CoChat
Sign Up
Cited by 423Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity

Open access
Palmer, Allyson K., Tchkonia, Tamara, LeBrasseur, Nathan K., Chini, Eduardo N., Xu, Ming, Kirkland, James L.·2015·Diabetes
DOI 10.2337/db14-1820PMC PMC4477358
Open this paper in CoChat — free account

Abstract

Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction. Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction. In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation. Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage. Therapeutic targeting of a basic aging mechanism such as cellular senescence may have a large impact on disease pathogenesis and could be more effective in preventing the progression of diabetes complications than currently available therapies that have limited impact on already existing tissue damage. Therefore, senescent cells and the SASP represent significant opportunities for advancement in the prevention and treatment of type 2 diabetes and its complications.

Integrity signals

Registry

Crossref · 10.2337/db14-1820

Cites

94 of 94 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 106 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Diabetes may be caused in part by a convergence of basic aging mechanisms, including chronic sterile inflammation, macromolecular damage, progenitor cell dysfunction, and cellular senescence.

    “Like other age-related chronic diseases, diabetes may be caused in part by a convergence of the basic aging mechanisms that underlie age-related tissue dysfunction, including chronic “sterile” (not pathogen-associated) inflammation, macromolecular damage, progenitor cell dysfunction, and cellular senescence (8).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] López-Otín, 2013, The hallmarks of aging, Cell source

      Not checked in the free run.

  • Premisecitation

    High glucose can promote the formation of senescent cells.

    “In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation.”
    • Also stated in: § High Glucose · plain
      “High glucose drives premature senescence in vitro in endothelial cells, renal mesangial cells, adipose-derived stem cells (also known as preadipocytes or fat cell progenitors), and fibroblasts (35–37).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [35] Yokoi, 2006, Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells, Diabetes source

      Not checked in the free run.

    • cites [36] Cramer, 2010, Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells, Stem Cells Dev source

      Not checked in the free run.

    • cites [37] Blazer, 2002, High glucose-induced replicative senescence: point of no return and effect of telomerase, Biochem Biophys Res Commun source

      Not checked in the free run.

  • Premisecitation

    Growth hormone axis perturbations can promote the formation of senescent cells.

    “In turn, metabolic and signaling changes seen in diabetes, such as high circulating glucose, altered lipid metabolism, and growth hormone axis perturbations, can promote senescent cell formation.”
    • Also stated in: § Growth Hormone/IGF-1 Axis · boosted
      “The ability of multiple individual components of this pathway to induce senescence has been recently shown, including growth hormone, IGF-1, and IGF binding protein 5 (IGFBP5) (27,28,41).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [27] Stout, 2014, Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice, Aging (Albany, NY Online)

      Not checked in the free run.

    • cites [28] Tran, 2014, Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence, Aging Cell source

      Not checked in the free run.

    • cites [41] Kim, 2007, Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism, Mol Biol Cell source

      Not checked in the free run.

  • Interpretationreasoning

    Senescent cells may contribute to type 2 diabetes pathogenesis through adipose tissue dysfunction.

    “Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Senescent cells may contribute to type 2 diabetes pathogenesis by directly affecting pancreatic β-cell function.

    “Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic β-cell function, senescence-associated secretory phenotype (SASP)-mediated tissue damage, and involvement in adipose tissue dysfunction.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 28
  • Classified as probably not a substantial claim. 13

  • May combine two claims.

    Premisecitation

    Senescent cells build up with aging and are also found in obesity and diabetes.

    “Accumulation of senescent cells occurs during aging and is also seen in the context of obesity and diabetes.”
    • Also stated in: § Cellular Senescence: A Basic Aging Mechanism · plain
      “Senescent cell burden is low in young individuals but increases with aging in several tissues including adipose tissue, skeletal muscle, kidney, and skin (20–22).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source

      Not checked in the free run.

    • cites [21] Melk, 2005, Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney, Am J Transplant source

      Not checked in the free run.

    • cites [22] Waaijer, 2012, The number of p16INK4a positive cells in human skin reflects biological age, Aging Cell source

      Not checked in the free run.

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

    Premisecitation

    Cellular senescence is thought to have evolved as an antitumor mechanism.

    “Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors, such as telomere erosion, DNA damage, oxidative stress, or oncogenic activation, and is thought to have arisen as an antitumor mechanism (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Campisi, 2007, Cellular senescence: when bad things happen to good cells, Nat Rev Mol Cell Biol source

      Not checked in the free run.

