Tchkonia, T., et al. (2021) · Nature Aging · doi:10.1038/s43587-021-00107-6 · Cited by 145 · see citing works
Self-citationEfeyan, A., Ortega-Molina, A., Velasco-Miguel, S., Herranz, D., Vassilev, L. T., & Serrano, M. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-0200 · Cited by 140 · see citing works
Increased renal cellular senescence in murine high-fat diet: effect of the senolytic drug quercetin
Kim, S. R., Jiang, K., Ogrodnik, M., Chen, X., Zhu, X.-Y., Lohmeier, H., Ahmed, L., Tang, H., Tchkonia, T., Hickson, L. J., et al. (2019) · Translational Research · doi:10.1016/j.trsl.2019.07.005 · Cited by 139 · see citing works
Self-citationTargeted Reduction of Senescent Cell Burden Alleviates Focal Radiotherapy-Related Bone Loss
Chandra, A., Lagnado, A. B., Farr, J. N., Monroe, D. G., Park, S., Hachfeld, C., Tchkonia, T., Kirkland, J. L., Khosla, S., Passos, J. F., et al. (2020) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3978 · Cited by 138 · see citing works
Self-citationChini, C., Hogan, K. A., Warner, G. M., Tarragó, M. G., Peclat, T. R., Tchkonia, T., Kirkland, J. L., & Chini, E. (2019) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2019.03.199 · Cited by 138 · see citing works
Self-citationPoblocka, M., Bassey, A. L., Smith, V. M., Falcicchio, M., Manso, A. S., Althubiti, M., Sheng, X., Kyle, A., Barber, R., Frigerio, M., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-99852-2 · Cited by 137 · see citing works
Moncsek, A., Al‐Suraih, M. S., Trussoni, C. E., O'Hara, S. P., Splinter, P. L., Zuber, C., Patsenker, E., Valli, P. V., Fingas, C. D., Weber, A., et al. (2018) · Hepatology · doi:10.1002/hep.29464 · Cited by 136 · see citing works
Self-citationNaqvi, K., Jabbour, E., Skinner, J., Anderson, K., Dellasala, S., Yilmaz, M., Ferrajoli, A., Bose, P., Thompson, P., Alvarado, Y., et al. (2020) · Cancer · doi:10.1002/cncr.32504 · Cited by 135 · see citing works
Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease
Cianflone, E., Torella, M., Biamonte, F., Angelis, A. D., Urbanek, K., Costanzo, F. S., Rota, M., Ellison, G. M., & Torella, D. (2020) · Cells · doi:10.3390/cells9061558 · Cited by 134 · see citing works
Tchkonia, T., Palmer, A. K., & Kirkland, J. L. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa728 · Cited by 129 · see citing works
Self-citationJustice, J. N., Gregory, H., Tchkonia, T., LeBrasseur, N. K., Kirkland, J. L., Kritchevsky, S. B., & Nicklas, B. J. (2018) · The Journals of Gerontology: Series A · doi:10.1093/gerona/glx134 · Cited by 129 · see citing works
Self-citationWhy NAD + Declines during Aging: It’s Destroyed
Schultz, M. B., & Sinclair, D. A. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.05.022 · Cited by 126 · see citing works
Farr, J. N., Rowsey, J. L., Eckhardt, B. A., Thicke, B. S., Fraser, D. G., Tchkonia, T., Kirkland, J. L., Monroe, D. G., & Khosla, S. (2019) · Journal of Bone and Mineral Research · doi:10.1002/jbmr.3729 · Cited by 123 · see citing works
Self-citationChandra, A., Lagnado, A. B., Farr, J. N., Doolittle, M., Tchkonia, T., Kirkland, J. L., LeBrasseur, N. K., Robbins, P. D., Niedernhofer, L. J., Ikeno, Y., et al. (2022) · Aging Cell · doi:10.1111/acel.13602 · Cited by 120 · see citing works
Self-citationStout, M. B., Steyn, F. J., Jurczak, M. J., Camporez, J.-P. G., Zhu, Y., Hawse, J. R., Jurk, D., Palmer, A. K., Xu, M., Pirtskhalava, T., et al. (2017) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glv309 · Cited by 119 · see citing works
Self-citationKandhaya‐Pillai, R., Yang, X., Tchkonia, T., Martin, G. M., Kirkland, J. L., & Oshima, J. (2022) · Aging Cell · doi:10.1111/acel.13646 · Cited by 119 · see citing works
Self-citationOocyte aging underlies female reproductive aging: biological mechanisms and therapeutic strategies
Igarashi, H., Takahashi, T., & Nagase, S. (2015) · Reproductive Medicine and Biology · doi:10.1007/s12522-015-0209-5 · Cited by 116 · see citing works
Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases
(2020) · International Review of Neurobiology · doi:10.1016/bs.irn.2020.03.019 · Cited by 114 · see citing works
Self-citationFisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite
Touil, Y. S., Auzeil, N., Boulinguez, F., Saighi, H., Regazzetti, A., Scherman, D., & Chabot, G. G. (2011) · Biochemical Pharmacology · doi:10.1016/j.bcp.2011.07.097 · Cited by 111 · see citing works
Strategies to Prevent or Remediate Cancer and Treatment-Related Aging
Guida, J., Agurs‐Collins, T., Ahles, T. A., Campisi, J., Dale, W., Demark‐Wahnefried, W., Dietrich, J., Fuldner, R., Gallicchio, L. M., Green, P. A., et al. (2020) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djaa060 · Cited by 108 · see citing works
Self-citationProgressive Cellular Senescence Mediates Renal Dysfunction in Ischemic Nephropathy
Kim, S. R., Puranik, A. S., Jiang, K., Chen, X., Zhu, X., Taylor, I., Khodadadi‐Jamayran, A., Lerman, A., Hickson, L. J., Childs, B. G., et al. (2021) · Journal of the American Society of Nephrology · doi:10.1681/asn.2020091373 · Cited by 108 · see citing works
Self-citationKrzystyniak, A., Wesierska, M., Petrazzo, G., Gadecka, A., Dudkowska, M., Bielak-Zmijewska, A., Mosieniak, G., Figiel, I., Wlodarczyk, J., & Sikora, E. (2022) · Aging · doi:10.18632/aging.203835 · Cited by 105 · see citing works
Tripathi, U., Misra, A., Tchkonia, T., & Kirkland, J. L. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111548 · Cited by 104 · see citing works
Self-citationCellular senescence and the skeleton: pathophysiology and therapeutic implications
Khosla, S., Farr, J. N., & Monroe, D. G. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154888 · Cited by 104 · see citing works
