Cellular Senescence in Traumatic Brain Injury: Evidence and Perspectives

Abstract

Mild traumatic brain injury (mTBI) can lead to long-term neurological dysfunction and increase one's risk of neurodegenerative disease. Several repercussions of mTBI have been identified and well-studied, including neuroinflammation, gliosis, microgliosis, excitotoxicity, and proteinopathy – however the pathophysiological mechanisms activating these pathways after mTBI remains controversial and unclear. Emerging research suggests DNA damage-induced cellular senescence as a possible driver of mTBI-related sequalae. Cellular senescence is a state of chronic cell-cycle arrest and inflammation associated with physiological aging, mood disorders, dementia, and various neurodegenerative pathologies. This narrative review evaluates the existing studies which identify DNA damage or cellular senescence after TBI (including mild, moderate, and severe TBI) in both experimental animal models and human studies, and outlines how cellular senescence may functionally explain both the molecular and clinical manifestations of TBI. Studies on this subject clearly show accumulation of various forms of DNA damage (including oxidative damage, single-strand breaks, and double-strand breaks) and senescent cells after TBI, and indicate that cellular senescence may be an early event after TBI. Further studies are required to understand the role of sex, cell-type specific mechanisms, and temporal patterns, as senescence may be a pathway of interest to target for therapeutic purposes including prognosis and treatment.

Photobiomodulation therapy alleviates repeated closed head injury‐induced anxiety‐like behaviors

“…The complex interrelationships among cellular senescence, neuroinflammation, and mitochondrial dysfunction in brain injury suggest approaches targeting neuroinflammation and mitochondrial might help attenuate cellular senescence [48]. In line with the previous study [48], rCHI induced neuronal senescence in the cortex, which was alleviated by PBM therapy. According to previous studies, persistent inflammation could accelerate the senescence process of neurons and other types of cells.…”

“…Growing evidence suggests the existence of cellular senescence in traumatic brain injury [47]. The complex interrelationships among cellular senescence, neuroinflammation, and mitochondrial dysfunction in brain injury suggest approaches targeting neuroinflammation and mitochondrial might help attenuate cellular senescence [48]. In line with the previous study [48], rCHI induced neuronal senescence in the cortex, which was alleviated by PBM therapy.…”

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

“…It is characterized by proliferative arrest, secretory phenotype, macromolecular damage, and alternation in metabolism [36,37]. Several studies suggested that DNA damage-induced cellular senescence was a possible driver of TBI-associated sequelae such as cognitive impairment [38][39][40]. Among the common DEGs, several genes might play a role in the response to DNA damage.…”

Non-Communicable Neurological Disorders and Neuroinflammation

“…Neuroinflammatory mechanisms contribute to clear the injured brain and spinal cord of damage and to foster tissue regenerative mechanisms, especially remyelination. The consequences of TBI and SCI, however, include cell senescence ( 12 ), that may contribute to secondary injury. While this may be the substrate for neurodegenerative mechanisms secondary to repeated head concussions, this may also explain why the severity of long-term consequences after TBI or SCI is increased in elderly ( 10 , 12 ).…”

“…The consequences of TBI and SCI, however, include cell senescence ( 12 ), that may contribute to secondary injury. While this may be the substrate for neurodegenerative mechanisms secondary to repeated head concussions, this may also explain why the severity of long-term consequences after TBI or SCI is increased in elderly ( 10 , 12 ).…”