Understanding Diabetic Induction of Cellular Senescence: A Concise Review

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. Cellular senescence also underlies many age-related chronic inflammatory diseases, including the components of metabolic syndrome (hypertension, obesity, and atherosclerosis); by translation, diabetes itself is a consequence of this cellular derangement. Senescent cells may play a role in type 2 diabetes pathogenesis through direct impact on pancreatic beta-cell function, senescence-associated secretory phenotype-mediated tissue damage, and involvement in adipose tissue dysfunction. Therefore, the metabolic dysfunctions seen in diabetes, such as hyperglycemia, alterations in lipid metabolism, and growth hormone axis deviations, 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.

Type 2 diabetes is increasing throughout the world at an alarming rate. This is occurring particularly in the face of growing obesity and a rapidly aging population. Diabetes incidence and prevalence increase with age, with almost 26% of Americans 65 years or older having diabetes compared with 9.3% in the general population.¹ Type 2 diabetes can be a consequence of obesity, and its prevalence remains at more than 30%^2,3 in adults older than 60 years. Diabetes is a major risk factor for the premature onset of multiple age-related conditions, including renal dysfunction, cardiovascular disease, stroke, impaired wound healing, infection, depression, and cognitive decline.^4-7

Despite increased understanding of the pathogenesis of diabetes and its comorbidities, clinicians must understand how cellular senescence plays a role in engendering the chronic inflammation that can lead to tremendous cellular and tissue dysfunction, thus ultimately leading to the impaired wound healing response.

CELLULAR SENESCENCE AND AGING

After undergoing a certain number of divisions, normal human diploid fibroblasts enter an irreversible non-dividing state known as replicative senescence. Hayflick et al^8,9 found that normal diploid fibroblasts can divide 50 to 60 times but after that they stop dividing irreversibly. The number of divisions that cells completely reach at the end of the replicated lifespan is called the Hayflick Limit. Senescence has been reported to occur in a number of other cell types, such as keratinocytes, melanocytes, endothelial cells, epithelial cells, glial cells, adrenocortical cells, T lymphocytes, and even tissue stem cells.^10-17

Like other age-related chronic diseases, diabetes may be caused in part by the convergence of basic aging mechanisms that underlie age-related tissue dysfunction. These would include chronic sterile (non-pathogen-associated) inflammation, macromolecular damage, progenitor cell dysfunction, and cellular senescence.¹⁸

Through the last several years, cellular senescence has emerged as a possible cause of general tissue dysfunction and aging phenotypes.^19,20 Cellular senescence is an essentially irreversible growth arrest that occurs in response to various cellular stressors, such as telomere erosion, DNA damage, and oxidative stress, and is most often associated with chronic inflammation engendered in diabetes or oncogenic activation. It is felt to have risen as an antitumor mechanism.²¹ Senescent cell burden is low in younger individuals, but it will increase with age in several tissues, including adipose tissue, skeletal muscle, kidney, and skin.^22-24 In addition, research has shown components of the metabolic syndrome are going to have increased senescent cell burden which will include abdominal obesity, diabetes, hypertension, and atherosclerosis.^{22, 25-27}

Although senescent cells are incapable of dividing, they are metabolically active. This high metabolic activity supports the release of a multitude of proinflammatory cytokines, chemokines, and growth factors collectively known as the senescence-associated secretory phenotype (SASP).^28,29 These factors would include interleukin (IL) 6 and IL-8, chemokines (ie, monocyte chemoattractant proteins [MCPs], macrophage inflammatory proteins, growth-regulated protein alpha), and growth factors (ie, vascular endothelial growth factor, granulocyte/macrophage, a colony-stimulating factor, transforming growth factor beta, and proteinases such as matrix metalloproteinases).^18,30

Because these factors act in autocrine and paracrine manners and have pleiotropic effects for surrounding cells, they may affect the surrounding microenvironment; the senescent cell itself may be involved in perpetuation of chronic inflammation and tissue remodeling in organisms. Because the SASP is very complex and has a multitude of effects that can be advantageous or deleterious depending on context, this may explain the role of cellular senescence in organismal aging and the incidence of age-related diseases and pathologies.

Studies^31-34 indicate senescent cells accumulate in aged and chronic disease-related tissues, which suggests cellular senescence actively contributes to the aging process and progression of diseases at this most basic molecular level. It has been suggested that the low level chronic inflammation often observed during aging in tissues without obvious infection is due to senescent cells and SASP.^35-37 Through the SASP, a low number of senescent cells in a tissue (typically < 20%) may be able to exert systemic effects. It is now evident that senescence can be transmitted to normal cells by SASP in a paracrine or autocrine manner.²¹

Obesity-associated senescent cells may promote chronic, sterile, low-grade inflammation through their production of these SASP factors. In this way, senescent cells can be the link between obesity and inflammation that contributes to the development and progression of type 2 diabetes.^38,39 Cellular senescence has often been thought of in evolutionary terms as a defense mechanism against tumor development. When there is the continued presence of a high number of senescent cells, they can promote tumor progression because of chronic persistent inflammation, tissue disruption, and growth signals due to the SASP.⁴⁰ Senescent cells also can initiate a very deleterious positive feedback mechanism by promoting the spread of senescence to nearby cells.^41-43