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

    Premisecitation

    Senescent cells display identifying features including flattened morphology in culture, increased p21 and p16, DNA damage foci, reactive oxygen species production, and a shifted lysosomal β-galactosidase pH optimum.

    “In addition to growth arrest, senescent cells adopt several unique identifying characteristics, including a flattened morphology in culture, upregulation of cell cycle inhibitors such as p21 and p16, accumulation of DNA damage foci, reactive oxygen species production, and shifted optimum pH of lysosomal β-galactosidase (senescence-associated β-galactosidase [SA-βgal] activity) (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Campisi, 2007, Cellular senescence: when bad things happen to good cells, Nat Rev Mol Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cell burden is low in young individuals but increases with aging in several tissues, including adipose tissue, skeletal muscle, kidney, and skin.

    “Senescent cell burden is low in young individuals but increases with aging in several tissues including adipose tissue, skeletal muscle, kidney, and skin (20–22).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source

      Not checked in the free run.

    • cites [21] Melk, 2005, Increased expression of senescence-associated cell cycle inhibitor p16INK4a in deteriorating renal transplants and diseased native kidney, Am J Transplant source

      Not checked in the free run.

    • cites [22] Waaijer, 2012, The number of p16INK4a positive cells in human skin reflects biological age, Aging Cell source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Cellular senescence is an essentially irreversible growth arrest triggered by cellular stressors such as telomere erosion, DNA damage, oxidative stress, or oncogenic activation.

    “Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors, such as telomere erosion, DNA damage, oxidative stress, or oncogenic activation, and is thought to have arisen as an antitumor mechanism (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Campisi, 2007, Cellular senescence: when bad things happen to good cells, Nat Rev Mol Cell Biol source

      Not checked in the free run.

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

    Premisecitation

    A high number or persistence of senescent cells can promote tumor progression through inflammation, tissue disruption, and growth signals from the SASP.

    “Although cellular senescence is normally a defense mechanism against tumor development, presence or persistence of a high number of senescent cells can promote tumor progression because of inflammation, tissue disruption, and growth signals due to the SASP (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Campisi, 2005, Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cellular senescence is a basic aging process linked to many age-related diseases and is an important contributor to tissue dysfunction.

    “Cellular senescence is a fundamental aging mechanism that has been implicated in many age-related diseases and is a significant cause of tissue dysfunction.”
    • Also stated in: § Cellular Senescence: A Basic Aging Mechanism · hedged
      “In the past decade, cellular senescence has emerged as a possible cause of general tissue dysfunction and aging phenotypes (9,10).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Kirkland, Clinical strategies and animal models for developing senolytic agents, Exp Gerontol. 28 October 2015 [Epub ahead of print]. DOI

      Not checked in the free run.

    • cites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The aging microenvironment limits the regenerative potential of young progenitor cells in vivo, and aged progenitor cells show improved function when exposed to a young systemic microenvironment.

    “The aging microenvironment limits regenerative potential of young progenitor cells in vivo, and conversely, aged progenitor cells exhibit improved function when exposed to a young systemic microenvironment (68).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Conboy, 2005, Rejuvenation of aged progenitor cells by exposure to a young systemic environment, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The senescence marker p27 increases in pancreatic β-cells in genetic mouse models of type 2 diabetes, and p27 deletion in those mice increased insulin secretion and islet mass through increased proliferation.

    “The cell cycle inhibitor p27, a marker of senescence, increases in pancreatic β-cells in genetic mouse models of type 2 diabetes, and p27 deletion in those mice increased insulin secretion and islet mass through increased proliferation (64).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Uchida, 2005, Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice lacking p53-dependent apoptosis, senescent cell burden increases rapidly and is associated with pancreatic β-cell dysfunction, causing an overt diabetic phenotype in 3-4 months.

    “In mice lacking p53-dependent apoptosis, the burden of senescent cells increases rapidly and is associated with dysfunction of pancreatic β-cells, causing an overt diabetic phenotype in 3–4 months (65).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Tavana, 2010, Absence of p53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in mice, Diabetes source

      Not checked in the free run.

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

    Premisecitation

    Senescent cell accumulation can occur due to various factors, such as age-related chronic diseases, oxidative stress, the hormonal milieu, developmental factors, chronic infection, certain medications, and radiation exposure.

