Foster Thomas C, Kumar Ashok
McKnight Brain Institute, Department of Neuroscience, University of Florida, Gainesville, FL, United States.
Genetics and Genomics Graduate Program, Genetics Institute, University of Florida, Gainesville, FL, United States.
Front Aging Neurosci. 2025 Mar 4;17:1555872. doi: 10.3389/fnagi.2025.1555872. eCollection 2025.
This review focuses on sexual dimorphism in cellular senescence and senolytic treatment in relation to brain health and age-related cognitive decline. The stressors of aging, DNA damage, inflammation, and oxidative stress induce cell senescence, a hallmark of aging. Senescent cells change their function and molecular profile and are primed to release pro-inflammatory cytokines. The functional changes include the activation of cell signals to prevent cell death. The release of pro-inflammatory cytokines from peripheral senescent cells during middle age induces senescence of neighbor cells and heightens the level of systemic inflammation, contributing to neuroinflammation. In response to neuroinflammation and oxidative stress, some neurons alter their physiology, decreasing neuronal excitability and synaptic transmission. Senescent neurophysiology is protective against cell death due to excitotoxicity, at the expense of a loss of normal cell function, contributing to age-related cognitive decline. The level of peripheral cell senescence and systemic inflammation may underlie sexual dimorphism in the prevalence, symptoms, and pathogenesis of age-related diseases, including neurodegenerative diseases. Sex differences have been observed for senescence of astrocytes, microglia, and peripheral cells, including those involved in innate and adaptive immune responses. Interventions that remove senescent cells, such as senolytic drugs, can reduce or ameliorate some of the aging-related loss of function. Similarities and differences in senolytic responses of males and females depend on the system examined, the treatment regimen, the level of senescent cell burden, and the age when treatment is initiated. Estrogen impacts several of these factors and influences the transcription of genes promoting growth, proliferation, and cell survival programs in a manner opposite that of senolytic drugs. In addition, estrogen has anti-aging effects that are independent of cell senescence, including rapidly modifying senescent neurophysiology. Thus, it is important to recognize that, in addition to sex differences in cell senescence, there are other sexually dimorphic mechanisms that contribute to the aging process. The results indicate that senolytics interact with fundamental biology, including sex hormones.
本综述聚焦于细胞衰老中的性别二态性以及与脑健康和年龄相关认知衰退有关的衰老细胞溶解疗法。衰老的应激源，如DNA损伤、炎症和氧化应激，会诱导细胞衰老，这是衰老的一个标志。衰老细胞会改变其功能和分子特征，并准备释放促炎细胞因子。功能变化包括激活细胞信号以防止细胞死亡。中年时期外周衰老细胞释放的促炎细胞因子会诱导邻近细胞衰老，并加剧全身炎症水平，从而导致神经炎症。作为对神经炎症和氧化应激的反应，一些神经元会改变其生理状态，降低神经元兴奋性和突触传递。衰老的神经生理学可保护细胞免受兴奋性毒性导致的细胞死亡，但代价是丧失正常细胞功能，这会导致与年龄相关的认知衰退。外周细胞衰老和全身炎症水平可能是包括神经退行性疾病在内的与年龄相关疾病的患病率、症状和发病机制中性别二态性的基础。在星形胶质细胞、小胶质细胞和外周细胞（包括参与先天和适应性免疫反应的细胞）的衰老方面已观察到性别差异。清除衰老细胞的干预措施，如衰老细胞溶解药物，可以减少或改善一些与衰老相关的功能丧失。男性和女性在衰老细胞溶解反应中的异同取决于所研究的系统、治疗方案、衰老细胞负担水平以及开始治疗时的年龄。雌激素会影响其中一些因素，并以与衰老细胞溶解药物相反的方式影响促进生长、增殖和细胞存活程序的基因转录。此外，雌激素具有独立于细胞衰老的抗衰老作用，包括快速改变衰老的神经生理学。因此，重要的是要认识到，除了细胞衰老中的性别差异外，还有其他性别二态性机制也会导致衰老过程。结果表明，衰老细胞溶解剂与包括性激素在内的基础生物学相互作用。
