Saliev Timur, Singh Prim B
Institute of Fundamental and Applied Medical Research, S.D. Asfendiyarov Kazakh National Medical University, Tole Bi Street 94, Almaty 050000, Kazakhstan.
School of Medicine, Nazarbayev University, Astana 010000, Kazakhstan.
Biomolecules. 2025 Jun 13;15(6):860. doi: 10.3390/biom15060860.
Cellular senescence is a fundamental mechanism in aging, marked by irreversible growth arrest and diverse functional changes, including, but not limited to, the development of a senescence-associated secretory phenotype (SASP). While transient senescence contributes to beneficial processes such as tissue repair and tumor suppression, the persistent accumulation of senescent cells is implicated in tissue dysfunction, chronic inflammation, and age-related diseases. Notably, the SASP can exert both pro-inflammatory and immunosuppressive effects, depending on cell type, tissue context, and temporal dynamics, particularly in early stages where it may be profibrotic and immunomodulatory. Recent advances in senotherapeutics have led to two principal strategies for targeting senescent cells: senolytics, which selectively induce their apoptosis, and senomorphics, which modulate deleterious aspects of the senescence phenotype, including the SASP, without removing the cells. This review critically examines the molecular mechanisms, therapeutic agents, and clinical potential of both approaches in the context of anti-aging interventions. We discuss major classes of senolytics, such as tyrosine kinase inhibitors, BCL-2 family inhibitors, and natural polyphenols, alongside senomorphics including mTOR and JAK inhibitors, rapalogs, and epigenetic modulators. Additionally, we explore the biological heterogeneity of senescent cells, challenges in developing specific biomarkers, and the dualistic role of senescence in physiological versus pathological states. The review also highlights emerging tools, such as targeted delivery systems, multi-omics integration, and AI-assisted drug discovery, which are advancing precision geroscience and shaping future anti-aging strategies.
细胞衰老乃是衰老过程中的一种基本机制，其特征为不可逆的生长停滞以及多种功能变化，包括但不限于衰老相关分泌表型（SASP）的形成。尽管短暂性衰老有助于诸如组织修复和肿瘤抑制等有益过程，但衰老细胞的持续积累却与组织功能障碍、慢性炎症以及年龄相关疾病有关。值得注意的是，SASP可根据细胞类型、组织背景和时间动态发挥促炎和免疫抑制作用，尤其是在早期阶段，它可能具有促纤维化和免疫调节作用。衰老治疗学的最新进展已催生出两种针对衰老细胞的主要策略：衰老细胞裂解剂，即选择性诱导其凋亡；以及衰老细胞形态调节剂，即调节衰老表型的有害方面，包括SASP，而不清除细胞。本综述批判性地审视了这两种方法在抗衰老干预背景下的分子机制、治疗药物及临床潜力。我们讨论了主要类别的衰老细胞裂解剂，如酪氨酸激酶抑制剂、BCL-2家族抑制剂和天然多酚，以及衰老细胞形态调节剂，包括mTOR和JAK抑制剂、雷帕霉素类似物和表观遗传调节剂。此外，我们还探讨了衰老细胞的生物学异质性、开发特定生物标志物所面临的挑战，以及衰老在生理与病理状态下的双重作用。本综述还强调了新兴工具，如靶向递送系统、多组学整合和人工智能辅助药物发现，这些工具正在推动精准老年科学发展并塑造未来的抗衰老策略。
