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Cited by 177Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

Reducing Senescent Cell Burden in Aging and Disease

Open access
Pignolo, Robert J., Passos, João F., Khosla, Sundeep, Tchkonia, Tamara, Kirkland, James L.·2020·Trends in Molecular Medicine
DOI 10.1016/j.molmed.2020.03.005PMC PMC7857028
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Abstract

Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin. In pre-clinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multi-morbidity, and accelerated aging phenotypes. In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae. Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells. We hypothesize that these pharmacologic interventions may have transformative effects on geriatric medicine.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that cellular senescence is a fundamental aging process and that reducing senescent cell burden through genetic or pharmacologic means can prevent, delay, or alleviate age-related conditions in preclinical models. It surveys senolytic and SASP-modulating agents and early human safety/target-engagement trials, while highlighting unresolved trial-design and biomarker gaps.

Key findings

  • In animal models, clearing senescent cells genetically or pharmacologically improved age-related phenotypes; an INK-ATTAC suicide transgene that eliminated p16Ink4a-expressing cells with roughly a 30% reduction extended healthspan and prevented multiple age-related morbidities in progeroid and naturally aged mice.
  • Senescent cells can be sparse yet harmful: old primate skin contains about 10–15% senescent cells, and transplanting even a small number into younger mice was sufficient to cause tissue dysfunction.
  • Senolytic strategies include repurposed cancer drugs and bioflavonoids; dasatinib plus quercetin targets more than one apoptosis-resistance pathway. SASP inhibitors/senomorphics, such as JAK/STAT inhibition, can produce some benefits without killing senescent cells. Senescent cell turnover is estimated at about four weeks, supporting intermittent dosing.
  • Early human pilot studies suggest minimal adverse effects and senescent cell clearance, but first-generation agents have contraindications and potential toxicities; larger trials are needed.

Methods

  • Narrative review and synthesis of preclinical and clinical literature on cellular senescence and senotherapeutics; no primary experiments or new patient data are reported.
  • Evidence base includes mouse genetic models such as INK-ATTAC, senescent cell transplantation studies, pharmacologic senolytics and senomorphics, and small early-phase human trials.
  • Main analysis is conceptual synthesis and hypothesis generation, not a systematic review or meta-analysis.

Limitations

  • The paper states that current clinical trials are limited by small recruitment sizes, few measurable clinically relevant outcomes for older adults, and a lack of biomarkers for pharmacokinetics, pharmacodynamics, mechanism, or surrogate endpoints.
  • The paper notes uncertainty about how dasatinib and quercetin adverse effects and contraindications translate to intermittent senolytic dosing, and states that the minimum senescent cell burden needed to cause tissue dysfunction is unknown.
  • Evident from the text: most senescent cell clearance evidence comes from mice, with rat models proposed but not yet established; the review is not systematic and does not pool quantitative effects.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.molmed.2020.03.005

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 114 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    In preclinical aging models, senescent cell accumulation is associated with chronic diseases, geriatric syndromes, multimorbidity, and accelerated aging phenotypes.

    “In pre-clinical aging models, accumulation of senescent cells is associated with multiple chronic diseases and disorders, geriatric syndromes, multi-morbidity, and accelerated aging phenotypes.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [3] Baker DJ (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479 (7372), 232– 6. 22048312 PMC3468323 source

      Not checked in the free run.

    • cites [4] Farr JN (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23 (9), 1072– 1079. 28825716 PMC5657592 source

      Not checked in the free run.

    • cites [5] Moncsek A (2018) 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 (1), 247– 259. 28802066 PMC5739965 source

      Not checked in the free run.

    • cites [6] Nath KA (2018) The murine dialysis fistula model exhibits a senescence phenotype: pathobiological mechanisms and therapeutic potential. Am J Physiol Renal Physiol 315 (5), F1493– F1499. 30019935 PMC6293292 source

      Not checked in the free run.

    • cites [7] Palmer AK (2019) Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18 (3), e12950. 30907060 PMC6516193 source

      Not checked in the free run.

    • cites [8] Roos CM (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15 (5), 973– 7. 26864908 PMC5013022 source

      Not checked in the free run.