Xu, L., Tang, F., Li, L., & Dong, X. Q. (2017) · The Journals of Gerontology Series A · doi:10.1093/gerona/glw186 · Cited by 103 · see citing works
Strategies for late phase preclinical and early clinical trials of senolytics
Gerdes, E. O. W., Misra, A., Espíndola‐Netto, J. M., Tchkonia, T., & Kirkland, J. L. (2021) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2021.111591 · Cited by 101 · see citing works
Self-citationTransposon-triggered innate immune response confers cancer resistance to the blind mole rat
Zhao, Y., Oreskovic, E., Zhang, Q., Lu, Q., Gilman, A., Lin, Y. S., He, J., Zheng, Z., Lu, J. Y., Lee, J., et al. (2021) · Nature Immunology · doi:10.1038/s41590-021-01027-8 · Cited by 99 · see citing works
Orally-active, clinically-translatable senolytics restore α-Klotho in mice and humans
Zhu, Y., Prata, L. G. P. L., Gerdes, E. O. W., Netto, J. M. E., Pirtskhalava, T., Giorgadze, N., Tripathi, U., Inman, C. L., Johnson, K. O., Xue, A., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.103912 · Cited by 96 · see citing works
Self-citationThe role of senescent T cells in immunopathology
Covre, L. P., De Maeyer, R. P. H., Gomes, D. C. O., & Akbar, A. N. (2020) · Aging Cell · doi:10.1111/acel.13272 · Cited by 93 · see citing works
Down-syndrome-induced senescence disrupts the nuclear architecture of neural progenitors
Meharena, H. S., Marco, A., Dileep, V., Lockshin, E. R., Akatsu, G. Y., Mullahoo, J., Watson, L. A., Ko, T., Guerin, L. N., Abdurrob, F., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2021.12.002 · Cited by 92 · see citing works
Tripathi, U., Nchioua, R., Prata, L. G. P. L., Zhu, Y., Gerdes, E. O. W., Giorgadze, N., Pirtskhalava, T., Parker, E., Xue, A., Espindola-Netto, J. M., et al. (2021) · Aging · doi:10.18632/aging.203560 · Cited by 88 · see citing works
Self-citationCellular senescence-mediated exacerbation of Duchenne muscular dystrophy
Sugihara, H., Teramoto, N., Nakamura, K., Shiga, T., Shirakawa, T., Matsuo, M., Ogasawara, M., Nishino, I., Matsuwaki, T., Nishihara, M., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-73315-6 · Cited by 85 · see citing works
Hyperoxia-Induced Cellular Senescence in Fetal Airway Smooth Muscle Cells
Parikh, P., Britt, R. D., Manlove, L. J., Wicher, S. A., Roesler, A. M., Ravix, J., Teske, J. J., Thompson, M. A., Sieck, G. C., Kirkland, J. L., et al. (2018) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2018-0176oc · Cited by 84 · see citing works
Self-citationTsuji, S., Minami, S., Hashimoto, R., Konishi, Y., Suzuki, T., Kondo, T., Sasai, M., Torii, S., Ono, C., Shichinohe, S., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00170-7 · Cited by 84 · see citing works
Vázquez-Villaseñor, I., Garwood, C. J., Heath, P. R., Simpson, J. E., Ince, P. G., & Wharton, S. B. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12559 · Cited by 80 · see citing works
Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice
Cavalcante, M. B., Saccon, T. D., Nunes, A. D. C., Kirkland, J. L., Tchkonia, T., Schneider, A., & Masternak, M. M. (2020) · Aging · doi:10.18632/aging.102772 · Cited by 80 · see citing works
Self-citationTransplanting cells from old but not young donors causes physical dysfunction in older recipients
Wang, B., Liu, Z., Chen, V. P., Wang, L., Inman, C. L., Zhou, Y., Guo, C., Tchkonia, T., Rowe, D. W., Kuchel, G. A., et al. (2020) · Aging Cell · doi:10.1111/acel.13106 · Cited by 76 · see citing works
Self-citationSuvakov, S., Cubro, H., White, W. M., Butler Tobah, Y. S., Weissgerber, T. L., Jordan, K. L., Zhu, X. Y., Woollard, J. R., Chebib, F. T., Milic, N. M., et al. (2019) · Biology of Sex Differences · doi:10.1186/s13293-019-0263-5 · Cited by 76 · see citing works
Self-citationGlaucoma: A Disease of Early Cellular Senescence
Caprioli, J. (2013) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.13-12716 · Cited by 72 · see citing works
Modulation of fracture healing by the transient accumulation of senescent cells
Saul, D., Monroe, D. G., Rowsey, J. L., Kosinsky, R. L., Vos, S. J., Doolittle, M. L., Farr, J. N., & Khosla, S. (2021) · eLife · doi:10.7554/elife.69958 · Cited by 71 · see citing works
Rocha, L. R., Nguyen Huu, V. A., Palomino La Torre, C., Xu, Q., Jabari, M., Krawczyk, M., Weinreb, R. N., & Skowronska‐Krawczyk, D. (2020) · Aging Cell · doi:10.1111/acel.13089 · Cited by 68 · see citing works
Josefsson, E. C., Vainchenker, W., & James, C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207591 · Cited by 68 · see citing works
Senolytic treatment rescues blunted muscle hypertrophy in old mice
Dungan, C. M., Figueiredo, V. C., Wen, Y., VonLehmden, G. L., Zdunek, C. J., Thomas, N. T., Mobley, C. B., Murach, K. A., Brightwell, C. R., Long, D. E., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00542-2 · Cited by 65 · see citing works
Selective Vulnerability of Senescent Glioblastoma Cells to BCL-XL Inhibition
Rahman, M., Olson, I., Mansour, M. A., Carlstrom, L. P., Sutiwisesak, R., Saber, R., Rajani, K. R., Warrington, A. E., Howard, A., Schroeder, M. A., et al. (2022) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-21-0029 · Cited by 63 · see citing works
Self-citationHickson, L. J., Langhi Prata, L. G. P., Bobart, S. A., Evans, T. K., Giorgadze, N., Hashmi, S. K., Herrmann, S. M., Jensen, M. D., Jia, Q., Jordan, K. L., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2019.12.004 · Cited by 59 · see citing works
Self-citationFatt, M. P., Tran, L. M., Vetere, G., Storer, M. A., Simonetta, J. V., Miller, F. D., Frankland, P. W., & Kaplan, D. R. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.12.010 · Cited by 58 · see citing works
BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells
