The epigenetic rejuvenation promise: Partial reprogramming as a therapeutic strategy for aging and disease

Reprogramming of somatic cells into induced pluripotent stem cells through the introduction of transcription factors Oct3/4, Sox2, Klf4, and c-Myc (OSKM) represents a landmark advance in regenerative biology. Building on this foundation, partial reprogramming can help reset epigenetic age. It further opens opportunities to treat degenerative diseases without the tumorigenic risks associated with full pluripotency. The review advances the field in three ways: it links lineage-preserving partial reprogramming to quantifiable rejuvenation endpoints; defines mesenchymal drift as an age- and disease-associated trajectory amenable to reversal; and maps strategies beyond OSKM, including small-molecule programs and CRISPR-based control circuits. Convergent phenotypes are surveyed in nervous, metabolic, musculoskeletal, and craniofacial systems, with emphasis on improved tissue repair and regeneration. A translational checklist is proposed that emphasizes schedule, delivery, and safety pharmacology to guide rigorous preclinical studies and de-risk early clinical entry points for partial reprogramming therapies. • Partial reprogramming can reverse epigenetic age. • Mesenchymal drift is a reversible transcriptomic hallmark of aging and disease. • Immune surveillance and inflammation constrain in vivo reprogramming efficacy. • Non-genetic strategies hold promises for safer rejuvenation. • CRISPR-based circuits and safe-harbor genomic integration improve specificity.