    • cites [9] Suvakov S (2019) Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Biol Sex Differ 10 (1), 49. 31521202 PMC6744626 source

      Not checked in the free run.

    • cites [10] Xu M (2017) Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. J Gerontol A Biol Sci Med Sci 72 (6), 780– 785. 27516624 PMC5861939

      Not checked in the free run.

    • cites [11] Xu M (2015) Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4, e12997. 26687007 PMC4758946 source

      Not checked in the free run.

    • cites [12] Xu M (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24 (8), 1246– 1256. 29988130 PMC6082705 source

      Not checked in the free run.

  • Premisecitation

    Early clinical trials have focused on safety and target engagement of senolytic agents that clear senescent cells.

    “Early clinical trials have thus far focused on safety and target engagement of senolytic agents that clear senescent cells.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [88] Hickson LJ (2019) Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446– 456. 31542391 PMC6796530 source

      Not checked in the free run.

    • cites [89] Hickson LJ (2020) 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. PMC6796530 31542391 source

      Not checked in the free run.

    • cites [90] Justice JN (2019) Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554– 563. 30616998 PMC6412088 source

      Not checked in the free run.

    • cites [91] Singh M (2016) Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study. J Frailty Aging 5 (4), 204– 207. 27883166

      Not checked in the free run.

  • Interpretationreasoning

    Interventions that genetically or pharmacologically remove senescent cells in animal models provide proof-of-concept for translation to human aging-associated conditions, especially those with heavy senescent cell burden.

    “Interventions that genetically or pharmacologically remove senescent cells in animal models of aging offer proof-of-concept that they can be translated for human conditions associated with aging, especially those with heavy senescent cell burden”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Results from animal models of senescent cell clearance predict human clinical outcomes for aging-associated conditions.
  • Interpretationreasoning

    Any intervention targeting a single fundamental aging process could affect multiple aging processes.

    “This suggests that any intervention that targets a single fundamental aging process could affect multiple processes that impact aging.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In animals, genetic and pharmacologic reduction of senescent cell burden prevents, delays, or alleviates various aging-related diseases and sequelae.

    “In animals, genetic and pharmacologic reduction of senescent cell burden results in the prevention, delay, and/or alleviation of a variety of aging-related diseases and sequelae.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [3] Baker DJ (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479 (7372), 232– 6. 22048312 PMC3468323 source

      Not checked in the free run.

    • cites [4] Farr JN (2017) Targeting cellular senescence prevents age-related bone loss in mice. Nat Med 23 (9), 1072– 1079. 28825716 PMC5657592 source

      Not checked in the free run.

    • cites [5] Moncsek A (2018) 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 (1), 247– 259. 28802066 PMC5739965 source

      Not checked in the free run.

    • cites [6] Nath KA (2018) The murine dialysis fistula model exhibits a senescence phenotype: pathobiological mechanisms and therapeutic potential. Am J Physiol Renal Physiol 315 (5), F1493– F1499. 30019935 PMC6293292 source

      Not checked in the free run.

    • cites [7] Palmer AK (2019) Targeting senescent cells alleviates obesity-induced metabolic dysfunction. Aging Cell 18 (3), e12950. 30907060 PMC6516193 source

      Not checked in the free run.

    • cites [8] Roos CM (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15 (5), 973– 7. 26864908 PMC5013022 source

      Not checked in the free run.

    • cites [9] Suvakov S (2019) Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia. Biol Sex Differ 10 (1), 49. 31521202 PMC6744626 source

      Not checked in the free run.

    • cites [10] Xu M (2017) Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. J Gerontol A Biol Sci Med Sci 72 (6), 780– 785. 27516624 PMC5861939

      Not checked in the free run.

    • cites [11] Xu M (2015) Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4, e12997. 26687007 PMC4758946 source

      Not checked in the free run.

    • cites [12] Xu M (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24 (8), 1246– 1256. 29988130 PMC6082705 source

      Not checked in the free run.

  • May combine two claims. 17
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    Primary aging processes include chronic low-grade non-microbial inflammation, cellular senescence, accumulation of damaged macromolecules, and stem/progenitor cell dysfunction.

