Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells
Publication date: 15/01/2025
Authors: Bi Y, Qiao X, Cai Z, Zhao H et al.
Journal: Cell metabolism
Commentary: The study by Bi et al identifies exosomal miR-302b as a potent mediator of rejuvenation through the reversal of cellular senescence. Using human embryonic stem cell–derived exosomes (hESC-Exos), the authors demonstrate that senescent cells can regain proliferative capacity both in vitro and in vivo, challenging the view that senescence represents an irreversible cell fate. Mechanistically, miR-302b, highly enriched in hESC-Exos, directly targets the cell-cycle inhibitors CDKN1A and CCNG2, thereby releasing senescent cells from proliferative arrest. In aged mice, systemic delivery of hESC-Exos or miR-302b-loaded exosomes resulted in robust functional rejuvenation, including extended lifespan, improved motor coordination, enhanced muscle strength, and better cognitive performance. These effects were accompanied by a marked reduction in senescence markers, chronic inflammation, and DNA damage across multiple tissues, alongside restoration of proliferation-associated transcriptional programs. Importantly, long-term miR-302b administration over 24 months did not increase tumor incidence or disease burden, underscoring the safety of this approach. The introduction of the “Senoreverse” strategy—aimed at restoring, rather than eliminating, senescent cells—represents a conceptual shift from conventional therapies. By preserving tissue integrity while reactivating regenerative potential, this approach may be particularly advantageous in advanced aging, where senescent cells are abundant and tissue resilience is limited. Collectively, these findings position exosomal miR-302b as a promising therapeutic candidate for treating aging-associated disorders, including neurodegenerative, metabolic, and inflammatory diseases, and open new avenues for interventions targeting the fundamental biology of aging.
Commented by: Marcello Serra (14/01/2026)
DOI: 10.1016/j.cmet.2024.11.013