The association between diabetes and senescence is synergistic and twisted in a macabre fashion. It is very likely that the diabetic microenvironment could be permissive to the development and accumulation of senescent cells. Diabetes through oxidative stress causes chronic inflammation that damages host cells, triggering a DNA damage response (DDR). This DDR then leads to cells undergoing senescence conversion and, as a result, becoming proinflammatory and perpetuating this phenotype in all tissues afflicted by this menace. Therefore, senescent cells may contribute to the tissue dysfunction and comorbidities observed in type 2 diabetes. It is possible that these complex interactions might lead to a malignant positive feedback loop³ in which this metabolic dysfunction in prediabetes leads to cellular senescence that contributes to the worsening of tissue and metabolic function, which then further increases the formation of and decreases the clearance of senescent cells.

In patients with diabetes, hyperglycemia accompanied by dyslipidemia, immune dysfunction, and growth hormone/insulin-like growth factor 1 dysregulation contribute to the development of cellular senescence. Aging and obesity also will accompany cellular senescence through the various reasons already stated. These senescent cells secreting their various SASP factors then lead to generalized tissue dysfunction and diabetic complications, thus eventually leading to inflammation, insulin resistance, metabolic dysfunction, and progenitor cell dysfunction.

DIABETIC MICROENVIRONMENT PROMOTES CELLULAR SENESCENCE

High glucose drives premature senescence in vivo in endothelial cells, renal mesangial cells, adipose-derived stem cells, and fibroblasts virtually affecting all cell lines, including stem cells. The mechanism of glucose-induced senescence is not clear, although potential candidates are mitochondrial dysfunction and increased reactive oxygen species (ROS).⁴⁴ Because mitochondria can generate ROS, which can be deleterious to many growth pathways, it is proposed that excessive mitochondrial ROS is important to establish cellular senescence.⁴⁵

There are multiple perturbations in mitochondrial homeostasis that can lead to senescence: excessive ROS production, impaired mitochondrial dynamics, electronic transport chain defects, bioenergetic imbalance/increased adenosine monophosphate-activated protein kinase activity, decreased mitochondrial nicotinamide adenine dinucleotide/altered metabolism, and mitochondrial calcium accumulation.^46-48 These cellular dysfunctions are seen within the mitochondria and can establish permanent growth arrest.⁴⁸

High glucose also can potentiate the formation of advanced glycosylation end products (AGEs). Increased AGE signaling through their receptors (RAGE), of which the SASP factor high-mobility group box 1 (HMGB1) is the agonistic ligand, has been shown to cause premature senescence in a multitude of tissues including renal tubular cells, endothelial cells, and pancreatic beta cells.^49,50

SASP POSSIBLE MEDIATOR OF 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.¹⁴ Components of the SASP, such as IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1), are increased in obese adults and adolescents and could contribute to a proinflammatory state together with the recruiting of macrophages, T lymphocytes, and other cell mediators of inflammation.^51,52 In turn, macrophage, T-cell, and B-cell accumulation would be promoted through the effects of the chemokine MCP-1 and other chemotactic proteins, which are produced by senescent cells as part of the SASP.⁵³

Case control studies have found elevated IL-6 and the combined elevation of IL-6 and IL-1 beta, both long identified SASP factors, are independent predictors of diabetes.^54,55 Another prominent SASP component, plasminogen activator inhibitor (PAI) 1, which is a potent stimulator of fibrosis and thrombosis, is increased in the circulation and tissues that are seen in coronary arteries of patients with diabetes.⁵⁶ Recently, HMGB1 has been shown to be involved in the inflammatory signaling during p53-dependent cellular senescence⁵⁷ signals through its ligand RAGE, which plays a vital role in driving diabetes complications as well.⁵⁸

SENESCENCE IN DIABETES COMPLICATIONS

A plethora of studies have indicated that senescent cell burden is increased in tissues that undergo damage in diabetes, such as the skin, pancreas, and kidneys.^59,60 The aging microenvironment limits regenerative potential in young progenitor cells in vivo, and conversely aged progenitor cells exhibit improved function when exposed to a young systemic microenvironment.⁶¹ It is very possible that senescent cells are a contributor to the aging microenvironment, which may limit the progenitor and stem cell potential in every tissue. 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.⁶²

An example of this would be the accumulation of senescent cells that contribute to infectious complications of diabetes and tissue repair in diabetic skin wounds. There is evidence indicating a role of senescent cells in neurodegeneration and cognitive dysfunction.⁶² Increased risk of cognitive impairment in diabetes could be tied to senescence in the brain, either neurons themselves or senescence of infiltrating glial cells, which are the macrophages of the central nervous system. Neurons can adapt a senescence-like phenotype, including DNA damage foci, and senescence-associated beta galactosidase activity in dementia and other neurodegenerative diseases.^63,64

Cardiac progenitor aging is accelerated in diabetes, and heart disease is a major complication of diabetes.⁶⁵ The systemic effect of increased senescent cell burden in diabetes contributes to this, together with the effects of lipotoxicity in endothelial cells and increased prothrombotic SASP factors such as PAI-1. In addition, senescent cells will accumulate within atherosclerotic plaques,²⁶ which can lead to the instability and volatility of plaque and ultimately to its rupture and embolization as is so often seen underlying the molecular catastrophe of major cardiovascular events.

