Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity

In the paper

“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).”

What the sources say

• Not checked yetcites [8] López-Otín, 2013, The hallmarks of aging, Cell source

In the paper

“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).”

What the sources say

• Not checked yetcites [35] Yokoi, 2006, Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells, Diabetes source
• Not checked yetcites [36] Cramer, 2010, Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells, Stem Cells Dev source
• Not checked yetcites [37] Blazer, 2002, High glucose-induced replicative senescence: point of no return and effect of telomerase, Biochem Biophys Res Commun source

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [28] Tran, 2014, Insulin-like growth factor-1 regulates the SIRT1-p53 pathway in cellular senescence, Aging Cell source
• Not checked yetcites [41] Kim, 2007, Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism, Mol Biol Cell source

In the paper

“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 the paper

“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 the paper

“Thus, senescent cells might be part of a pathogenic loop in diabetes, as both a cause and consequence of metabolic changes and tissue damage.”

In the paper

“Although senescent cells are incapable of dividing, they are metabolically active. This high metabolic activity supports the release of proinflammatory cytokines, chemokines, and growth factors collectively known as the SASP (12,13).”

What the sources say

• Not checked yetcites [12] Coppé, 2008, Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor, PLoS Biol source
• Not checked yetcites [13] Kuilman, 2009, Senescence-messaging secretome: SMS-ing cellular stress, Nat Rev Cancer source

In the paper

“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 the paper

“Through the SASP, a low absolute number of senescent cells in a tissue (typically <20%) may be able to exert systemic effects (11).”

What the sources say

• Not checked yetcites [11] Campisi, 2007, Cellular senescence: when bad things happen to good cells, Nat Rev Mol Cell Biol source

In the paper

“Senescent cells can also initiate a deleterious positive feedback mechanism by promoting the spread of senescence to nearby cells (17–19).”

What the sources say

• Not checked yetcites [17] Zhu, 2014, Cellular senescence and the senescent secretory phenotype in age-related chronic diseases, Curr Opin Clin Nutr Metab Care source
• Not checked yetcites [18] Tchkonia, 2013, Cellular senescence and the senescent secretory phenotype: therapeutic opportunities, J Clin Invest source
• Not checked yetcites [19] Nelson, 2012, A senescent cell bystander effect: senescence-induced senescence, Aging Cell source

In the paper

“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: § Ceramides · hedged

  “Ceramides induce senescence markers in fibroblasts and endothelial cells in vitro, suggesting that high circulating or local levels of ceramides could be a driver of cellular senescence (48).”

What the sources say

• Not checked yetcites [48] Mouton, 2000, Ceramide induces expression of the senescence histochemical marker, beta-galactosidase, in human fibroblasts, Mech Ageing Dev source

In the paper

“For example, obesity-associated senescent cells may promote chronic, low-grade sterile inflammation.”

What the sources say

• Not checked yetcites [14] Esser, 2014, Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes, Diabetes Res Clin Pract source
• Not checked yetcites [15] Dandona, 2004, Inflammation: the link between insulin resistance, obesity and diabetes, Trends Immunol source

In the paper

“In particular, components of the metabolic syndrome, including abdominal obesity, diabetes, hypertension, and atherosclerosis, are among the many pathologies associated with increased senescent cell burden (20,23–25).”

What the sources say

• Not checked yetcites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source
• Not checked yetcites [23] Minamino, 2009, A crucial role for adipose tissue p53 in the regulation of insulin resistance, Nat Med source
• Not checked yetcites [24] Minamino, 2007, Vascular cell senescence: contribution to atherosclerosis, Circ Res source
• Not checked yetcites [25] Westhoff, 2008, Hypertension induces somatic cellular senescence in rats and humans by induction of cell cycle inhibitor p16INK4a, Hypertension source

In the paper

“Of note, we and our colleagues recently identified a possibly causal link between cellular senescence and aging phenotypes by showing that the clearance of senescent cells in a mouse progeroid model in vivo can delay age-related tissue dysfunction, including cataract formation, lipodystrophy, and lordokyphosis (7).”

What the sources say

• Not checked yetcites [7] Baker, 2011, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature source

In the paper

“In this way, senescent cells might be a link between obesity and inflammation that contributes to the development and progression of type 2 diabetes (Fig. 1) (14,15).”