Afreen, S., Bohler, S., Müller, A., Demmerath, E.-M., Weiss, J. M., Jutzi, J. S., Schachtrup, K., Kunze, M., & Erlacher, M. (2020) · Cell Death & Disease · doi:10.1038/s41419-019-2203-z · Cited by 55 · see citing works
Inflammation and survival pathways: Chronic lymphocytic leukemia as a model system
Chen, L. S., Balakrishnan, K., & Gandhi, V. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.07.039 · Cited by 55 · see citing works
Yu, S., Kim, S. R., Jiang, K., Ogrodnik, M. B., Zhu, X. Y., Ferguson, C. M., Tchkonia, T., Lerman, A., Kirkland, J. L., & Lerman, L. O. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/8875729 · Cited by 53 · see citing works
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Kim, D. H., & Rockwood, K. J. (2024) · New England Journal of Medicine · doi:10.1056/nejmra2301292 · Cited by 892 · see citing works
Chronic inflammation and the hallmarks of aging
Baechle, J. J., Chen, N., Makhijani, P., Winer, S., Furman, D., & Winer, D. A. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101755 · Cited by 471 · see citing works
“com Notably, caloric restriction-mimetic therapies, such as metformin [176], rilmenidine [177], rapamycin, and “rapalogs” [178], as well as senolytic drugs [179,180], are proposed to exert anti-inflammaging effect by activating autophagic processes, including mitophagy and CMA, thus promoting the proper disposal of da…”
BackgroundSenNet recommendations for detecting senescent cells in different tissues
Suryadevara, V., Hudgins, A. D., Rajesh, A., Pappalardo, A., Karpova, A., Dey, A. K., Hertzel, A., Agudelo, A., Rocha, A., Soygur, B., et al. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00738-8 · Cited by 408 · see citing works
“We refer the readers to the many Review articles that cover topics such as the links between cellular senescence, metastatic cancer 267 and endocrine diseases 268 , and the current status of the search for senolytics 269 .”
Bao, H., Cao, J., Chen, M., Min, C., Chen, W., Chen, X., Chen, Y., Chen, Y., Chen, Y., Chen, Z., et al. (2023) · Science China Life Sciences · doi:10.1007/s11427-023-2305-0 · Cited by 389 · see citing works
Guidelines for minimal information on cellular senescence experimentation in vivo
Ogrodnik, M., Carlos Acosta, J., Adams, P. D., d’Adda di Fagagna, F., Baker, D. J., Bishop, C. L., Chandra, T., Collado, M., Gil, J., Gorgoulis, V., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.059 · Cited by 376 · see citing works
Self-citationObese visceral fat tissue inflammation: from protective to detrimental?
Kolb, H. (2022) · BMC Medicine · doi:10.1186/s12916-022-02672-y · Cited by 378 · see citing works
Targeting angiogenesis in oncology, ophthalmology and beyond
Cao, Y., Langer, R., & Ferrara, N. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-023-00671-z · Cited by 333 · see citing works
Current and investigational medications for the treatment of sarcopenia
Rolland, Y., Dray, C., Vellas, B., & Barreto, P. D. S. (2023) · Metabolism · doi:10.1016/j.metabol.2023.155597 · Cited by 195 · see citing works
P16INK4A—More Than a Senescence Marker
Safwan‐Zaiter, H., Wagner, N., & Wagner, K. (2022) · Life · doi:10.3390/life12091332 · Cited by 194 · see citing works
Current and Future Treatment Landscape for Idiopathic Pulmonary Fibrosis
Bonella, F., Spagnolo, P., & Ryerson, C. J. (2023) · Drugs · doi:10.1007/s40265-023-01950-0 · Cited by 188 · see citing works
Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases
Zeng, Q., Gong, Y., Zhu, N., Shi, Y., Zhang, C., & Li, Q. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102294 · Cited by 188 · see citing works
The role of p21 in cellular senescence and aging-related diseases
Yan, J., Chen, S., Yi, Z., Zhao, R., Zhu, J., Shuwen, D., & Wu, J. (2024) · Molecules and Cells · doi:10.1016/j.mocell.2024.100113 · Cited by 181 · see citing works
Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases
Ji, S., Xiong, M., Chen, H., Liu, Y., Zhou, L., Hong, Y., Wang, M., Wang, C., Fu, X., & Sun, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01343-5 · Cited by 166 · see citing works
“The fact that SCs exhibit resistance to apoptosis supports the idea that these SCs rely on antiapoptotic, pro-survival mechanisms to prevent selfdestruction.(288) Recent advances have evoked the development of senolytic compounds that work to target the SCAP network nodes and impair the defenses of SCs against apoptos…”
BackgroundAntiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
Jiang, Q., Liu, J., Huang, S., Wang, X.-Y., Chen, X., Liu, G.-H., Ye, K., Song, W., Masters, C. L., Wang, J., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02145-7 · Cited by 165 · see citing works
Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
Tao, W., Yu, Z., & Han, J.-D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.009 · Cited by 147 · see citing works
Cellular senescence in brain aging and neurodegeneration
dos Santos, L. M., Trombetta-Lima, M., Eggen, B. J. L., & Demaria, M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102141 · Cited by 158 · see citing works
SGLT2 inhibition eliminates senescent cells and alleviates pathological aging
Katsuumi, G., Shimizu, I., Suda, M., Yoshida, Y., Furihata, T., Joki, Y., Hsiao, C.-L., Liang, J., Fujiki, S., Abe, M., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00642-y · Cited by 145 · see citing works
“…have shown that in mice, elimination of senescent cells (senolysis) improves some of the pathological consequences of aging, such as cardiovascular disease, metabolic disease, renal dysfunction and bone loss, and extends the healthy lifespan without increasing the incidence of cancer 7,11–15 .”