Microvascular complications of diabetes, such as retinopathy, neuropathy, and nephropathy, can be linked to cellular senescence as well. Endothelial cells that line these tissues have been shown to be susceptible to glucose-induced senescence.⁴⁴ Senescent cells therefore not only contribute to the causes of diabetes but also accelerate tissue injury and can be a central mechanism underlying the devastating and destructive complications of diabetes.

PATHOGENIC POSITIVE FEEDBACK LOOPS OF DIABETES

One of the main characteristics of cellular senescence is that it promotes development and accumulation of more senescent cells in nearly every tissue leading to this accumulative effect. This may be accompanied through the SASP, promotion of chronic sterile inflammation, production of ROS, and impedance of immune clearance of senescence cells.

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.^66,67 Oxidative species produced by dysfunctional mitochondria may also induce neighboring cells to undergo senescence, which amplifies senescent cell burden effect in the pancreas and kidneys, potentially establishing another pathogenic loop that would cause senescence cell accumulation.

Immune cells, which are responsible for clearing senescent cells, are susceptible to developing both age- and metabolic-related dysfunction.^68,69 Therefore, the SASP could contribute to a chronic proinflammatory microenvironment in diabetes that causes a decline in natural killer cell function as seen in aging and obesity.^70-72 Through these means, senescent cells contribute to their own propagation within tissues, outrunning mechanisms of the immune system that normally clear them.

Senescent cell burden increases with aging and obesity and can play a significant role in causing or exacerbating type 2 diabetes. As people age, there is an increase in senescent cells within virtually all tissues of the body. Is it no wonder that people with wounds have difficulty recovering and regenerating after injury or infection as they age? Therefore, the features of diabetes can cause an increase in senescent cell numbers, which would further promote chronic inflammation and initiate this vicious cycle of senescent cell formation in multiple tissues. This increased in senescent cell burden plays a role in the tissue damage that contributes to diabetic complications, including chronic diabetic skin ulcerations. Diabetes complications, especially cardiovascular disease and microvascular complications, including neuropathy, nephropathy, and retinopathy, have been shown to have particularly high senescent cell burden.⁷³

As this review has demonstrated, there are multiple cellular dysfunctions contributing to the chronic wound phenotype. Diabetes will engender hyperglycemia, insulin resistance, and oxidative stress, as well as dyslipidemia with elevated free fatty acid levels. This stimulates nerve dysfunction, cellular dysfunction, and growth factor and cytokine imbalance, thus leading to failed extracellular matrix formation, limited reepithelization, impaired angiogenesis, and a prolonged inflammatory response, impairing the wound healing potential. Through this, senescent cell burden and the SASP factors they produce will stimulate chronic inflammatory pathways. These inflammatory proteins will stimulate and upregulate AGE binding to RAGE, increasing mitogen-activated protein kinase pathway overactivation, which impairs insulin signaling. Chronic inflammation also inhibits the activation and signaling of the PI3K pathway, which impairs insulin signaling, as well as increases protein kinase C activity, a major proinflammatory-stimulating protein that has multiple downstream targets. These inflammatory pathways then will perpetuate the elevation of proinflammatory cytokines (such as elevated PAI-1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1, P-selectin, E-selectin, etc); this leads to decreased endothelial nitric oxide synthase activity, thereby decreasing a very powerful vasodilator in nitric oxide. This will eventually end in microvascular complications and endothelial dysfunction.

CONCLUSIONS

This review is a concise presentation of how diabetes affects cells and their function that in turn perpetuates chronic inflammation, cellular dysfunction, and irreparable tissue damage that leads to poor wound healing and multi-organ complications.

Understanding this process will help clinicians more accurately avail themselves of therapies that can possibly target and mitigate chronic inflammation and thus cellular senescence. Therefore, it is absolutely critical that clinicians understand these molecular dysfunctions are not only integral to diabetic complications of the intact tissue, but also these dysfunctional and destructive pathways are translatable to the wounded tissue of the diabetes. By comprehending and appreciating these precise deficiencies, clinicians will be better equipped and prepared to treat the entire diabetic state.

As the old wound healing axiom states, “we do not treat the hole in the patient, we treat the whole patient.” Diabetes is a whole body disease; therefore, understanding these molecular aberrancies and how they affect not only the wounded tissue but the whole body system is crucial. Through better understanding of these molecular dysfunctions, clinicians will be more apt to treat and prevent its devastating complications.

Acknowledgments

Affiliation: Ocean County Foot and Ankle Surgical Associates, Manahawkin, NJ

Correspondence: Matthew Regulski, DPM, Ocean County Foot and Ankle Surgical Associates, 1104 Seashell Avenue, Manahawkin, NJ 08050;
mregulski@comcast.net

Disclosure: The author discloses no financial or other conflicts of interest.

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