Evidence of the Cellular Senescence Stress Response in Mitotically Active Brain Cells—Implications for Cancer and Neurodegeneration

Abstract

Cellular stress responses influence cell fate decisions. Apoptosis and proliferation represent opposing reactions to cellular stress or damage and may influence distinct health outcomes. Clinical and epidemiological studies consistently report inverse comorbidities between age-associated neurodegenerative diseases and cancer. This review discusses how one particular stress response, cellular senescence, may contribute to this inverse correlation. In mitotically competent cells, senescence is favorable over uncontrolled proliferation, i.e., cancer. However, senescent cells notoriously secrete deleterious molecules that drive disease, dysfunction and degeneration in surrounding tissue. In recent years, senescent cells have emerged as unexpected mediators of neurodegenerative diseases. The present review uses pre-defined criteria to evaluate evidence of cellular senescence in mitotically competent brain cells, highlights the discovery of novel molecular regulators and discusses how this single cell fate decision impacts cancer and degeneration in the brain. We also underscore methodological considerations required to appropriately evaluate the cellular senescence stress response in the brain.

A Computational Analysis in a Cohort of Parkinson’s Disease Patients and Clock-Modified Colorectal Cancer Cells Reveals Common Expression Alterations in Clock-Regulated Genes

“…According to our results, these shared altered pathways are likely circadian regulated. These commonly altered mechanisms include malfunctions in several processes including redox homeostasis, functioning of immune system, cell cycle, DNA repair and circadian regulation [ 3 , 6 , 13 , 14 ]. Our analysis shows that upon perturbation of core-clock genes, the rhythmicity pattern of genes involved in such processes was altered.…”

“…The hallmarks of physiologic aging and neurodegeneration include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication [ 11 , 12 ]. Many of these processes are also relevant to tumorigenesis [ 3 , 6 , 13 , 14 ]. Genetic forms of PD are particularly interesting in this overlap.…”

“…Thus, increasing evidence points to the disruption of common cellular events in both cancer and PD [ 2 , 3 , 4 , 5 ], but the mechanisms underlying these associations require further studies. These mechanisms include the regulation of cell cycle, DNA repair, immune response and redox homeostasis [ 3 , 6 , 13 , 14 ]. Recent work from our group using time series data for an in vitro model of colorectal cancer (CRC) progression pointed to a link between cancer and neurodegenerative diseases, involving the circadian system [ 17 ], and suggested that altered oscillatory patterns of cancer-associated genes may also be involved in neurodegeneration in Huntington’s disease, but also revealed differential enrichment of genes involved in Alzheimer’s disease and PD.…”

Gonadal sex patterns p21-induced cellular senescence in mouse and human glioblastoma

“…This has important implications for the fields of aging and neurodegenerative disease. Senescent cells contribute to a wide range of normal and pathological changes with aging 30,31 , and are increasingly thought to play a role in neurodegenerative disease 32,33 . Sex differences in p16 and p21 expression in aged mice in vivo have been reported, although this study actually found higher levels of these in male mice than female mice 34 .…”

An Insight into Aging, Senescence, and Their Impacts on Wound Healing

“…When cells are exposed to oxidative stress and/or DNA damage as a result of physical or chemical agents, premature senescence occurs [ 10 ]. Senescent cells are characterized by cell cycle arrest, resistance to apoptosis, chromatin remodeling, morphological changes, such as flattened shape, cell enlargement, and a disrupted nuclear membrane [ 11 , 12 ]. These cells have a senescence-associated secretory phenotype (SASP) which influences surrounding cells and tissues [ 13 , 14 ].…”