Cell Senescence in Type II Diabetes: Therapeutic Potential

Snata Pandey, St. Xavier’s College (Autonomous), Kolkata

The dark side of cell cycle

Cell senescence is a permanent arrest of the cycle of a damaged or stressed cell, at either the gap 1 (G₁) or the gap 2 (G₂) phase. Senescence starts during embryogenesis, occurs throughout life, but senescent cells are regularly cleared by the immune system. However, with age, organ-specific accumulation of senescent cells is visible in adipose tissue, kidney, skin etc. which drives aging and aging-related disorders, including type 2 diabetes mellitus (T2DM).

Type II Diabetes and progress in its treatment

According to the World Health Organisation (WHO), type 2 diabetes occurs due to the body’s ineffective use of insulin, occurring largely due to ageing and obesity, leading to complications including renal dysfunction, cardiovascular disease, impaired wound healing, depression, and cognitive decline. Limited efficacy characterizes treatments for diabetes, so novel approaches must be undertaken.. It was seen that diabetic environmental features drive senescence, whereas SASP¹ drives diabetic symptoms. Clearance of senescent cells relieves age-related disorders (Baker et al., 2011), hence, senotherapeutic approaches may prove to be effective in treating type 2 diabetes.

Cell Senescence: Causes and General Mechanism

DNA damage is the primary cause of senescence. DNA damage may be due to subsequent replicative cycles or due to different detrimental mutations leading to oncogene activation or loss of tumour suppressor functions. Besides this, loss of cell cycle control, organelle damage, accumulation of reactive oxygen species, and epigenetic changes can result in senescence.

Overall, senescence is activated via one of two pathways, either the p53-p21 pathway or the p16-RB pathway². Different causes can trigger different cascades of signals, which ultimately switch on either one of the two mentioned cases (Huang et al., 2022). Generally, if DNA damage occurs, the cell activates the p53-p21 pathway, while the accumulation of ROS and epigenetic alterations (such as methylation or acetylation) activates the p16-RB pathway. Oncogene activation can also activate p53-p21 pathway without DNA damage as well as the p16-RB pathway.

Senescence And Type 2 Diabetes

Various experiments make it clear that senescence and T2DM are closely interlinked:

• Inflammation and Insulin Resistance

Researchers use the term “inflammaging” (Huang et al., 2022) because various SASP components cause non-pathogen-related chronic inflammation, which is associated with aging. Aging and obesity both induce inflammation, which causes insulin resistance (Esser et al., 2014). Pro-inflammatory cytokines, which act in an autocrine and paracrine manner, are a part of SASP (Spranger et al., 2003), and can interfere with insulin signaling in peripheral tissues or induce β-cell dysfunction and subsequent insulin deficiency (Palmer et al., 2015). Plasminogen Activator Inhibitor-1 (PAI-1)³, another SASP component, is increased in the circulation and tissues, such as coronary arteries of patients with diabetes (Schneider et al., 2012).

• Adipose Tissue Dysfunction due to Cell Senescence

Preadipocytes become senescent, and age-independently, their burden increases with obesity (Tchkonia et al., 2010). Such preadipocytes have less adipogenic and lipogenic potential, leading to lipotoxicity and inflammation (Tchkonia et al., 2010). SASP (inflammatory cytokines) can also affect adipogenesis, where preadipocytes develop into adipocytes with insulin and other receptors (Palmer et al., 2015). A novel transgene, INK-ATTAC⁴ was shown to remove p16-positive senescent cells when treated with drug in BubR1 progeroid mice⁵, and this life-long removal of p16-expressing cells delayed onset of age-related pathologies in adipose tissues, skeletal muscle and eye as well as reduced progression of already established ARDs⁶ (Baker et al., 2011). Palmer et al. (2015) have not yet established whether senescent cell clearance has a positive response in reversing age-related lipodystrophy in diabetic individuals.

• Pancreatic Beta-cell Senescence

When mice were fed a high fat diet for 4 to 12 months, insulin levels and beta cell amount increased then decreased, and senescence-associated beta galactosidase positive area (with negative correlation with insulin) increased when compared to control (Sone et al., 2005). Moreover, Sone et al. (2005) found that beta cells from the high-fat diet group had small amounts of p38, which is induced by oxidative stress and mediates cellular senescence, while beta cells from the control group did not have p38. This finding indicates that beta cell senescence occurred in diet-induced type 2 diabetes and led to lesser insulin release.

P27⁷ was also heightened in beta cells, whose deletion increased insulin secretion, which ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice (Uchida et al., 2005).Tavana et al. (2010) observed an accelerated model of diabetes, where increased age led to a decrease in insulin production and secretion associated with senescence. They accomplished this by creating p53-apoptosis-nullified mice, whose burden of senescent cells increased rapidly, causing dysfunction of pancreatic β-cells and resulting in an overt diabetic phenotype in 3–4 months. Thus, senolytic therapy administered after the first diagnosis of prediabetes might help reduce diabetes progression by preserving some β-cell function (Palmer et al., 2015).

Senotherapy: Its Potential in Treating Type 2 Diabetes Mellitus

Senotherapy is a novel approach to targeting senescent cells to regulate age-related disorders. The senotherapeutic approach for diabetes can be two-fold, depending on tissue localization and the disease concerned: clearance of senescent cells and inhibiting local and systemic effects of SASP.