Emerging role of senescent microglia in brain aging-related neurodegenerative diseases
Rim, C., You, M., Nahm, M., & Kwon, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00402-3 · Cited by 147 · see citing works
“According to the threshold theory of senescent cell accumulation [54], when the number of senescent cells in the body rises to surpass a threshold, the immune system and other organs would be more prone to aging-related diseases [55].”
BackgroundThe role of cellular senescence in skin aging and age-related skin pathologies
Chin, T., Lee, X. E., Ng, P. Y., Lee, Y., & Dreesen, O. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1297637 · Cited by 154 · see citing works
Stress, epigenetics, and aging: Unraveling the intricate crosstalk
Wu, Z., Qu, J. T., Zhang, W., & Liu, G. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.10.006 · Cited by 142 · see citing works
Lelarge, V., Capelle, R., Oger, F., Mathieu, T., & Calvé, B. L. (2024) · npj Aging · doi:10.1038/s41514-024-00138-4 · Cited by 147 · see citing works
“Different senolytics have been developed in the antibody or small drug fi elds but nothing regarding senescent cells due to the lack of identi fi cation of speci fi c surface targets on these cells 51 .”
BackgroundThe Impact of Immune System Aging on Infectious Diseases
Quiros-Roldan, E., Sottini, A., Natali, P. G., & Imberti, L. (2024) · Microorganisms · doi:10.3390/microorganisms12040775 · Cited by 133 · see citing works
“Several senolytic clinical trials have been completed, are current, or are planned for the near future [259], which include those focusing on immunosenescence or inflammaging [260–262].”
Targeting Senescence: A Review of Senolytics and Senomorphics in Anti-Aging Interventions
Saliev, T. M., & Singh, P. B. (2025) · Biomolecules · doi:10.3390/biom15060860 · Cited by 140 · see citing works
“Moreover, long-term administration of senomorphics may create pharmacodynamic tolerance, necessitating escalating doses or combination therapies [96].”
Li, S., Livingston, M. J., Ma, Z., Hu, X., Wen, L., Ding, H., Zhou, D., & Dong, Z. (2023) · JCI Insight · doi:10.1172/jci.insight.166643 · Cited by 130 · see citing works
“Targeted elimination of chronic senescent cells by small-molecule senolytic drugs and/or disruption of the key events of senescence, such as SASP, by senomorphic agents have recently emerged as a promising therapeutic strategy for preventing or treating these diseases in both preclinical settings and clinical trials (…”
New Dawn for Atherosclerosis: Vascular Endothelial Cell Senescence and Death
Bu, L.-L., Yuan, H., Xie, L., Guo, M.-H., Liao, D., & Zheng, X. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015160 · Cited by 129 · see citing works
Cigarette Smoke-Induced Respiratory Response: Insights into Cellular Processes and Biomarkers
Cha, S.-R., Jang, J., Park, S., Ryu, S. M., Cho, S.-J., & Yang, S. (2023) · Antioxidants · doi:10.3390/antiox12061210 · Cited by 132 · see citing works
Cellular senescence in lung cancer: Molecular mechanisms and therapeutic interventions
Jha, S. K., Rubis, G. D., Devkota, S. R., Zhang, Y., Adhikari, R., Jha, L. A., Bhattacharya, K., Mehndiratta, S., Gupta, G., Singh, S. K., et al. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102315 · Cited by 122 · see citing works
“Contrarily, other research revealed that getting rid of senescent cells is advantageous and that they can even cause harm to those same tissues (Chaib et al., 2022b).”
BackgroundLocal H2 release remodels senescence microenvironment for improved repair of injured bone
Chen, S., Yu, Y., Xie, S., Liang, D., Shi, W. K., Chen, S., Li, G., Tang, W., Liu, C., & He, Q. (2023) · Nature Communications · doi:10.1038/s41467-023-43618-z · Cited by 130 · see citing works
“But moderate senescence can induce the generation of regeneration-associated SASP components such as Ereg in favor of tissue regeneration 38 – 40 , possibly because the degree of senescence is below the threshold.”
Farr, J. N., Atkinson, E. J., Achenbach, S. J., Volkman, T. L., Tweed, A. J., Vos, S. J., Ruan, M., Sfeir, J., Drake, M. T., Saul, D., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-03096-2 · Cited by 127 · see citing works
“Although preclinical studies have found beneficial effects of clearing senescent cells in aged mice on measures of frailty, cognition, glucose tolerance, cardiovascular function and others 6 , we chose bone metabolism as an outcome for several reasons.”
Self-citationInflammation‐mediated metabolic regulation in adipose tissue
Xu, S., Lu, F., Gao, J., & Yuan, Y. (2024) · Obesity Reviews · doi:10.1111/obr.13724 · Cited by 129 · see citing works
“54 In addition, the concentration of adiponectin increases in aging adipose tissue, 55 and leptin resistance develops.”
BackgroundBelle, J. I., Sen, D., Baer, J. M., Liu, X., Lander, V. E., Ye, J., Sells, B. E., Knolhoff, B. L., Ahmad, F. F., Kang, L., et al. (2024) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0428 · Cited by 123 · see citing works
Gaikwad, S., Senapati, S., Haque, M. A., & Kayed, R. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13490 · Cited by 117 · see citing works
Cellular senescence: Neither irreversible nor reversible
Reimann, M., Lee, S., & Schmitt, C. A. (2024) · The Journal of Experimental Medicine · doi:10.1084/jem.20232136 · Cited by 120 · see citing works
Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment
Maggiorani, D., Lê, O., Lisi, V., Landais, S., Moquin‐Beaudry, G., Lavallée, V., Decaluwe, H., & Beausejour, C. M. (2024) · Nature Communications · doi:10.1038/s41467-024-46769-9 · Cited by 123 · see citing works
“However, there are no candidate factors identified as mediating these effects and thus we are left with an interesting description that is not further substantiated by offering potential hits to revert this immunosuppressive tumor microenvironment.”
Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging
Zhou, Z., Yao, J., Wu, D., Huang, X., Wang, Y., Li, X., Lu, Q., & Qiu, Y. (2024) · Immunity · doi:10.1016/j.immuni.2024.01.001 · Cited by 120 · see citing works
The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2
Chaib, S., López-Domínguez, J. A., Lalinde-Gutiérrez, M., Prats, N., Marin, I., Boix, O., García-Garijo, A., Meyer, K., Muñoz, M. I., Aguilera, M., et al. (2024) · Nature Cancer · doi:10.1038/s43018-023-00712-x · Cited by 114 · see citing works
“The SASP is complex and heterogeneous, including pro-inflammatory cytokines, chemokines, matrix remodeling enzymes and growth factors, which result in cell-extrinsic effects known to facilitate tumor growth 22–25 .”
InfluentialSelf-citationCell senescence in liver diseases: pathological mechanism and theranostic opportunity
Sanfeliu-Redondo, D., Gibert-Ramos, A., & Gracia-Sancho, J. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00913-4 · Cited by 117 · see citing works
“…to the intermittent administration of senolytics, which proves effective, the beneficial effects of senom-orphics might necessitate regular and prolonged usage, which could potentially give rise to unforeseen adverse effects and induce off-target effects by suppressing cytokine secretion 151 .”
Increased cell senescence in human metabolic disorders
Spinelli, R., Baboota, R. K., Gogg, S., Bèguinot, F., Blüher, M., Nerstedt, A., & Smith, U. (2023) · Journal of Clinical Investigation · doi:10.1172/jci169922 · Cited by 117 · see citing works
“Senescent cells have also been directly linked to the development of IR, as demonstrated with the use of senolytics in several preclinical models of aging and metabolic disease (15, 101).”
Senescent Cells: A Therapeutic Target in Cardiovascular Diseases
Suda, M., Paul, K. H., Minamino, T., Miller, J. D., Lerman, A., Ellison, G. M., Tchkonia, T., & Kirkland, J. L. (2023) · Cells · doi:10.3390/cells12091296 · Cited by 116 · see citing works
“Furthermore, since cellular senescence and other underlying causes of these age-associated chronic diseases (the hallmarks of aging) are interlinked with each other, intervening against any one of them may affect most or all of the other aging processes, as expressed in “The Unitary Theory of Fundamental Aging Mechani…”
BackgroundInfluentialSelf-citationRejuvenating Aged Bone Repair through Multihierarchy Reactive Oxygen Species‐Regulated Hydrogel
He, Z., Sun, C., Ma, Y., Chen, X., Wang, Y., Chen, K., Xie, F., Zhang, Y., Yuan, Y., & Liu, C. (2023) · Advanced Materials · doi:10.1002/adma.202306552 · Cited by 106 · see citing works
Ahuja, S. K., Manoharan, M. S., Lee, G. C., McKinnon, L. R., Meunier, J. A., Steri, M., Harper, N., Fiorillo, E., Smith, A. M., Restrepo, M. I., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38238-6 · Cited by 106 · see citing works
Systemic Aging Fuels Heart Failure: Molecular Mechanisms and Therapeutic Avenues
Fang, Z., Raza, U., Song, J., Lu, J., Yao, S., Liu, X., Zhang, W., & Li, S. (2024) · ESC Heart Failure · doi:10.1002/ehf2.14947 · Cited by 114 · see citing works
“117 Growing evidence suggests that senescent cells contribute to cardiac remodelling and dysfunction during aging.”
Obesity-related kidney disease: Beyond hypertension and insulin-resistance
Arabi, T. Z., Shafqat, A., Sabbah, B. N., Ashraf, N., Shah, H., Abdulkader, H. S., Razak, A., Sabbah, A. N., & Arabi, Z. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1095211 · Cited by 98 · see citing works
“Many preclinical studies have shown senolytics to alleviate aging phenotypes, including cancer, chemotherapy-and radiation-induced premature aging, diabetes, osteoarthritis, neurodegeneration, glaucoma, age-related macular degeneration, idiopathic pulmonary fi brosis, heart failure, and CKD (180).”
Clayton, Z. S., Rossman, M. J., Mahoney, S. A., Venkatasubramanian, R., Maurer, G. S., Hutton, D. A., VanDongen, N. S., Greenberg, N. T., Longtine, A. G., Ludwig, K. R., et al. (2023) · Hypertension · doi:10.1161/hypertensionaha.123.21392 · Cited by 84 · see citing works
Challenges in developing Geroscience trials
Rolland, Y., Sierra, F., Ferrucci, L., Barzilai, N., de Cabo, R., Mannick, J. B., Oliva, A. A., Evans, W. J., Angioni, D., Barreto, P. D. S., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39786-7 · Cited by 94 · see citing works
“Indeed,the concepts of Geroscience potentially apply to the entire life course and open up therapeutic perspectives beyond geriatric medicine 6 .”
