Translational potential of GADD45α: biomarker and therapeutic target in age-associated neurodegeneration and longevity.

Abstract

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.