    “Senescent cell accumulation can occur due to a variety of factors, such as various age-related chronic diseases, oxidative stress, the hormonal milieu, developmental factors, chronic infection (e.g., HIV), certain medications (e.g., chemotherapy or certain HIV protease inhibitors), and radiation exposure (9,10,27,28).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Kirkland, Clinical strategies and animal models for developing senolytic agents, Exp Gerontol. 28 October 2015 [Epub ahead of print]. DOI

      Not checked in the free run.

    • cites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source

      Not checked in the free run.

    • cites [27] Stout, 2014, Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice, Aging (Albany, NY Online)

      Not checked in the free run.

    • cites [28] Tran, 2014, Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cardiac progenitor aging is accelerated in diabetes, and heart disease is a major complication of diabetes.

    “Cardiac progenitor aging is accelerated in diabetes, and heart disease is a major complication of diabetes (74).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Rota, 2006, Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene, Circ Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SASP components IL-6, IL-8, and MCP-1 are increased in obese adults and adolescents and could contribute to a proinflammatory state.

    “Components of the SASP, such as interleukin (IL)-6, IL-8, and MCP-1, are increased in obese adults and adolescents and could contribute to such a proinflammatory state, together with effects of macrophages and other mediators of inflammation (31,53,54).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Freund, 2010, Inflammatory networks during cellular senescence: causes and consequences, Trends Mol Med source

      Not checked in the free run.

    • cites [53] Kim, 2006, Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters, Int J Obes (Lond) source

      Not checked in the free run.

    • cites [54] Utsal, 2012, Elevated serum IL-6, IL-8, MCP-1, CRP, and IFN-γ levels in 10- to 11-year-old boys with increased BMI, Horm Res Paediatr source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Senescent cells may contribute to the aging microenvironment, which may limit regenerative potential in every tissue.

    “It is possible that senescent cells are a contributor to the aging microenvironment, which may limit the regenerative potential of cells in every tissue.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Overexpression of IGFBP3 in mice leads to decreased glucose tolerance, insulin resistance, and hyperglycemia.

    “In addition, overexpression of IGFBP3 in mice leads to decreased glucose tolerance, insulin resistance, and hyperglycemia (46).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Silha, 2002, Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

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

    Premisecitation

    Several possible subtypes of cellular senescence have been identified, including oncogene-induced senescence, stress-induced premature senescence, and classical replicative senescence.

    “Several possible “subtypes” of cellular senescence have been identified, including oncogene-induced senescence, stress-induced premature senescence, and the classical replicative senescence (10).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic sterile low-grade inflammation is associated with obesity and aging and is thought to be a major contributor to insulin resistance.

    “Chronic, sterile, low-grade inflammation is associated with both obesity and aging and is thought to be a major contributing factor for the development of insulin resistance (Fig. 1) (14,52).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Esser, 2014, Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes, Diabetes Res Clin Pract source

      Not checked in the free run.

    • cites [52] Xu, 2003, Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance, J Clin Invest source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Increased senescent preadipocytes could contribute to declines in adipogenic and lipogenic potential, leading to age-related lipodystrophy, lipotoxicity, and inflammation.

    “Increased senescent preadipocytes could contribute to declines in adipogenic and lipogenic potential, with consequent development of age-related lipodystrophy, leading to lipotoxicity and inflammation (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IGFBP3 is a SASP component that may help propagate senescence signals to neighboring cells.

    “Other related factors, such as IGFBP3, have been implicated as SASP components that may play a role in the propagation of senescence signals to neighboring cells (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Elzi, 2012, Plasminogen activator inhibitor 1—insulin-like growth factor binding protein 3 cascade regulates stress-induced senescence, Proc Natl Acad Sci U S A source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of de novo ceramide synthesis in diet-induced obese and ob/ob mice decreases SASP factors PAI-1 and MCP-1 and improves glucose and insulin tolerance.

    “Moreover, inhibition of de novo ceramide synthesis in diet-induced obese and ob/ob mice has been shown to decrease the SASP factors PAI-1 and MCP-1 and improve metabolic phenotypes such as glucose and insulin tolerance (51).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Yang, 2009, Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Microvascular complications of diabetes, such as retinopathy, neuropathy, and nephropathy, could be linked to cellular senescence because endothelial cells are susceptible to glucose-induced senescence.

    “Microvascular complications of diabetes, such as retinopathy, neuropathy, and nephropathy, could be linked to cellular senescence as well, as endothelial cells have been shown to be susceptible to glucose-induced senescence (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Yokoi, 2006, Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Growth hormone, IGF-1, and IGFBP5 can each induce senescence.