BackgroundSelf-citationLópez-Polo, V., Maus, M., Zacharioudakis, E., Lafarga, M., Attolini, C. S., Marques, F. M., Kovatcheva, M., Gavathiotis, E., & Serrano, M. (2024) · Nature Communications · doi:10.1038/s41467-024-51363-0 · Cited by 96 · see citing works
Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells
Bi, Y., Qiao, X., Cai, Z., Zhao, H., Ye, R., Liu, Q., Gao, L., Liu, Y., Liang, B., Liu, Y., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2024.11.013 · Cited by 98 · see citing works
Fisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases
Tavenier, J., Nehlin, J. O., Houlind, M. B., Rasmussen, L. J., Tchkonia, T., Kirkland, J. L., Andersen, O., & Rasmussen, L. J. H. (2024) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2024.111995 · Cited by 97 · see citing works
“…discovery of senotherapeutic agents: senomorphics that inhibit and/or modulate the SASP, and senolytics that selectively eliminate senescent cells (Chaib et al., 2022; Dolgin, 2020; Gur ˘ au et al., 2018; Kirkland and Tchkonia, 2020; Lagoumtzi and Chondrogianni, 2021; Nehlin, 2023, 2021; Tchkonia…”
InfluentialSelf-citationp53/MDM2 signaling pathway in aging, senescence and tumorigenesis
Huang, Y., Che, X., Wang, P., & Qu, X. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.05.001 · Cited by 92 · see citing works
Ferroptosis and Senescence: A Systematic Review
Coradduzza, D., Congiargiu, A., Chen, Z., Zinellu, A., Carru, C., & Medici, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24043658 · Cited by 93 · see citing works
“[17] have shown that it is possible to affect longevity by interfering with several metabolic pathways such as insulin-like growth factor-1 (IGF-1), hypoxia-inducible factor (hif-1) and heat shock factor (HSF-1) on C.”
BackgroundPathological mechanisms of kidney disease in ageing
Yamamoto, T., & Isaka, Y. (2024) · Nature Reviews Nephrology · doi:10.1038/s41581-024-00868-4 · Cited by 94 · see citing works
“senomorphic agents, or through the inhibition of processes that promote the accumulation of senescent cells, might therefore represent promising therapeutic strategies for preventing or treating age-related diseases 36,47,48 .”
Emerging insights in senescence: pathways from preclinical models to therapeutic innovations
Mansfield, L., Ramponi, V., Gupta, K., Stevenson, T., Mathew, A. B., Barinda, A. J., Herbstein, F., & Morsli, S. (2024) · npj Aging · doi:10.1038/s41514-024-00181-1 · Cited by 91 · see citing works
Current senolytics: Mode of action, efficacy and limitations, and their future
Rad, A. N., & Grillari, J. (2023) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2023.111888 · Cited by 86 · see citing works
Millar, C. L., Iloputaife, I., Baldyga, K., Norling, A. M., Boulougoura, A., Vichos, T., Tchkonia, T., Deisinger, A., Pirtskhalava, T., Kirkland, J. L., et al. (2025) · EBioMedicine · doi:10.1016/j.ebiom.2025.105612 · Cited by 88 · see citing works
Self-citationSenolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
Aguado, J., Amarilla, A. A., Taherian Fard, A., Albornoz, E. A., Tyshkovskiy, A., Schwabenland, M., Chaggar, H. K., Modhiran, N., Gómez-Inclán, C., Javed, I., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00519-6 · Cited by 80 · see citing works
“Among these, the pharmacological removal of senescent cells with senolytic drugs has become one of the most explored interventions, with many currently in human clinical trials 26 .”
Redox changes and cellular senescence in Alzheimer's disease
Yu, N., Pasha, M., & Chua, J. J. E. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103048 · Cited by 80 · see citing works
“Many clinical trials involving senolytic therapeutic interventions are ongoing [156], with a recently completed D + Q trial (NCT04063124) that has focused on AD [157, 158].”
BackgroundCellular senescence and the host immune system in aging and age-related disorders
Giannoula, Y., Kroemer, G., & Pietrocola, F. (2023) · Biomedical Journal · doi:10.1016/j.bj.2023.02.001 · Cited by 81 · see citing works
“cells) and senolytics, defined as molecules that trigger the selective apoptosis of senescent cells [12].”
BackgroundStrategies for senolytic drug discovery
Power, H., Valtchev, P., Dehghani, F., & Schindeler, A. (2023) · Aging Cell · doi:10.1111/acel.13948 · Cited by 81 · see citing works
“…vary across cell types, within the same cells in response to various senescence inducers, at different time points post-induction, and even between experiments conducted in the same lab (Althubiti et al., 2014 ; Hernandez-Segura et al., 2017). ing to phase III or beyond (Chaib et al., 2022).”
BackgroundJang, D. S., Shin, J., Shim, E., Ohtani, N., & Jeon, O. H. (2024) · Aging Cell · doi:10.1111/acel.14315 · Cited by 84 · see citing works
“These interventions target inflam - mation or oxidative stress to attenuate inflammageing (Diwan & Sharma, 2022 ) and promote healthy aging by addressing cellular senescence (Chaib et al., 2022; Zhang et al., 2017 ; Zhu et al., 2021 ).”
BackgroundThe YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress
Anerillas, C., Mazan-Mamczarz, K., Herman, A. B., Munk, R., Lam, K.-W. G., Calvo-Rubio, M., Garrido, A., Tsitsipatis, D., Martindale, J. L., Altés, G., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00480-4 · Cited by 76 · see citing works
Cheng, Z., Gan, W., Xiang, Q., Zhao, K., Gao, H., Chen, Y., Shi, P., Zhang, A., Li, G., Song, Y., et al. (2024) · Autophagy · doi:10.1080/15548627.2024.2395797 · Cited by 81 · see citing works
Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction
Suda, M., Paul, K. H., Tripathi, U., Minamino, T., Tchkonia, T., & Kirkland, J. L. (2024) · Endocrine Reviews · doi:10.1210/endrev/bnae010 · Cited by 81 · see citing works
Self-citationTargeting cellular senescence in metabolic disease
Palmer, A. K., Tchkonia, T., & Kirkland, J. L. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101601 · Cited by 75 · see citing works
“Challenges for clinical trials targeting senescent cells Standard biomarkers for aging have not been established, although expert panels have convened to tackle a framework for clinical trials going forward [80,81].”
