Decoding Aging through iPSC Reprogramming: Advances and Challenges.

Abstract

Aging is characterized by cellular senescence and increased susceptibility to age-related diseases. Induced pluripotent stem cell (iPSC) technology demonstrates the potential to reverse aging hallmarks, including telomere attrition, mitochondrial dysfunction, and oxidative stress. Reprogramming somatic cells using factors such as Oct4, Sox2, Klf4, and c-Myc (OSKM) restores pluripotency and reverses aging markers. Partial reprogramming, involving transient OSKM expression, rejuvenates cells by resetting epigenetic clocks, reducing senescence-associated secretory phenotypes (SASPs), and improving mitochondrial function, as evidenced by lifespan extension in progeroid mouse models. These advancements facilitate disease modeling and autologous therapies for neurodegeneration, etc. Critical challenges, including tumorigenicity risks associated with oncogenic reprogramming factors, have been mitigated through non-integrative delivery systems (e.g., mRNA, small molecules) and suicide genes. Persistent epigenetic memory and incomplete reprogramming impede iPSC differentiation, but CRISPR-based tools (e.g., dCas9-DNMT3A, CRISPRoff) allow precise epigenetic editing to erase residual somatic signatures. Variability in iPSC quality, influenced by cell source and culture conditions, necessitates standardized protocols and CRISPR-enhanced quality control. Ethical considerations, such as informed consent and genetic discrimination, highlight the need for governance frameworks that align innovation with societal values. Subsequent priorities include optimizing reprogramming efficiency, validating safety in preclinical models, and translating findings into therapies for age-related disorders. In conclusion, iPSC and CRISPR technologies collectively present transformative strategies to delay aging and restore cellular vitality, paving the way for rejuvenation therapies. Future studies should focus on improving the reprogramming efficiency, minimizing the risk of tumorigenicity, and exploring the optimized CRISPR-based epigenetic editing technique.