    “The ability of multiple individual components of this pathway to induce senescence has been recently shown, including growth hormone, IGF-1, and IGF binding protein 5 (IGFBP5) (27,28,41).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Stout, 2014, Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice, Aging (Albany, NY Online)

      Not checked in the free run.

    • cites [28] Tran, 2014, Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence, Aging Cell source

      Not checked in the free run.

    • cites [41] Kim, 2007, Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism, Mol Biol Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Case-control studies have found that elevated IL-6 and combined elevation of IL-6 and IL-1β are independent predictors of diabetes.

    “Case-control studies have found that elevated IL-6 and the combined elevation of IL-6 and IL-1β, both SASP factors, are independent predictors of diabetes (55,56).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Pradhan, 2001, C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus, JAMA source

      Not checked in the free run.

    • cites [56] Spranger, 2003, Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study, Diabetes source

      Not checked in the free run.

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

    Interpretationnone given

    Features of diabetes may raise senescent cell numbers, which would further drive chronic inflammation and start a self-reinforcing cycle of senescent cell formation across multiple tissues.

    “In turn, features of diabetes may cause an increase in senescent cell number, which would further promote chronic inflammation and initiate a vicious cycle of senescent cell formation in multiple tissues.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Eliminating senescent cells or their systemic effects might both stop the progression of diabetic tissue damage and improve insulin sensitivity.

    “By removing senescent cells or their systemic effects, it may be possible to both halt the progression of diabetic tissue damage as well as to improve insulin sensitivity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cellular senescence can be accompanied by mitochondrial dysfunction that causes oxidative stress, which has been implicated as a cause of insulin resistance in muscle tissue with aging.

    “Cellular senescence can be accompanied by mitochondrial dysfunction that, in turn, causes oxidative stress, which has been implicated as a cause of insulin resistance in muscle tissue with aging (78,79).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [78] Petersen, 2003, Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science source

      Not checked in the free run.

    • cites [79] Passos, 2010, Feedback between p21 and reactive oxygen production is necessary for cell senescence, Mol Syst Biol source

      Not checked in the free run.

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

    Interpretationcitation

    Which immune cell types clear senescent cells and the kinetics of that clearance are unknown.

    “It has been suggested that senescent cells are cleared by the immune system, but the specific immune cell types involved and the kinetics of clearance are unknown (83).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature source

      Not checked in the free run.

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

    Interpretationreasoning

    Clearing senescent cells or targeting the senescence-associated secretory phenotype may open the way to new therapies for diabetes and its complications.

    “We hypothesize that clearing senescent cells or targeting the SASP may present opportunities for the development of revolutionary therapies for diabetes and its complications.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Interleukin-6 is a major component of the senescence-associated secretory phenotype and appears to mark frailty.

    “For example, the cytokine IL-6 is an important component of the SASP and appears to be an indicator of frailty (92).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Leng, 2002, Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study, J Am Geriatr Soc source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The diabetes drugs metformin and acarbose prolong lifespan in mice that do not have diabetes.

    “Existing diabetes therapies, namely metformin and acarbose, extend lifespan in nondiabetic mice (86,87).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] Harrison, 2014, Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males, Aging Cell source

      Not checked in the free run.

    • cites [87] Martin-Montalvo, 2013, Metformin improves healthspan and lifespan in mice, Nat Commun source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Developing interventions that extend lifespan or healthspan by targeting senescence and the senescence-associated secretory phenotype is difficult because the clinical trials such interventions require are impractical.

    “Developing strategies to increase lifespan or healthspan, such as strategies that target cellular senescence and the SASP, is challenging due to the impractical nature of the required clinical trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cellular senescence has been associated with disease states such as renal tubular senescence in diabetes, but when senescent cells appear is unclear.

    “Many studies have drawn associations between cellular senescence and disease states, such as renal tubular senescence in diabetes; however, the timeline for senescent cell appearance is unclear (67).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Verzola, 2008, Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy, Am J Physiol Renal Physiol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The difficulty of treating diabetes complications with glucose control alone may arise because much damage occurs before diagnosis and treatment begin.

    “This may be because much damage occurs before diagnosis and initiation of treatment.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Senescent cell burden rises with aging and with obesity.

    “Senescent cell burden increases in aging and obesity”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Because insulin resistance and cellular senescence share mechanisms, clearing senescent cells might improve both the metabolic features and the complications of diabetes.

