Kirkland James L, Tchkonia Tamara, Zhu Yi, Niedernhofer Laura J, Robbins Paul D
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota.
Department of Molecular Medicine and the Center on Aging, Scripps Research Institute, Jupiter, Florida.
J Am Geriatr Soc. 2017 Oct;65(10):2297-2301. doi: 10.1111/jgs.14969. Epub 2017 Sep 4.
Senolytic drugs are agents that selectively induce apoptosis of senescent cells. These cells accumulate in many tissues with aging and at sites of pathology in multiple chronic diseases. In studies in animals, targeting senescent cells using genetic or pharmacological approaches delays, prevents, or alleviates multiple age-related phenotypes, chronic diseases, geriatric syndromes, and loss of physiological resilience. Among the chronic conditions successfully treated by depleting senescent cells in preclinical studies are frailty, cardiac dysfunction, vascular hyporeactivity and calcification, diabetes mellitus, liver steatosis, osteoporosis, vertebral disk degeneration, pulmonary fibrosis, and radiation-induced damage. Senolytic agents are being tested in proof-of-concept clinical trials. To do so, new clinical trial paradigms for testing senolytics and other agents that target fundamental aging mechanisms are being developed, because use of long-term endpoints such as lifespan or healthspan is not feasible. These strategies include testing effects on multimorbidity, accelerated aging-like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. If senolytics or other interventions that target fundamental aging processes prove to be effective and safe in clinical trials, they could transform geriatric medicine by enabling prevention or treatment of multiple diseases and functional deficits in parallel, instead of one at a time.
衰老细胞裂解药物是一类能选择性诱导衰老细胞凋亡的药物。随着年龄增长，这些细胞在许多组织中以及多种慢性疾病的病理部位累积。在动物研究中，采用基因或药理学方法靶向衰老细胞可延缓、预防或减轻多种与年龄相关的表型、慢性疾病、老年综合征以及生理适应能力的丧失。在临床前研究中，通过清除衰老细胞成功治疗的慢性疾病包括虚弱、心脏功能障碍、血管反应性降低和钙化、糖尿病、肝脂肪变性、骨质疏松症、椎间盘退变、肺纤维化以及辐射诱导损伤。衰老细胞裂解药物正在概念验证临床试验中接受测试。为此，正在开发用于测试衰老细胞裂解药物和其他针对基本衰老机制的药物的新临床试验范式，因为使用诸如寿命或健康寿命等长期终点是不可行的。这些策略包括测试对多种疾病、加速衰老样状况、衰老细胞局部累积的疾病、与衰老细胞累积相关的潜在致命疾病、与年龄相关的生理适应能力丧失以及虚弱的影响。如果衰老细胞裂解药物或其他针对基本衰老过程的干预措施在临床试验中被证明是有效且安全的，它们可能会改变老年医学，通过并行预防或治疗多种疾病和功能缺陷，而不是一次治疗一种疾病。
