Advancing genetic enhancement of mesenchymal stem cells for combating aging and age-related diseases: Opportunities and challenges

Mesenchymal stem cells (MSCs) hold substantial promise for treating aging and age-related diseases due to their regenerative and immunomodulatory properties. However, clinical applications remain limited by the poor survival and short retention of transplanted cells within the hostile aged microenvironment. Emerging genetic-engineering approaches, including viral vector-mediated genetic modification and genome-editing technologies such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) systems, offer powerful strategies to enhance MSC resilience, functionality, and reparative capacity. Recent advances, such as the development of senescence-resistant mesenchymal progenitor cells (SRCs), demonstrate that precise modification of key longevity pathways can produce MSCs with superior stress resistance, reduced senescence, and improved regenerative performance in both rodent and non-human primate models. These findings highlight the potential of genetically enhanced MSCs as next-generation cellular therapeutics for precision interventions in aging. Nevertheless, challenges related to long-term safety, immunogenicity, off-target effects, and large-scale manufacturing must be addressed before clinical translation.