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.
Highlights
Mild traumatic brain injury occurs frequently in the general population and includes concussions and subconcussive hits to the head (Carrol et al, 2004)
In the long-term, people who have a history of Mild traumatic brain injury (mTBI) are at a higher risk of developing several neurodegenerative diseases, including “classic” types such as Alzheimer’s disease (AD) (Mortimer et al, 1991) and Parkinson’s disease (PD) (Jafari et al, 2013), and more recently mTBI has been linked to chronic traumatic encephalopathy (CTE) (Stein et al, 2014; Maroon et al, 2015; McKee et al, 2016)
There is a growing body of evidence showing DNA damage and cellular senescence in various forms of Traumatic brain injury (TBI), including mTBI. As both the clinical and molecular substrates of mTBI are associated with cellular senescence, this evidence suggests that cellular senescence may be an upstream overriding mechanism at play in mTBI and may represent a therapeutic target for early interventions
Summary
Mild traumatic brain injury (mTBI) occurs frequently in the general population and includes concussions and subconcussive hits to the head (Carrol et al, 2004). Patients may have minimal symptoms and recover quickly, some may experience PCS and recover over time, and others may have long-term neurological problems, develop dementia, or be diagnosed with a neurodegenerative disease at autopsy Several of these clinical phenotypes including depression (Diniz et al, 2017), anxiety (Ogrodnik et al, 2019), sleep disturbances (Carroll et al, 2016), dementia (Baker and Petersen, 2018), and neurodegeneration (Martínez-Cué and Rueda, 2020) are associated with elevated levels of senescent cells in the brain. Subsequent sections will summarize the evidence showing accumulation of DNA damage and senescent cells after mTBI, and how known molecular changes in mTBI may be downstream repercussions of stressinduced senescence
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