Kazmi Imran, Al-Abbasi Fahad A, Zeyadi Mustafa, Rafeeq Misbahuddin, Habib Alaa Hamed, Iqbal Johar, Alzarea Sami I, Alsaidan Omar Awad, Nadeem Muhammad Shahid
Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, 21589, Jeddah, Saudi Arabia.
Department of Pharmacology Faculty of Medicine, Rabigh King Abdulaziz University, 21589, Jeddah, Saudi Arabia.
Biogerontology. 2025 Jun 30;26(4):135. doi: 10.1007/s10522-025-10277-0.
Aging features a gradual decline in genomic integrity, epigenetic fidelity, and cellular homeostasis, driving the onset of chronic pathologies such as cancer, neurodegeneration, and metabolic disease. Growth arrest and DNA damage-inducible 45 alpha (GADD45α) functions as a pivotal stress-response mediator, coordinating DNA repair, cell-cycle arrest, oxidative stress defence, mitochondrial quality control, and chromatin remodeling. Researchers have extensively studied GADD45α in tumor suppression, but its roles in healthy aging and age-related disorders remain underexplored. Here, we provide a comprehensive synthesis of recent findings illuminating GADD45α's contributions to aging biology. We detail its engagement with nucleotide and base excision repair pathways to preserve genome stability, enforce G₂/M checkpoints to prevent damaged DNA propagation, and promote mitochondrial resilience under oxidative challenge. We then examine how GADD45α modulates epigenetic landscapes, mitigating age-associated DNA methylation drift and sustaining chromatin plasticity, and highlight its emerging neuroprotective actions in Alzheimer's and Parkinson's models. Integrating multi-omics analyses, in vivo rodent investigations, and Drosophila lifespan assays, we establish GADD45α as a dynamic biomarker of cellular aging and a promising geroprotective target. Finally, we discuss translational strategies to harness GADD45α activity, ranging from small-molecule enhancers and epigenetic modifiers to precision gene-editing to reinforce DNA repair capacity, delay senescence onset, and extend organismal healthspan. This review reframes GADD45α from a cancer-centric effector to a versatile regulator of aging processes, underscoring its therapeutic potential for promoting healthy longevity.
衰老的特征是基因组完整性、表观遗传保真度和细胞稳态逐渐下降，从而引发癌症、神经退行性疾病和代谢疾病等慢性疾病。生长停滞和DNA损伤诱导蛋白45α（GADD45α）作为关键的应激反应介质，协调DNA修复、细胞周期停滞、氧化应激防御、线粒体质量控制和染色质重塑。研究人员已对GADD45α在肿瘤抑制中的作用进行了广泛研究，但其在健康衰老和与年龄相关的疾病中的作用仍未得到充分探索。在这里，我们全面综合了最近的研究结果，阐明了GADD45α对衰老生物学的贡献。我们详细介绍了它与核苷酸和碱基切除修复途径的相互作用，以维持基因组稳定性，加强G₂/M检查点以防止受损DNA的传播，并在氧化应激下促进线粒体恢复力。然后，我们研究了GADD45α如何调节表观遗传景观，减轻与年龄相关的DNA甲基化漂移并维持染色质可塑性，并强调了其在阿尔茨海默病和帕金森病模型中新兴的神经保护作用。通过整合多组学分析、体内啮齿动物研究和果蝇寿命测定，我们将GADD45α确立为细胞衰老的动态生物标志物和有前景的老年保护靶点。最后，我们讨论了利用GADD45α活性的转化策略，从小分子增强剂和表观遗传修饰剂到精确基因编辑，以增强DNA修复能力、延迟衰老 onset并延长生物体的健康寿命。这篇综述将GADD45α从以癌症为中心的效应器重新定义为衰老过程的多功能调节剂，强调了其促进健康长寿的治疗潜力。