    “Shared mechanisms between the development of insulin resistance and cellular senescence indicate that perhaps by clearing senescent cells, both the metabolic components and complications of diabetes could be ameliorated.”
    Quote in the paperSubstantial claim
35 of 35

  • The paper relies on this without support.

    Current therapies for type 2 diabetes have limited efficacy in slowing disease progression and complications.

    “Despite increased understanding of the pathogenesis of diabetes and its comorbidities, current therapies have limited efficacy with respect to its progression and complications.”

  • The paper relies on this without support.

    Metformin improves diabetes, its complications and the metabolic syndrome.

    “Metformin alleviates diabetes, diabetes complications, and the metabolic syndrome.”

  • The paper relies on this without support.

    The composition of the senescence-associated secretory phenotype differs by cell type, tissue type and organism, and its factors have several roles in inflammation, immunity and normal physiology.

    “This issue is complicated by cell-type, tissue-type, and organismal differences in the composition of the SASP, as well as the multiple effects that SASP factors can play in inflammation, immunity, and normal physiology.”
3 of 3

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?

  • Elevated glucose and lipid levels themselves, like inflammation, can induce cellular senescence.

    “For example, elevated glucose and lipid levels themselves, like inflammation, can induce cellular senescence [11, 37].”

    From Cellular senescence: at the nexus between ageing and diabetes (2019) · cites this paper as [11]

  • Various cardiovascular risk factors including obesity, hypertension, diabetes and atherosclerosis that compromise metabolism are associated with an inflammatory state and increased cellular senescence and SASP.

    “various cardiovascular risk factors including obesity, hypertension, diabetes and atherosclerosis that compromise metabolism are associated with an inflammatory state and increased cellular senescence and SASP”

    From Redox control of senescence and age-related disease. (2017) · cites this paper as [96]

  • Obese individuals with type-2 diabetes show increased levels of SASP factors IL-6, IL-8, and the chemokine MCP-1.

    “Obese individuals with type-2 diabetes show increased levels of SASP factors IL-6, IL-8, and the chemokine MCP-1”

    From Redox control of senescence and age-related disease. (2017) · cites this paper as [96]

  • Both IL-6 and IL-1β are independent predictors of diabetes.

    “both IL-6 and IL-1β are independent predictors of diabetes”

    From Redox control of senescence and age-related disease. (2017) · cites this paper as [96]

  • Obesity is proposed to drive cellular senescence through mechanisms that include oxidative stress, high glucose in the local microenvironment, and increased IGF and ceramides.

    “Obesity is thought to promote cell senescence through various means including oxidative stress, high glucose concentrations in the microenvironment, and increased IGF and ceramides (104).”

    From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [104]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Palmer, A. K., Tchkonia, T., LeBrasseur, N. K., Chini, E. N., Xu, M., & Kirkland, J. L.
Affiliations
  • Mayo Clinic (US)
  • Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN
Corresponding author
Kirkland, James L.
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2015-06-17
Volume
64
Issue
7
Pages
2289-2298
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db14-1820
PMC
PMC4477358
OpenAlex
W1908141864
Semantic Scholar
85b2a4f3a4cebcc4dbbf69fcf3bd383219229501
Cited by
423
References
94
Citations by year
2026: 33 · 2025: 32 · 2024: 47 · 2023: 33 · 2022: 62 · 2021: 47 · 2020: 48 · 2019: 41 · 2018: 29 · 2017: 27 · 2016: 18 · 2015: 4
FWCI
3.20
Type
journal article
Language
en
Open access
Licence
www.diabetesjournals.org/site/license (vor, 198 d)
Locations
  • Diabetes (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Noaber Foundation
  • Glenn Foundation for Medical Research
  • National Institute on Aging (AG044396, AG046061)
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, type 2 diabetes, senescence-associated secretory phenotype, beta-cell dysfunction, adipose tissue dysfunction, aging, obesity, growth hormone axis, diabetes complications, senolytics
MeSH terms
Adipose Tissue, Animals, Ceramides, Diabetes Mellitus, Type 2, Humans, Insulin Resistance, Insulin-Like Growth Factor I, Cellular Senescence, Insulin-Like Growth Factor Binding Protein 3, Insulin-Secreting Cells, Cellular Microenvironment

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 2026-10-04.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-04.

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 ›

Are you an author, or do you see a problem with this page? Request a review