What the sources say

• Not checked yetcites [14] Esser, 2014, Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes, Diabetes Res Clin Pract source
• Not checked yetcites [15] Dandona, 2004, Inflammation: the link between insulin resistance, obesity and diabetes, Trends Immunol source

In the paper

“Without effective cell turnover and tissue repair, phenotypes seen in diabetes, such as retinopathy, islet degeneration, and renal damage, may potentially be initiated or worsened.”

In the paper

“There are emerging data indicating a role of senescent cells in neurodegeneration and cognitive dysfunction (69).”

What the sources say

• Not checked yetcites [69] Golde, 2009, Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer’s and other neurodegenerative diseases, Alzheimers Res Ther source

In the paper

“Because the SASP includes macrophage attractant proteins such as MCP-1, it is possible that senescent cells in adipose tissue could be a driver of the macrophage infiltration that has been proposed to play an important role in adipose tissue inflammation leading to insulin resistance in obesity (12,52).”

What the sources say

• Not checked yetcites [12] Coppé, 2008, Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor, PLoS Biol source
• Not checked yetcites [52] Xu, 2003, Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance, J Clin Invest source

In the paper

“Increased AGE signaling through their receptors (RAGE), of which the SASP factor HMGB1 is also the agonistic ligand (see below), has been shown to cause premature senescence in renal tubular cells (40).”

What the sources say

• Not checked yetcites [40] Liu, 2014, Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling, Cell Signal source

In the paper

“Certain SASP factors originating from senescent cells in particular tissues or types of senescent cells may be able to induce senescence in neighboring cells, propagating senescence signals (19).”

What the sources say

• Not checked yetcites [19] Nelson, 2012, A senescent cell bystander effect: senescence-induced senescence, Aging Cell source

In the paper

“Senescent cells also accumulate in atherosclerotic plaques (24).”

What the sources say

• Not checked yetcites [24] Minamino, 2007, Vascular cell senescence: contribution to atherosclerosis, Circ Res source

In the paper

“Ceramides induce senescence markers in fibroblasts and endothelial cells in vitro, suggesting that high circulating or local levels of ceramides could be a driver of cellular senescence (48).”

What the sources say

• Not checked yetcites [48] Mouton, 2000, Ceramide induces expression of the senescence histochemical marker, beta-galactosidase, in human fibroblasts, Mech Ageing Dev source

In the paper

“Another prominent SASP component, PAI-1, is increased in the circulation and tissues, such as coronary arteries of patients with diabetes (57).”

What the sources say

• Not checked yetcites [57] Schneider, 2012, PAI-1 and diabetes: a journey from the bench to the bedside, Diabetes Care source

In the paper

“Adipose tissue dysfunction related to both obesity and aging is associated with an increase in senescent cell burden (20).”

What the sources say

• Not checked yetcites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source

In the paper

“This appears to be an accelerated model of age-related diabetes and is consistent with the hypothesis that cellular senescence over the lifespan could be a cause of decreased insulin synthesis and release from pancreatic β-cells.”

In the paper

“Adipogenesis is crucial for insulin responsiveness, as insulin receptors and GLUT4 increase as preadipocytes differentiate into mature adipocytes (60).”

What the sources say

• Not checked yetcites [60] Hamm, 1999, Role of PPAR gamma in regulating adipocyte differentiation and insulin-responsive glucose uptake, Ann N Y Acad Sci source

In the paper

“Furthermore, PAI-1 knockdown extends lifespan and healthspan in Klotho-deficient mice, which have an accelerated aging-like phenotype (77).”

What the sources say

• Not checked yetcites [77] Eren, 2014, PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice, Proc Natl Acad Sci U S A source

In the paper

“For example, PAI-1, a SASP factor produced by many cell types, can stabilize IGFBP3 by inhibition of tissue plasminogen activator, which normally cleaves it.”

What the sources say

• Not checked yetcites [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

In the paper

“Pancreatic β-cell senescence has been implicated as a contributor to type 2 diabetes, at least in a model of high-fat feeding (63).”

What the sources say

• Not checked yetcites [63] Sone, 2005, Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice, Diabetologia source

In the paper

“Experiments in progeroid INK-ATTAC;BubR1H/H mice showed that senescent cell clearance could reverse age-related lipodystrophy.”

