BioDrugs. 2026 Jan 3. doi: 10.1007/s40259-025-00761-x. Online ahead of print.
ABSTRACT
The rapid growth in the global aging population has intensified concerns regarding age-related diseases (ARDs), which pose substantial health and socioeconomic burdens. Current therapeutic strategies, such as small-molecule drugs, primarily target downstream pathophysiological manifestations, including inflammation, fibrosis, and metabolic imbalance, but have limited ability to address the underlying molecular causes of disease. Antisense oligonucleotides (ASOs) are emerging as a promising modality capable of precise, sequence-specific regulation of gene expression at the RNA level, offering the potential to directly modulate disease etiology. This review examines the relationship between major ARD categories and the hallmarks of aging and highlights recent research trends in ASO-based therapeutics. We explore the connections between hallmark aging processes and major ARDs, including neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders, emphasizing dysregulated genes that contribute to disease progression. Preclinical and clinical studies demonstrate that ASOs can offer targeted intervention against key pathological mechanisms such as protein aggregation, chronic inflammation, metabolic dysfunction, and tissue fibrosis by modulating gene expression. Despite their promise, major challenges remain, including poor tissue-specific delivery, limited penetration into certain tissues, and concerns around long-term safety. Emerging delivery strategies such as ligand conjugates and lipid nanoparticle systems are expanding the therapeutic reach of ASOs. By providing a programmable approach to precisely regulate pathogenic gene expression, ASOs have the potential to redefine the therapeutic landscape for ARDs in an aging society. This review provides an integrated perspective on these advances and their implications for future therapeutic development.
PMID:41484831 | DOI:10.1007/s40259-025-00761-x