    “Cellular and molecular processes that account for primary aging include chronic, low-grade, non-microbial inflammation, cellular senescence (see Glossary), accumulation of damaged macromolecules (DNA, proteins, carbohydrates, lipids), as well as stem and progenitor cell dysfunction [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Kirkland JL (2016) Translating the Science of Aging into Therapeutic Interventions. Cold Spring Harb Perspect Med 6 (3), a025908. 26931808 PMC4772076 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular senescence is a primary aging process and tumor suppressive mechanism with features including irreversible growth arrest, apoptosis resistance, SASP, mitochondrial dysfunction, and DNA/chromatin changes.

    “Cellular senescence is a primary aging process and tumor suppressive mechanism characterized by irreversible growth arrest, apoptosis resistance, production of a senescence-associated secretory phenotype (SASP), mitochondrial dysfunction, and alterations in DNA and chromatin.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [16] Liu J (2019) Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing. Cells 8 (1). PMC6356700 30650660 source

      Not checked in the free run.

    • cites [17] Chapman J (2019) Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett 593 (13), 1566– 1579. 31211858 source

      Not checked in the free run.

    • cites [18] Childs BG (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15 (11), 1139– 53. 25312810 PMC4253488 source

      Not checked in the free run.

    • cites [21] Passos JF (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 5 (5), e110. 17472436 PMC1858712 source

      Not checked in the free run.

    • cites [22] Rodier F (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11 (8), 973– 9. 19597488 PMC2743561 source

      Not checked in the free run.

    • cites [23] Narita M (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113 (6), 703– 16. 12809602 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular senescence is a major mechanism of aging at the cellular level, though likely not the only one.

    “Cellular senescence has been described as a major mechanism for aging at the cellular level, although likely not the only mechanism.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Liu J (2019) Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing. Cells 8 (1). PMC6356700 30650660 source

      Not checked in the free run.

    • cites [17] Chapman J (2019) Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett 593 (13), 1566– 1579. 31211858 source

      Not checked in the free run.

    • cites [18] Childs BG (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15 (11), 1139– 53. 25312810 PMC4253488 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Multiple inducers of cellular senescence include DNA damage, reactive metabolites, inflammation, oncogenes, mitogens, proteotoxic stress, and damage-associated molecular patterns.

    “There are multiple inducers of cellular senescence, including DNA damage, reactive metabolites, inflammation, oncogenes, mitogens, proteotoxic stress, and damage-associated molecular patterns [16–18].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [16] Liu J (2019) Roles of Telomere Biology in Cell Senescence, Replicative and Chronological Ageing. Cells 8 (1). PMC6356700 30650660 source

      Not checked in the free run.

    • cites [17] Chapman J (2019) Mitochondrial dysfunction and cell senescence: deciphering a complex relationship. FEBS Lett 593 (13), 1566– 1579. 31211858 source

      Not checked in the free run.

    • cites [18] Childs BG (2014) Senescence and apoptosis: dueling or complementary cell fates? EMBO Rep 15 (11), 1139– 53. 25312810 PMC4253488 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elimination of even a relatively small proportion of existing senescent cells (~30% reduction) using INK-ATTAC extends healthspan and prevents multiple age-related morbidities in progeroid and normal chronologically-aged mice.

    “Elimination of even a relatively small proportion of existing senescent cells (~30% reduction) using a “suicide” transgene, INK-ATTAC, that permits inducible elimination of p16Ink4a-expressing senescent cells upon administration of a drug (AP20187; Figure 2), extends healthspan and prevents the development of multiple age-related morbidities in both progeroid and normal chronologically-aged mice [”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Baker DJ (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479 (7372), 232– 6. 22048312 PMC3468323 source

      Not checked in the free run.

    • cites [8] Roos CM (2016) Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15 (5), 973– 7. 26864908 PMC5013022 source

      Not checked in the free run.

    • cites [11] Xu M (2015) Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4, e12997. 26687007 PMC4758946 source

      Not checked in the free run.

    • cites [35] Ogrodnik M (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8, 15691. 28608850 PMC5474745 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Senescent cells may have transient beneficial effects but accumulate chronically in virtually all tissues with aging, causing detrimental consequences.

    “Although senescent cells may have beneficial effects in a transient fashion (Box 2), they accumulate chronically in virtually all tissues with aging, promoting detrimental consequences.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The rat is particularly amenable to measurements of cognitive-behavioral, endocrine, muscle, and cardiovascular endpoints, and extensive historical data exist on physiological changes with aging.

