Promises of reprogramming-induced rejuvenation.

Abstract

Reprogramming-induced rejuvenation (RIR) reverses cellular aging by transiently engaging early reprogramming states without full dedifferentiation. This review examines current developments in the molecular mechanisms, technological advances, and tissue-specific applications of RIR. Recent mechanistic insights highlight persisting questions in timing, heterogeneity, and pathways engaged in the epigenetic response. New technological advances have expanded RIR modalities beyond traditional Yamanaka factors to include mRNA-based delivery, CRISPRa, and chemical cocktails, while high-throughput screening platforms are systematically identifying novel rejuvenation factors with improved safety profiles. Recent tissue-specific applications demonstrate functional restoration across brain, liver, intestine, cardiovascular, and epithelial systems through reversal of cellular senescence, reduction of DNA damage and epigenetic age, and enhanced regenerative capacity. However, clinical translation faces challenges including narrow therapeutic windows, incomplete mechanistic understanding, and limited biomarker standardization. We discuss how single-cell technologies, computational prediction tools, and systematic in vivo testing may advance RIR toward geroscience therapies for age-related diseases.