BackgroundSelf-citationThe role of the dynamic epigenetic landscape in senescence: orchestrating SASP expression
Dasgupta, N., Arnold, R., Equey, A., Gandhi, A., & Adams, P. D. (2024) · npj Aging · doi:10.1038/s41514-024-00172-2 · Cited by 86 · see citing works
Cellular senescence in brain aging and cognitive decline
Shafqat, A., Khan, S., Omer, M. H., Niaz, M., Albalkhi, I., AlKattan, K. M., Yaqinuddin, A., Tchkonia, T., Kirkland, J. L., & Hashmi, S. K. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1281581 · Cited by 75 · see citing works
“The timeline of senolytic drug discovery, i.e., their evolution from benchwork to clinical trials, has recently been reviewed (see Chaib et al., 2022).”
BackgroundSelf-citationMuthamil, S., Kim, H., Jang, H., Lyu, J., Shin, U. C., Go, Y., Park, S., Lee, H. G., & Park, J. H. (2024) · Advanced Biology · doi:10.1002/adbi.202400079 · Cited by 79 · see citing works
Giroud, J., Bouriez, I., Paulus, H., Pourtier, A., Debacq‐Chainiaux, F., & Pluquet, O. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310788 · Cited by 77 · see citing works
Bloom, S. I., Liu, Y., Tucker, J. R., Islam, M. T., Machin, D. R., Abdeahad, H., Thomas, T. G., Bramwell, R. C., Lesniewski, L. A., & Donato, A. J. (2023) · Aging Cell · doi:10.1111/acel.13875 · Cited by 72 · see citing works
Senescence-resistant human mesenchymal progenitor cells counter aging in primates
Lei, J., Xin, Z., Liu, N., Ning, T., Jing, Y., Qiao, Y., He, Z., Jiang, M., Yang, Y., Zhang, Z., et al. (2025) · Cell · doi:10.1016/j.cell.2025.05.021 · Cited by 82 · see citing works
Emerging epigenetic insights into aging mechanisms and interventions
Wu, Z., Zhang, W., Qu, J. T., & Liu, G. (2024) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2023.12.002 · Cited by 74 · see citing works
Venn-Watson, S. K., & Schork, N. J. (2023) · Nutrients · doi:10.3390/nu15214607 · Cited by 74 · see citing works
Targeting senescent cells with NKG2D-CAR T cells
Deng, Y., Kumar, A., Xie, K., Schaaf, K., Scifo, E., Morsy, S., Li, T., Ehninger, A., Bano, D., & Ehninger, D. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-01976-7 · Cited by 70 · see citing works
“However, existing pharmacological approaches are not speci fi c for senescent cells and are, hence, associated with side effects, which limits their translational potential [21].”
Hallmarks and mechanisms of cellular senescence in aging and disease
Ajoolabady, A., Praticò, D., Bahijri, S., Eldakhakhny, B. M., Tuomilehto, J. O., Wu, F., & Ren, J. T. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02655-x · Cited by 79 · see citing works
“More notably, they secret a variety of cytokines, chemokines, growth factor, immune modulators, proteases, and matrix metalloproteinases (MMPs), collectively known as the “ senescence-associated secretary phenotype (SASP) ” [12 – 14].”
Lyons, C. E., Razzoli, M., & Bartolomucci, A. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105359 · Cited by 74 · see citing works
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 74 · see citing works
“These broad-spectrum senolytics have the capacity to impact multiple senescence pathways simultaneously 177 ; however, they present a challenge in predicting efficacy owing to the considerable heterogeneity between senescent cell populations.”
Senescence: A DNA damage response and its role in aging and Neurodegenerative Diseases
Shreeya, T., Ansari, M. S., Kumar, P., Saifi, M., Shati, A. A., Alfaifi, M. Y., & Elbehairi, S. E. I. (2024) · Frontiers in Aging · doi:10.3389/fragi.2023.1292053 · Cited by 67 · see citing works
“Exploiting both of these could be a useful therapeutic strategy against cancer and age related neurodegenerative diseases (Chaib et al., 2022).”
BackgroundSenescent stromal cells: roles in the tumor microenvironment
Gabai, Y., Assouline, B., & Ben‐Porath, I. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.09.002 · Cited by 63 · see citing works
Gustafsson, T. P., & Ulfhake, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252010932 · Cited by 65 · see citing works
“These strategies include stem cell transplantation, adjuvant endocrine therapy, senotherapies against senescent cells burden and their SAPs, and the use of molecules secreted by exercised myofibres (secretome) [62,69,93,94,121–126].”
BackgroundSenescence 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 65 · see citing works
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 67 · see citing works
“Cellular senescence, a state of irreversible cell cycle arrest accompanied by characteristic molecular, morphological, and functional alterations, has emerged as a key therapeutic target in aging and chronic diseases, including neurodegenerative diseases (Kirkland et al., 2017; Kirkland and Tchkonia, 2017, 2020; Herna…”
BackgroundSenescent 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 61 · see citing works
Osteoclasts and osteoarthritis: Novel intervention targets and therapeutic potentials during aging
Wang, H., Yuan, T., Wang, Y., Liu, C., Li, D., Li, Z., & Sun, S. (2024) · Aging Cell · doi:10.1111/acel.14092 · Cited by 60 · see citing works
“Due to the huge challenges and costs involved in new drug development, current studies of senotherapies mainly focus on identifying the therapeutic effects of natural compounds or existing drugs which have already received Food and Drug Administration (FDA) approval (Chaib et al., 2022).”
BackgroundInfluentialMitochondrial dysfunction and aging: multidimensional mechanisms and therapeutic strategies
Wei, P., Zhang, X., Yan, C., Sun, S., Chen, Z., & Lin, F. (2025) · Biogerontology · doi:10.1007/s10522-025-10273-4 · Cited by 60 · see citing works
“…studies have confirmed that NF-κB pathway-specific antagonists effectively suppress pro-inflammatory cytokine networks in vitro and in vivo, demonstrating significant therapeutic potential through the selective modulation of the senescence-associated secretory circuitry (Chaib et al. 2022).”