What the sources say

• Not checked yetcites [7] Baker, 2011, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [35] Yokoi, 2006, Apoptosis signal-regulating kinase 1 mediates cellular senescence induced by high glucose in endothelial cells, Diabetes source
• Not checked yetcites [36] Cramer, 2010, Persistent high glucose concentrations alter the regenerative potential of mesenchymal stem cells, Stem Cells Dev source
• Not checked yetcites [37] Blazer, 2002, High glucose-induced replicative senescence: point of no return and effect of telomerase, Biochem Biophys Res Commun source

In the paper

“As discussed above, one of the main characteristics of cellular senescence is that it promotes development and accumulation of more senescent cells in nearby and distant tissues, leading to a “snowball” effect (Fig. 1).”

In the paper

“Senescent preadipocyte abundance is greater in obese subjects compared with lean age-matched counterparts, even in young individuals (20).”

What the sources say

• Not checked yetcites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source

In the paper

“IGFBP3 has been shown to cause insulin resistance independently of IGF binding, as evidenced by decreased GLUT4 translocation to the plasma membrane as well as reduced Akt phosphorylation in response to insulin in adipocytes and omental adipose explants (45).”

What the sources say

• Not checked yetcites [45] Chan, 2005, Insulin-like growth factor binding protein-3 leads to insulin resistance in adipocytes, J Clin Endocrinol Metab source

In the paper

“Importantly, overexpression of PAI-1 is sufficient to induce replicative senescence as indicated by SA-βgal activity in mouse embryonic fibroblasts (75).”

What the sources say

• Not checked yetcites [75] Kortlever, 2006, Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence, Nat Cell Biol source

In the paper

“Although much work still needs to be done to link cellular senescence to the pathogenesis of diabetes, many studies have indicated that senescent cell burden is increased in tissues that undergo damage in diabetes, such as the skin, pancreas, and kidney (22,63,67).”

What the sources say

• Not checked yetcites [22] Waaijer, 2012, The number of p16INK4a positive cells in human skin reflects biological age, Aging Cell source
• Not checked yetcites [63] Sone, 2005, Pancreatic beta cell senescence contributes to the pathogenesis of type 2 diabetes in high-fat diet-induced diabetic mice, Diabetologia source
• Not checked yetcites [67] Verzola, 2008, Accelerated senescence in the kidneys of patients with type 2 diabetic nephropathy, Am J Physiol Renal Physiol source

In the paper

“Recently, senescent cells induced by chemotherapy in oncology patients were metabolically targeted by the administration of 2-deoxyglucose to exploit the increased glucose utilization observed in senescent lymphoma cells (93).”

What the sources say

• Not checked yetcites [93] Dörr, 2013, Synthetic lethal metabolic targeting of cellular senescence in cancer therapy, Nature source

In the paper

“In human cancer patients with diabetes, metformin was associated with a decrease in 2-year mortality compared with other glucose-lowering medications (88).”

What the sources say

• Not checked yetcites [88] Yin, 2013, Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis, Oncologist source

In the paper

“As organisms age, immune system function declines, and this could decrease the rate at which organisms are able to clear senescent cells from various tissues (80).”

What the sources say

• Not checked yetcites [80] Aw, 2007, Immunosenescence: emerging challenges for an ageing population, Immunology source

In the paper

“It is possible that, in addition to their antidiabetes effects, these agents target basic aging mechanisms, such as cellular senescence and the SASP.”

In the paper

“Through these means, senescent cells may contribute to their own propagation within tissues, outpacing mechanisms of the immune system that normally clear them.”

In the paper

“it might also have effects on other cellular processes involving those SASP factors, such as immune function, tumorigenesis, wound healing, or hemostasis (10,34).”

What the sources say

• Not checked yetcites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source
• Not checked yetcites [34] Demaria, 2014, An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA, Dev Cell source

In the paper

“In another example, PAI-1 inhibitors reduced senescent cell abundance in Klotho-deficient mice (77).”

What the sources say

• Not checked yetcites [77] Eren, 2014, PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice, Proc Natl Acad Sci U S A source

In the paper

“Senolytics or SASP-protective agents, used alone or in conjunction with current glucose-lowering therapies, may be a way to delay, prevent, alleviate, or even treat hitherto resistant complications of diabetes (66) (Fig. 2).”

