The Role of Senescent Cells in Disease

Cellular senescence is a process of irreversible cell-cycle arrest in response to various internal or external stressors. In addition to preventing the uncontrolled proliferation of damaged cells, cellular senescence plays vital roles in fetal development, tissue repair, wound healing, aging, and age-related diseases.

Image Credit: Billion Photos/Shutterstock.com

Image Credit: Billion Photos/Shutterstock.com

What is cellular senescence?

Cellular senescence is a state of permanent growth arrest of old or damaged cells in response to various stressors, including oncogenic, genotoxic, and oxidative stress, radiation and chemotherapeutics, and mitochondrial malfunction. Besides undergoing a range of phenotypic changes, including metabolic remodeling and chromatic rearrangement, senescent cells secrete a panel of proinflammatory mediators collectively known as senescence-associated secretory phenotype.

In normal physiological conditions, senescent cells play crucial roles in maintaining cellular homeostasis and preventing neoplastic transformation by inhibiting the proliferation of abnormal cells. However, excessive accumulation of senescent cells can lead to the induction of various pathological conditions, including age-related disorders and cancer.

Cellular senescence can be broadly categorized into two forms. Acute senescence is a programmed process primarily associated with the maintenance of cellular homeostasis. Acute senescent cells are produced in response to acute stressors and target a specific population of cells to facilitate tissue repair, wound healing, or embryonic development. These cells are effectively cleared by the components of the immune system.

In contrast, chronic senescence is not a programmed process and occurs in response to prolonged stress or damage. Chronic senescent cells do not undergo scheduled clearance by immune cells and are primarily associated with the progression of aging and age-related pathologies. An age-related reduction in immune system efficiency or production of less inflammatory secretome could be the primary reason behind the unscheduled clearance of chronic senescent cells.      

What is senescence-associated secretory phenotype?

Senescent cells are capable of modulating the surrounding microenvironment through senescence-associated secretory phenotype (SASP). The secretome is characterized by a combination of proinflammatory mediators (cytokines and chemokines), growth factors, extracellular matrix proteases, and other signaling molecules. The composition and functionality of SASP strictly depend on the stage of senescence, type of stressor, affected cell type, and surrounding environment.

Overview of Cell Senescence

Senescent cells in malignancies

Induction of SASP by senescent cells can have beneficial or detrimental consequences. By inducing an autocrine positive-feedback loop, SASP can support growth arrest and contribute to tumor-suppressing processes. Moreover, SASP can further augment the anticancer effect by inducing senescence of nearby non-cancerous cells exposed to similar stressors and susceptible to neoplastic transformation.

In contrast, proinflammatory mediators of SASP can trigger the transformation of premalignant cells to malignant cells. In senescent fibroblasts, SASP increases the proliferation of premalignant epithelial cells. Similarly, in xenograft transplants, SASP triggers tumor vascularization.

The SASP secreted by senescent hepatic cells can also trigger the proliferation and malignant properties of nearby hepatocytes in obese mice. Senescent cells that accumulate in response to chemotherapy are known to mediate detrimental effects through SASP. Therapeutic elimination of these cells can prevent tumor relapse.  

From the immunological perspective, SASP-mediated recruitment of immune cells is considered to be a beneficial process for eliminating premalignant cells and preventing cancer progression. In contrast, the immunosuppressing properties of SASP can positively influence tumorigenesis. For example, the coexistence of senescent hepatocytes and hepatic cancer cells can trigger SASP-mediated recruitment of immature myeloid cells, which can facilitate hepatic cancer progression via suppression of natural killer cell functions.

Senescent cells in aging and age-related diseases

The accumulation of senescent cells in tissues and organs increases with age. These cells contribute significantly to the overall reduction in tissue regenerative properties. Such age-related accumulation of senescent cells could be because of increased levels of senescence-inducing stressors or reduced elimination of senescent cells.

One of the major hallmarks of age-related diseases is low-level chronic inflammation, which is associated, at least in part, with senescent cell-secreted inflammatory mediators. In aged mice, a reduction in inflammatory cytokines (IL-6, IL-1α, and TNF-α) in adipose tissue, kidney, and skeletal muscle has been observed after the elimination of senescent cells (senolysis).

In epithelial tissues, SASP cytokines trigger tissue fibrosis by inducing epithelial-to-mesenchymal transition. In addition, chronic secretion of proteases by senescent cells can disrupt tissue organization by cleaving extracellular matrix proteins, membrane-bound receptors, and receptor ligands. These proteases, together with inflammatory components of SASP, induce a tissue microenvironment that facilitates the survival, growth, and propagation of premalignant cells. This explains the fact of increasing cancer risk with age.

Age-related decline in tissue function can also be triggered by certain cytokines and chemokines of SASP that eventually help transmit senescence phenotypes to nearby healthy tissues.

In patients with Alzheimer’s disease, increased senescence has been observed in astrocytes, microglia, and neurons. It has been documented in the literature that exposure of neurons to amyloid β-protein (a major hallmark of Alzheimer’s disease) can significantly induce the expression of senescence-associated genes. In mouse models of Alzheimer’s disease, elimination of senescent cells has been found to reduce amyloid β-protein deposition and improve cognitive abilities.

In patients with Parkinson’s disease, increased levels of senescent cells have been observed in cerebrospinal fluid and different brain tissues. In both Alzheimer’s disease and Parkinson’s disease, senescence phenotype is triggered by inflammation, aging, oxidative stress, misfolded proteins, and mitochondrial dysfunction. Increased senescence reduces genetic stability and induces neurodegeneration by increasing SASP, free radical production, telomere attrition, DNA damage, altered proteostasis, and epigenetic modifications.

References

Further Reading

 

Last Updated: May 4, 2022

Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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