    “The rat is particularly amendable to measurements of cognitive-behavioral, endocrine (e.g., glucose tolerance), muscle, and cardiovascular endpoints, and there is extensive historical data on physiological changes with aging [42–46].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [42] Bader M (2010) Rat models of cardiovascular diseases. Methods Mol Biol 597, 403– 14. 20013248 source

      Not checked in the free run.

    • cites [43] Carter CS (2002) Physical performance and longevity in aged rats. J Gerontol A Biol Sci Med Sci 57 (5), B193– 7. 11983716 source

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    • cites [44] Ellenbroek B and Youn J (2016) Rodent models in neuroscience research: is it a rat race? Dis Model Mech 9 (10), 1079– 1087. 27736744 PMC5087838 source

      Not checked in the free run.

    • cites [45] King AJ (2012) The use of animal models in diabetes research. Br J Pharmacol 166 (3), 877– 94. 22352879 PMC3417415 source

      Not checked in the free run.

    • cites [46] Like AA (1982) Spontaneous autoimmune diabetes mellitus in the BB rat. Diabetes 31 (Suppl 1 Pt 2), 7– 13. 6761194 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Hallmarks of cellular senescence include irreversible growth arrest, SASP, apoptosis resistance, mitochondrial dysfunction, persistent DNA damage foci, and epigenetic remodeling including senescence-associated heterochromatin foci.

    “Hallmarks of the cellular senescence phenotype include irreversible growth arrest, a senescence-associated secretory phenotype (SASP) (Box 1), apoptosis resistance, mitochondrial dysfunction [21], persistent DNA damage foci [22] and epigenetic remodeling, which includes formation of senescence-associated heterochromatin foci [23].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Passos JF (2007) Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 5 (5), e110. 17472436 PMC1858712 source

      Not checked in the free run.

    • cites [22] Rodier F (2009) Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol 11 (8), 973– 9. 19597488 PMC2743561 source

      Not checked in the free run.

    • cites [23] Narita M (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113 (6), 703– 16. 12809602 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The rat has potential for geroscience research because its aging physiology is closer to humans than mice, especially for onset of certain age-related conditions, and its larger size permits serial sampling and imaging not feasible in mice.

    “However, the rat has tremendous potential for use in geroscience research, owning to its aging physiology being closer to humans compared to mice, especially with respect to onset of certain age-related conditions, as well as its larger size, which permits serial sampling and imaging studies not feasible in the mouse [36–41].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [36] Febo M (2011) Technical and conceptual considerations for performing and interpreting functional MRI studies in awake rats. Front Psychiatry 2, 43. 21808625 PMC3137945 source

      Not checked in the free run.

    • cites [37] Gallagher M (2011) Mindspan: lessons from rat models of neurocognitive aging. ILAR J 52 (1), 32– 40. 21411856 PMC3199952 source

      Not checked in the free run.

    • cites [38] Iannaccone PM and Jacob HJ (2009) Rats! Dis Model Mech 2 (5–6), 206– 10. 19407324 PMC2675817 source

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    • cites [39] Jacob HJ (1999) Functional genomics and rat models. Genome Res 9 (11), 1013– 6. 10568741 source

      Not checked in the free run.

    • cites [40] Mashimo T (2005) Rat Phenome Project: the untapped potential of existing rat strains. J Appl Physiol (1985) 98 (1), 371– 9. 15591307 source

      Not checked in the free run.

    • cites [41] Shimoyama M (2016) Exploring human disease using the Rat Genome Database. Dis Model Mech 9 (10), 1089– 1095. 27736745 PMC5087824 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transposons can be produced in senescent cells, re-insert into their DNA, contribute to the senescent phenotype, and exacerbate the SASP.

    “Transposons (“jumping genes”) can be produced within senescent cells that re-insert into senescent cell DNA, contributing to the senescent cell phenotype and exacerbating their SASP [24, 25].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] De Cecco M (2013) Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12 (2), 247– 56. 23360310 PMC3618682 source

      Not checked in the free run.

