Terpenoids as Emerging Senotherapeutics: Mechanistic Insights and Therapeutic Potential.

Traumatic brain injury (TBI) is a devastating neurological disease caused by external mechanical forces, leading to structural damage or functional impairment of the brain. It is one of the leading causes of death and long-term disability worldwide. Over 50 million cases of TBI occur annually globally, and in the United States, approximately 1.7 million people seek medical attention for TBI each year, with about 275,000 being hospitalized, and 50,000 dying from this disease (). In China, the annual incidence of TBI is similarly high, making TBI one of the leading causes of long-term disability and economic burden (). Despite significant advances in emergency and surgical treatment, early complications, especially lower extremity deep vein thrombosis (LEDVT), remain an important factor influencing patient prognosis. TBI patients typically exhibit consciousness disturbances, memory loss, neurological deficits, and intracranial lesions confirmed by imaging studies. LEDVT, a common complication in TBI patients, can lead to more severe complications, such as pulmonary embolism (PE), which is one of the leading causes of death in TBI patients if not diagnosed and treated promptly. Garcia et al. () analyzed the incidence of PE in TBI patients in the United States from 2016 to 2020, finding that approximately 0.6% of TBI patients developed PE, which was associated with longer hospitalization and higher mortality. Therefore, early identification and intervention for LEDVT in TBI patients are crucial, as it not only helps reduce the occurrence of complications but also significantly improves patient survival rates and quality of life. Although routine prophylaxis protocols, including pharmacological agents (e.g., low-molecular-weight heparin) and mechanical measures (e.g., intermittent pneumatic compression), have been widely adopted to counterbalance thromboembolic risks in neurosurgical populations, the optimal application of these strategies remains a subject of ongoing debate. As reviewed by Epstein, while appropriate prophylaxis can substantially reduce the incidence of venous thromboembolism, it also carries inherent risks, particularly intracranial hemorrhage expansion in TBI patients, necessitating a careful risk–benefit assessment (). Ganau et al. further emphasized that prophylactic strategies must be dynamically tailored to individual patient profiles, as fixed regimens often fail to account for the heterogeneity of TBI pathophysiology (). Moreover, comparative studies, such as the prospective work by Chibbaro et al., have demonstrated that combined approaches (pharmacological plus mechanical) may offer superior efficacy, yet their applicability in the acute phase of TBI requires further validation (). Despite these advances in prophylaxis, the residual risk of LEDVT remains non-negligible, and current clinical practices still heavily rely on empirical judgment rather than individualized, data-driven risk stratification. This gap underscores the urgent need for a robust predictive tool that can identify high-risk patients prior to the occurrence of thromboembolic events, thereby enabling more precise and personalized prophylactic interventions. The pathophysiology of LEDVT formation is multifactorial, involving coagulation dysfunction, inflammatory cascades, and endothelial injury. Previous studies have identified several risk factors, such as age, gender, severity of the injury, type of trauma, and whether anticoagulant therapy was administered. Among these, age is not merely a demographic variable but rather a proxy for physiological reserve and frailty, which has emerged as a critical determinant of outcomes in older adults with TBI—a population increasingly recognized as “silver trauma” patients (). As highlighted by Depreitere et al., frailty, rather than chronological age per se, may better account for the elevated risks of complications, including thromboembolic events, in this vulnerable cohort, as it reflects the cumulative decline in multiple physiological systems that impairs the resilience to injury and subsequent stressors. This perspective suggests that the relationship between age and LEDVT risk in TBI patients may be mediated by frailty-related factors, which are often not captured by conventional risk assessments. Additionally, laboratory parameters like platelet count, interleukins, and D-dimer are also associated with deep vein thrombosis formation (). However, the predictive ability of traditional regression models remains limited. These models often assume linear relationships, struggle to handle high-dimensional data, and fail to fully capture the complex nonlinear interactions underlying LEDVT occurrence.