Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity

In the paper

“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).”

What the sources say

• Not checked yetcites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source
• Not checked yetcites [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 yetcites [22] Waaijer, 2012, The number of p16INK4a positive cells in human skin reflects biological age, Aging Cell source

In the paper

“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).”

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

“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).”

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 cell burden is low in young individuals but increases with aging in several tissues including adipose tissue, skeletal muscle, kidney, and skin (20–22).”

What the sources say

• Not checked yetcites [20] Tchkonia, 2010, Fat tissue, aging, and cellular senescence, Aging Cell source
• Not checked yetcites [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 yetcites [22] Waaijer, 2012, The number of p16INK4a positive cells in human skin reflects biological age, Aging Cell source

In the paper

“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).”

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

“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).”

What the sources say

• Not checked yetcites [16] Campisi, 2005, Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors, Cell source

In the paper

“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).”

What the sources say

• Not checked yetcites [9] Kirkland, Clinical strategies and animal models for developing senolytic agents, Exp Gerontol. 28 October 2015 [Epub ahead of print]. DOI
• Not checked yetcites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source

In the paper

“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).”

What the sources say

• Not checked yetcites [68] Conboy, 2005, Rejuvenation of aged progenitor cells by exposure to a young systemic environment, Nature source

In the paper

“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).”

What the sources say

• Not checked yetcites [64] Uchida, 2005, Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice, Nat Med source

In the paper

“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).”

What the sources say

• Not checked yetcites [65] Tavana, 2010, Absence of p53-dependent apoptosis combined with nonhomologous end-joining deficiency leads to a severe diabetic phenotype in mice, Diabetes source

In the paper

“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).”

What the sources say

• Not checked yetcites [9] Kirkland, Clinical strategies and animal models for developing senolytic agents, Exp Gerontol. 28 October 2015 [Epub ahead of print]. DOI
• Not checked yetcites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source
• 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

In the paper

“Cardiac progenitor aging is accelerated in diabetes, and heart disease is a major complication of diabetes (74).”

What the sources say

• Not checked yetcites [74] Rota, 2006, Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene, Circ Res source

In the paper

“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).”

What the sources say

• Not checked yetcites [31] Freund, 2010, Inflammatory networks during cellular senescence: causes and consequences, Trends Mol Med source
• Not checked yetcites [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 yetcites [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

In the paper

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

In the paper

“In addition, overexpression of IGFBP3 in mice leads to decreased glucose tolerance, insulin resistance, and hyperglycemia (46).”

What the sources say

• Not checked yetcites [46] Silha, 2002, Impaired glucose homeostasis in insulin-like growth factor-binding protein-3-transgenic mice, Am J Physiol Endocrinol Metab source

In the paper

“Several possible “subtypes” of cellular senescence have been identified, including oncogene-induced senescence, stress-induced premature senescence, and the classical replicative senescence (10).”

What the sources say

• Not checked yetcites [10] Muñoz-Espín, 2014, Cellular senescence: from physiology to pathology, Nat Rev Mol Cell Biol source

In the paper

“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).”

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 [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 senescent preadipocytes could contribute to declines in adipogenic and lipogenic potential, with consequent development of age-related lipodystrophy, leading to lipotoxicity and inflammation (20).”

What the sources say

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

In the paper

“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).”

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

“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).”

What the sources say

• Not checked yetcites [51] Yang, 2009, Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome, Am J Physiol Endocrinol Metab source

In the paper

“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).”

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

In the paper

“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

“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).”

What the sources say

• Not checked yetcites [55] Pradhan, 2001, C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus, JAMA source
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [78] Petersen, 2003, Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science source
• Not checked yetcites [79] Passos, 2010, Feedback between p21 and reactive oxygen production is necessary for cell senescence, Mol Syst Biol source

In the paper

“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).”

What the sources say

• Not checked yetcites [83] Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature source

In the paper

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

In the paper

“For example, the cytokine IL-6 is an important component of the SASP and appears to be an indicator of frailty (92).”

What the sources say

• Not checked yetcites [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

In the paper

“Existing diabetes therapies, namely metformin and acarbose, extend lifespan in nondiabetic mice (86,87).”

What the sources say

• Not checked yetcites [86] Harrison, 2014, Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males, Aging Cell source
• Not checked yetcites [87] Martin-Montalvo, 2013, Metformin improves healthspan and lifespan in mice, Nat Commun source

In the paper

“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.”

In the paper

“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).”

What the sources say

• 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

“This may be because much damage occurs before diagnosis and initiation of treatment.”

In the paper

“Senescent cell burden increases in aging and obesity”

In the paper

“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.”