细胞衰老的病理生理学意义和新型抗衰老药物的发展前景

Pathophysiological implications of cellular senescence and prospects for novel anti-aging drugs

衰老是人类疾病最大的风险因素,而细胞水平的衰老则是机体衰老的根本驱动力量。细胞衰老对多种生命过程的影响,包括正常生理、机体衰老和各种增龄相关病理的进展,长期以来一度被忽视,但随着近年来相关领域的不断进步,细胞衰老愈发成为衰老生物学和老年医学研究的核心。尽管衰老细胞在组织修复、伤口愈合和胚胎发育等生理环节发挥关键作用,但它们在机体成年之后的各阶段更会促进组织紊乱、器官退行和大量病理状况的出现。衰老细胞通过形成衰老相关分泌表型对组织微环境中的其它细胞施以旁分泌影响,维持长期而活跃的胞间通讯,最终导致各种病理生理学效应,这是本世纪以来生命科学最重要的发现之一。通过诱导凋亡的方式选择性清除衰老细胞或特异性抑制衰老相关分泌表型,已在机体衰老和增龄相关疾病的预临床和临床干预中彰显出巨大的潜力,充分证实衰老细胞是缓解多种老年综合征的关键药物靶标。然而,衰老细胞在形式、功能和组织分布上是异质性的,甚至在物种间存在着差异,给衰老研究关键成果在将来的临床转化带来了一定挑战。本文将从衰老细胞的特征、当前靶向策略和未来发展趋势等方面进行综述和讨论,为当前发展迅猛的衰老生物学和衰老医学提供有益的参考和积极的借鉴。

Chronological aging is the leading risk factor for human diseases,while aging at the cellular level,namely cellular senescence,is the fundamental driving force of organismal aging.The impact of cellular senescence on various life processes,including normal physiology,organismal aging and the progress of various age-related pathologies,has been largely ignored for a long time.However,with recent advancement in relevant fields,cellular senescence has become the core of aging biology and geriatric medicine.Although senescent cells play important roles in physiological processes including tissue repair,wound healing,and embryonic development,they can also contribute to tissue dysfunction,organ degeneration and various pathological conditions during adulthood.Senescent cells exert paracrine effects on neighboring cells in tissue microenvironments by developing a senescence-associated secretory phenotype,thus maintaining long-term and active intercellular communications that ultimately results in multiple pathophysiological effects.This is regarded as one of the most important discoveries in life science of this century.Notably,selective elimination of senescent cells through inducing their apoptosis or specifically inhibiting the senescence-associated secretory phenotype has shown remarkable potential in preclinical and clinical interventions of aging and age-related diseases.This reinforces the belief that senescent cells are the key drug target to alleviate various aging syndromes.However,senescent cells exhibit heterogeneity in terms of form,function and tissue distribution,and even differ among species,which presents a challenge for the translation of significant research achievements to clinical practice in future.This article reviews and discusses the characteristics of senescent cells,current targeting strategies and future trends,providing useful and valuable references for the rapidly blooming aging biology and geriatric medicine.