None of the current therapies for diabetes target senescence directly. Recently, metformin has been seen to reduce DNA damage and inflammation in human adipose mesenchymal stromal cells undergoing replicative senescence, and its senomorphic function seemed related to its reactive oxygen species (ROS) scavenging activity (Acar et al., 2021).

Challenges in senotherapy

Challenges of senotherapy are numerous. First, abundant clinical trials for senotherapy are not feasible (Palmer et al., 2015). Second, there is no unique senescent burden marker which can help understand the efficiency of senotherapy (Palmer et al., 2015). Third, timelines of organ-specific senescence are yet to be delineated (Palmer et al., 2015). Fourth, the senescence clearing mechanism of the immune system is unknown; age-related immune dysfunction further reduces killing (Palmer et al., 2015). Fifth, it is not known if there are any unique features of diabetes-associated senescence which may be specifically targeted (Palmer et al., 2015). Sixth, the unique features of senescent cells themselves need to be more properly identified (Palmer et al., 2015). Finally, SASP targeting is problematic since several factors are essential for normal physiology like wound healing and tumour suppression (Palmer et al., 2015).

Conclusion and Future Prospects

Aging and obesity primarily drive the multi-factor origins of T2DM. Cell senescence occurs due to DNA damage or cellular stress, and it accumulates in different organs with age. Researchers have not yet properly characterized the exact interrelationship between type 2 diabetes and cell senescence. However, it is obvious that SASP drives diabetic symptoms and alternately, diabetes enhances senescence in near and distant tissues.

Researchers may identify methods to reverse cellular senescence in adipose tissues and pancreatic beta-cells, particularly when keeping in mind the pivotal roles of p53 and p16. Complete removal of p53 or p16-positive cells might lead to other complications, and so their partial reprogramming is preferable (Chen et al., 2022).

Since ROS is central to the senescence mechanism due to mitochondrial dysfunction, intake of antioxidants can be effective. Finally, since proinflammatory SASP is instrumental in diabetic complications, reviving the normal microflora while focusing on anti-inflammatory probiotics, like multiple strains of lactobacilli and bifidobacteria, may be useful in restoring a normal gut microbiome.

References

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2. Huang, Weijun, et al. “Cellular Senescence: The Good, the Bad and the Unknown.” Nature Reviews Nephrology, vol. 18, no. 10, Oct. 2022, pp. 611–27. https://doi.org/10.1038/s41581-022-00601-z.
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Footnotes:

1. Senescence-Associated Secretory Phenotype (SASP): It refers to a complex and unique secretion profile that is characteristic of senescent cells. The SASP includes a wide range of secreted molecules, such as proinflammatory cytokines, growth factors, and proteases, which can have various effects on neighbouring cells and tissues. ↩︎
2. p53-p21 Pathway:
   p53: The p53 protein is a crucial regulator of the cell cycle and a key player in the response to DNA damage and cellular stress. It is often referred to as the “guardian of the genome.”
   p21: p21 (also known as p21WAF1/Cip1) is a cyclin-dependent kinase inhibitor (CKI) that is transcriptionally activated by p53.
   Mechanism: In response to cellular stress, such as DNA damage or oncogenic signals, p53 is activated. Activated p53, in turn, upregulates the expression of p21.
   Effect: p21 inhibits the activity of cyclin-dependent kinases (CDKs), particularly CDK2, leading to cell cycle arrest. This prevents the cell from progressing through the cell cycle.
   Senescence: Activation of the p53-p21 pathway can result in cellular senescence, a stable, non-dividing state that prevents damaged cells from contributing to further tissue damage or becoming cancerous.
   p16-RB Pathway:
   p16: The p16 protein (also known as INK4a) is another cyclin-dependent kinase inhibitor (CKI) that plays a critical role in regulating the cell cycle.
   RB: The Retinoblastoma protein (RB) is a key regulator of the G1 phase of the cell cycle.
   Mechanism: p16 inhibits the activity of CDK4 and CDK6, which are responsible for phosphorylating and inactivating RB.
   Effect: Inhibition of CDK4/6 by p16 prevents phosphorylation and inactivation of RB. As a result, RB remains in its active, hypophosphorylated state.
   Senescence: Hypophosphorylated RB sequesters transcription factors like E2F, preventing them from promoting the expression of genes required for cell cycle progression. This leads to cell cycle arrest and senescence. ↩︎
3. PAI-1 plays a role in regulating the activity of the plasminogen activation system, which is involved in the breakdown of blood clots (fibrinolysis) and tissue remodeling. By secreting PAI-1, senescent cells can influence processes such as inflammation, tissue repair, and the extracellular matrix. ↩︎
4. INK-ATTAC is a genetic mouse model used in biological and medical research to study cellular senescence. The name “INK-ATTAC” stands for “INK4a Arrest in Turn Allows Continuous Attenuation of Cellular Senescence.” ↩︎
5. BubR1 progeroid mice are engineered to have mutations in the BubR1 gene, which is associated with the mitotic spindle checkpoint, a critical cellular process that ensures accurate chromosome segregation during cell division (mitosis) ↩︎
6. ARDs: Age-Related Diseases. ↩︎
7. P27, also known as Cyclin-Dependent Kinase Inhibitor 1B (CDKN1B), is a crucial protein involved in the regulation of the cell cycle. P27 is a negative regulator of the cell cycle. It functions by inhibiting the activity of CDK-cyclin complexes, particularly CDK2-cyclin complexes. CDKs are enzymes that drive cell cycle progression. ↩︎

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