What the sources say

• Not checked yetcites [66] Zhu, The Achilles' heel of senescent cells: from transcriptome to senolytic drugs, Aging Cell. 9 March 2015 [Epub ahead of print]. DOI

In the paper

“Similarly, the mechanism of senescent cell clearance is largely unidentified.”

In the paper

“Current methods for assessing senescent cell burden in vivo are at the tissue level, either by quantification of senescent cells through methods such as immunohistochemistry for markers including heterochromatin foci, p16 expression, SA-βgal activity, or screening for transgenic labels such as the p16INK4A promoter-driven GFP in the INK-ATTAC mouse (7).”

What the sources say

• Not checked yetcites [7] Baker, 2011, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature source

In the paper

“However, due to the ubiquity of IL-6 in proinflammatory processes, circulating levels may not be specific enough to quantify senescent cell burden.”

In the paper

“However, targeting senescent cells and the SASP in the setting of disease, such as diabetes, could provide proof of principle for therapies that target aging mechanisms.”

In the paper

“Current therapies for diabetes may have other beneficial effects in addition to solely lowering glucose.”

In the paper

“In addition to increasing susceptibility to infection, senescence-induced immune dysfunction may contribute to decreased senescent cell clearance in aging and diabetes, accelerating the increase in senescent cell burden.”

In the paper

“Glucose-lowering medications have limited effects on ameliorating existing tissue damage”

In the paper

“In turn, SASP factors may contribute to immune dysfunction, leading to a vicious positive feedback cycle of increasing senescent cell burden.”

In the paper

“In vivo studies of senescent cell clearance as a preventative therapy would potentially be difficult because little is known about the time frame of senescent cell formation.”

In the paper

“Senescent cell burden increases in aging and obesity and may play a role in causing or exacerbating type 2 diabetes.”

In the paper

“For patients with prediabetes, therapy targeting senescent cells may prevent progression to frank diabetes and its complications.”

In the paper

“While targeting the SASP could inhibit senescent cell formation by disrupting cytokine, RAGE, or serine protease inhibitor signaling pathways”

What the sources say

• Not checked yetcites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source
• Not checked yetcites [34] Demaria, 2014, An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA, Dev Cell source

In the paper

“Metformin may also confer a decreased cancer risk in patients with diabetes (90).”

What the sources say

• Not checked yetcites [90] Noto, 2012, Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis, PLoS One source

In the paper

“There are currently no ideal systemic markers of senescent cell burden that could be used to assess the efficacy of senescent cell clearing, or senolytic, drugs.”

In the paper

“A recent study linked this antineoplastic activity of metformin to inhibition of the SASP by interfering with proinflammatory nuclear factor-κB signaling (91).”

What the sources say

• Not checked yetcites [91] Moiseeva, 2013, Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation, Aging Cell source

In the paper

“Surprisingly, metformin was recently shown to confer a slight but significant lifespan benefit to patients with diabetes compared with control subjects without diabetes (89).”

What the sources say

• Not checked yetcites [89] Bannister, 2014, Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls, Diabetes Obes Metab source

In the paper

“and might not be very effective in reducing senescent cell burden.”

In the paper

“This may be one mechanism by which senescent cell burden increases with chronological age.”

In the paper

“As organisms age, immune system function declines”

What the sources say

• Not checked yetcites [80] Aw, 2007, Immunosenescence: emerging challenges for an ageing population, Immunology source

In the paper

“The development of transgenic mice from which senescent cells can be selectively cleared allowed the demonstration of senescent cells' causal role in disease (7).”

What the sources say

• Not checked yetcites [7] Baker, 2011, Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders, Nature source

In the paper

“This increased senescent cell burden may play a role in the tissue damage that contributes to diabetes complications.”

In the paper

“Therefore, testing whether senescent cells have a causal role in these pathologies is challenging to delineate.”

In the paper

“Diabetes complications, especially cardiovascular disease and microvascular complications including neuropathy, nephropathy, and retinopathy, have been particularly difficult to treat by glucose control alone (94).”

What the sources say

• Not checked yetcites [94] Stolar, 2010, Glycemic control and complications in type 2 diabetes mellitus, Am J Med source

In the paper

“Also, IL-6, a prominent SASP factor, interferes with macrophage migration (85).”

What the sources say

• Not checked yetcites [85]