    • cites [25] De Cecco M (2019) L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566 (7742), 73– 78. 30728521 PMC6519963 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Combinations of senolytics targeting more than one apoptosis-resistance pathway will conceptually clear larger numbers and types of senescent cell subpopulations, and this appears true for dasatinib plus quercetin.

    “Combinations of senolytics that target more than one pathway conferring apoptosis resistance will conceptually clear larger numbers and types of senescent cell subpopulations, and appears to be the case for the combination of the first generation senolytics dasatinib and quercetin [59].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Kirkland JL and Tchkonia T (2017) Cellular Senescence: A Translational Perspective. EBioMedicine 21, 21– 28. 28416161 PMC5514381 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Limitations of current clinical trials include small recruitment sizes, few measurable clinically-relevant outcomes appropriate for older adults, and need for biomarkers tracking pharmacokinetic, pharmacodynamic, and mechanistic properties and serving as surrogate endpoints.

    “Limitations of current clinical trials include small recruitment sizes, the paucity of measurable, clinically-relevant outcomes appropriate for older adults, as well as the need for biomarkers that follow pharmacokinetic, pharmacodynamic, and mechanistic properties of study drugs and could serve as surrogate endpoints [92–94].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92] Burd CE (2016) Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms. J Gerontol A Biol Sci Med Sci 71 (11), 1388– 1394. 27535964 PMC5055650 source

      Not checked in the free run.

    • cites [93] Justice J (2016) Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes. J Gerontol A Biol Sci Med Sci 71 (11), 1415– 1423. 27535966 PMC5055651 source

      Not checked in the free run.

    • cites [94] Niedernhofer LJ (2017) Molecular pathology endpoints useful for aging studies. Ageing Res Rev 35, 241– 249. 27721062 PMC5357461 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dasatinib has contraindications including QTc interval > 450 msec, hepatic insufficiency, drug interactions with CYP3A4 inhibitors, CYP3A4 inducers, antacids, H2 antagonists/proton pump inhibitors, and other cautions.

    “However, with the first generation senolytic dasatinib contraindications exist, including QTc interval > 450 msec, hepatic insufficiency, drug interactions with CYP3A4 inhibitors, CYP3A4 inducers, antacids, H2 antagonists/proton pump inhibitors, and other cautions as indicated by the full prescribing information.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Quercetin has contraindications for potential drug-drug interactions and common side effects such as headache.

    “Similarly, the first generation senolytic quercetin has contraindications with respect to potential drug-drug interactions (e.g., strong inhibitors of CYP3A4) and common side effects (e.g., headache)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Early results from small pilot clinical studies suggest minimal adverse effects of senotherapeutic agents and clearance of senescent cells in humans.

    “Early results from small pilot clinical studies suggest minimal adverse effects of senotherapeutic agents and clearance of senescent cells in humans [88–91].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [88] Hickson LJ (2019) Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446– 456. 31542391 PMC6796530 source

      Not checked in the free run.

    • cites [89] Hickson LJ (2020) 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. PMC6796530 31542391 source

      Not checked in the free run.

    • cites [90] Justice JN (2019) Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554– 563. 30616998 PMC6412088 source

      Not checked in the free run.

    • cites [91] Singh M (2016) Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study. J Frailty Aging 5 (4), 204– 207. 27883166

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Reduction in senescent cell burden could be transformative to clinical practice, especially geriatric medicine.

    “Reduction in senescent cell burden could be transformative to clinical practice, especially geriatric medicine.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Results from animal models of senescent cell clearance predict human clinical outcomes for aging-associated conditions.

  • May combine two claims.

    Premisereasoning

    Single or intermittent doses of senolytics appear to attenuate at least some age- or senescence-related conditions, which may not be the case for SASP-inhibitors because they do not clear senescent cells.

    “Single or intermittent doses of senolytics appear to attenuate at least some age- or senescence-related conditions, which may not be the case for SASP-inhibitors, since they do not clear senescent cells.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based). May combine two claims.

    Interpretationreasoning

    Clinically relevant primary endpoints for older adults will likely include objective and subjective physical functioning because these predict morbidity and mortality, contribute to cognitive decline and injury risk, are prominent in geriatric syndromes, and are consistent with short-term measurable improvements.