Xu, W., Li, X., Zhong, Y.-S., He, J., Xie, W., Kang, Y.-K., Ying, H., & Yu, C.-H. (2025) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2025.123381 · Cited by 57 · see citing works
Magkouta, S., Veroutis, D., Papaspyropoulos, A., Georgiou, M., Lougiakis, N., Pippa, Ν., Havaki, S., Palaiologou, A., Thanos, D.-F., Kambas, K., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00747-4 · Cited by 62 · see citing works
Cellular Senescence in Human Skin Aging: Leveraging Senotherapeutics
Wyles, S. P., CARRUTHERS, J. D. A., Dashti, P., Yu, G., Yap, J. Q., Gingery, A., Tchkonia, T., & Kirkland, J. L. (2023) · Gerontology · doi:10.1159/000534756 · Cited by 65 · see citing works
Self-citationRoadmap for alleviating the manifestations of ageing in the cardiovascular system
Liberale, L., Tual-Chalot, S., Sedej, S., Ministrini, S., Georgiopoulos, G., Grunewald, M., Bäck, M., Bochaton-Piallat, M.-L., Boon, R. A., Ramos, G. C., et al. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01130-5 · Cited by 59 · see citing works
Self-citationDańczak‐Pazdrowska, A., Gornowicz‐Porowska, J., Polańska, A., Krajka‐Kuźniak, V., Stawny, M., Gostyńska, A., Rubiś, B., Noureddine, S. A., Ashiqueali, S., Schneider, A., et al. (2023) · Aging Cell · doi:10.1111/acel.13845 · Cited by 63 · see citing works
“, embryonic development) and detrimental roles (tumor promotion, age- related disorders, obesity, diabetes) (Chaib et al., 2022; Tominaga, 2015).”
BackgroundInfluentialSelf-citationLivshits, G., & Kalinkovich, A. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101852 · Cited by 55 · see citing works
Impact of Geroscience on Therapeutic Strategies for Older Adults With Cardiovascular Disease
Forman, D. E., Kuchel, G. A., Newman, J. C., Kirkland, J. L., Volpi, E., Taffet, G. E., Barzilai, N., Pandey, A., Kitzman, D. W., Libby, P., et al. (2023) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2023.05.038 · Cited by 63 · see citing works
Self-citationKandhaya‐Pillai, R., Miró‐Mur, F., Alijotas‐Reig, J., Tchkonia, T., Schwartz, S., Kirkland, J. L., & Oshima, J. (2023) · Aging · doi:10.18632/aging.204743 · Cited by 53 · see citing works
Self-citationSenescence as a molecular target in skin aging and disease
Thau, H., Gerjol, B. P., Hahn, K., Gudenberg, R. W. V., Knoedler, L., Stallcup, K., Emmert, M. Y., Buhl, T., Wyles, S. P., Tchkonia, T., et al. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102686 · Cited by 62 · see citing works
Self-citationAging and injury drive neuronal senescence in the dorsal root ganglia
Donovan, L. J., Brewer, C. L., Bond, S. F., Laslavic, A. M., Lopez, A. P., Colman, L., Jordan, C. E., Hansen, L., Gonzalez, O. C., Pujari, A., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01954-x · Cited by 57 · see citing works
de Bartolomeis, A., Simone, G. D., Prisco, M. D., Barone, A., Napoli, R., Beguinot, F., Billeci, M., & Fornaro, M. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02065-4 · Cited by 52 · see citing works
“In light of the Geroscience Hypothesis, interventions that regulate cellular senescence may attenuate neuroin fl ammation, tissue remodeling, and mitochondrial dysfunction and exert, at once, bene fi cial effects on the course of multiple chronic diseases, including schizophrenia and diabetes [188].”
BackgroundLee, J. Y., Reyes, N. S., Ravishankar, S., Zhou, M., Krasilnikov, M., Ringler, C., Pohan, G., Wilson, C., Ang, K. K. H., Wolters, P. J., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci173371 · Cited by 53 · see citing works
Calabrò, A., Accardi, G., Aiello, A., Caruso, C., Galimberti, D., & Candore, G. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031792 · Cited by 56 · see citing works
“Certain SASPs encompass proinflammatory factors (such as cytokines, and chemokines), growth factors, metalloproteases, extracellular vesicles, and proapoptotic and profibrotic factors, albeit in varying proportions among SCs [11,22].”
BackgroundInfluentialLawrence, M., Goyal, A., Pathak, S., & Ganguly, P. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137411 · Cited by 54 · see citing works
“Pharmacological approaches use various types of drugs or conditions that reduce or eliminate senescence [37,116].”
BackgroundTargeting Cellular Senescence for Healthy Aging: Advances in Senolytics and Senomorphics
Alum, E. U., Izah, S. C., Uti, D. E., Ugwu, O. P.-C., Betiang, P. A., Basajja, M., & Ejemot-Nwadiaro, R. I. (2025) · Drug Design Development and Therapy · doi:10.2147/dddt.s543211 · Cited by 64 · see citing works
Chen, W., Altshuler, R. D., Daschner, P., Salvador-Morales, C., Germain, D. S., Guida, J., Prasanna, P. G. S., & Buchsbaum, J. C. (2024) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djae163 · Cited by 59 · see citing works
Cardiovascular aging: spotlight on mitochondria
Ali, M. A., Gioscia‐Ryan, R. A., Yang, D., Sutton, N. R., & Tyrrell, D. J. (2023) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00632.2023 · Cited by 53 · see citing works
- Authors
- Chaib, S., Tchkonia, T., & Kirkland, J. L.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Kirkland, James L.
- Venue
- Nature Medicine
- Published
- 2022-08
- Volume
- 28
- Issue
- 8
- Pages
- 1556-1568
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC9599677
- OpenAlex
- W4292488030
- Semantic Scholar
- 6088d989a0da63569aa5a064559c21fe6e5792a9
- Cited by
- 1,105
- References
- 242
- Citations by year
- 2026: 205 · 2025: 323 · 2024: 328 · 2023: 184 · 2022: 27
- FWCI
- 101.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health (R37AG13925, R33AG61456, R01AG072301, R01AG61414, P01AG62413, UH3AG56933)
- the Connor Fund, Robert J. and Theresa W. Ryan, and the Noaber Foundation.
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, senolytics, senescence-associated secretory phenotype, aging, age-related diseases, clinical trials, drug repurposing
- MeSH terms
- Senotherapeutics, Aging, Humans, Cellular Senescence
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