Cellular senescence: Molecular mechanisms and pathogenicity

Abstract

Cellular senescence is the arrest of normal cell division. Oncogenic genes and oxidative stress, which cause genomic DNA damage and generation of reactive oxygen species, lead to cellular senescence. The senescence-associated secretory phenotype is a distinct feature of senescence. Senescence is normally involved in the embryonic development. Senescent cells can communicate with immune cells to invoke an immune response. Senescence emerges during the aging process in several tissues and organs. In fact, increasing evidence shows that cellular senescence is implicated in aging-related diseases, such as nonalcoholic fatty liver disease, obesity and diabetes, pulmonary hypertension, and tumorigenesis. Cellular senescence can also be induced by microbial infection. During cellular senescence, several signaling pathways, including those of p53, nuclear factor-κB (NF-κB), mammalian target of rapamycin, and transforming growth factor-beta, play important roles. Accumulation of senescent cells can trigger chronic inflammation, which may contribute to the pathological changes in the elderly. Given the variety of deleterious effects caused by cellular senescence in humans, strategies have been proposed to control senescence. In this review, we will focus on recent studies to provide a brief introduction to cellular senescence, including associated signaling pathways and pathology.

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

“…The secretion of chemokines and cytokines such as IL‐1b, IL‐8, and MCP‐1 through SASP attracts immune cells, leading to immunological clearance of the senescent cells . Consistently, aging and chronic stress induce telomere attrition and excessive SASP, leading to accumulation of senescent cells and insufficient tissue regeneration . Concurrently, hematopoietic stem cells decrease with age, resulting in fewer immune cells and a decline in the immune response, provoking a vicious cycle of defective clearance of senescent cells .…”

“…(14,15) Consistently, aging and chronic stress induce telomere attrition and excessive SASP, leading to accumulation of senescent cells and insufficient tissue regeneration. (14,16) Concurrently, hematopoietic stem cells decrease with age, resulting in fewer immune cells and a decline in the immune response, provoking a vicious cycle of defective clearance of senescent cells. (17) The combination of ineffective regeneration, excessive SASP, and inefficient clearance may explain the accumulation of senescent cells in aged organisms, thus increasing the risk for chronic age-related diseases such as dementia, osteoarthritis, metabolic dysregulation, and carcinogenesis.…”

Senescent cells: Living or dying is a matter of NK cells

“…On the other hand, the proinflammatory feature of SASP facilitates tumor progression . Indeed, its proinflammatory activity results in enhanced proliferation and tumorigenesis of epithelial cells, stimulation of angiogenesis, triggering of epithelial to mesenchymal transition, promotion of cancer cell invasion, increased growth of xenograft tumors in vivo, and, in general, is responsible for multiple aging‐related pathologies …”

Senescent dermal fibroblasts negatively influence fibroblast extracellular matrix‐related gene expression partly via secretion of complement factor D

“…Cellular senescence is associated with reduced cell proliferation, and has a critical influence on the response to cellular damage, inhibiting the progression of aberrant cells . Further, senescent cells contribute to age‐associated tissue disorders, such as impaired tissue homeostasis and tumorigenesis, because of the impairment of tissue regeneration .…”