    “Clinically relevant primary endpoints for older adults will likely include aspects of both objective and subjective physical functioning, since these are predictive of morbidity and mortality, contribute to risks of cognitive decline and injury, are prominent components of geriatric syndromes, and are consistent with measureable improvements being made in the short-term.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    At anti-cancer doses and frequency, dasatinib can cause myelosuppression, bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, cell lysis syndrome, and embryo-fetal toxicity.

    “At doses and frequency used for anti-cancer effects, dasatinib can cause myelosuppression, bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, cell lysis syndrome, and embryo-fetal toxicity”
    Quote in the paperSubstantial claim
19 of 19

  • The paper relies on this without support.

    Results from animal models of senescent cell clearance predict human clinical outcomes for aging-associated conditions.

    “Interventions that genetically or pharmacologically remove senescent cells in animal models of aging offer proof-of-concept that they can be translated for human conditions associated with aging”
    “Reduction in senescent cell burden could be transformative to clinical practice, especially geriatric medicine.”

  • The paper relies on this without support.

    Senescent cells do not replicate.

    “Because senescent cells do not replicate, concerns over possible drug resistance seem unlikely.”

  • The paper relies on this without support.

    Clinical stressors such as chemotherapy, radiotherapy, elective surgery, bone marrow transplantation, rehabilitation after myocardial infarction, and hypoxia-reoxygenation generate senescent cells.

    “Senolytics and/or senomorphics could also be used prophylactically in the setting of clinical stressors that are known to generate senescent cells, such as chemotherapy, radiotherapy, elective surgery, bone marrow transplantation, rehabilitation after myocardial infarction, and hypoxia-reoxygenation as well as other stresses associated with arteriovenous fistulae for hemodialysis.”

  • The paper relies on this without support.

    Intermittent dosing of senolytics reduces side effects compared with continuous dosing.

    “Thus, intermittent treatment with senolytics may be a reasonable approach in humans, potentially reducing side effects.”
4 of 4

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?

  • Due to their proinflammatory phenotype, senescent cells have been causally linked with many age-related pathologies and diseases.

    “In particular, due to their profound proinflammatory phenotype63, senescent cells have been causally linked with many age-related pathologies and diseases64.”

    From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [64]

  • Reduction of senescent cells through genetic and pharmacological methods can prevent and alleviate various senescence-related diseases.

    “It has been reported that the reduction of senescent cells through genetic and pharmacological methods can prevent and alleviate various senescence-related diseases [165, 166].”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [165]

  • Dasatinib, quercetin, and other senolytics were discovered using a mechanism-based approach.

    “Dasatinib, quercetin, and other senolytics were discovered using a mechanism-based approach.7,26,105”

    From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [105]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Corrigendum repeats the original article's identifiers

    Minor

    References 88 and 89 describe different publications, but the corrigendum is assigned the same DOI, PubMed ID, and PMC ID as the original article. The listed identifiers therefore do not distinguish the two records.

1 of 1

The citation lists haven’t been fetched yet

References 110 · Cited by 177

Authors
Pignolo, R. J., Passos, J. F., Khosla, S., Tchkonia, T., & Kirkland, J. L.
Affiliations
Mayo Clinic (US)
Corresponding author
Pignolo, Robert J.
ORCID
Venue
Trends in Molecular Medicine
Publisher
Elsevier BV
Published
2020-07
Volume
26
Issue
7
Pages
630-638
ISSN
1471-4914 (ISSN-L)
DOI
10.1016/j.molmed.2020.03.005
PMC
PMC7857028
OpenAlex
W3017264526
Semantic Scholar
4ff5bc62d3903f379541ed696243874e49c9732f
Cited by
177
References
110
Citations by year
2026: 18 · 2025: 26 · 2024: 30 · 2023: 36 · 2022: 24 · 2021: 31 · 2020: 12
FWCI
3.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Molecular Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
cellular senescence, senolytics, aging, senescence-associated secretory phenotype, geriatric syndromes, multimorbidity, accelerated aging, chronic disease, geriatrics, mitochondrial dysfunction, DNA damage, chromatin alterations
MeSH terms
Aging, Animals, Humans, Phenotype, Cellular Senescence, Apoptosis, Mitochondrial Diseases

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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