Journal of translational medicine · 2026
Synergistic senolytic-regenerative therapy significantly extends healthspan and lifespan.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Ichim Thomas E, Markov Nikola, Lopes Gilberto, Pascual Karenjan A, Evans Anastasiia, Reznik Robert, Bykoriz Vladyslav, Fortunati Christian A, Minev Boris, Ramos Roman A, Bajnath Anil, Lin Emma, Hu Joyce, Marincola Francesco M, Rath Armin, Barrett Barbie, Jurow Andrew, Sankhala Kamlesh Kumar, Furman David, Reznik Boris N
Аннотация
BACKGROUND: Current barriers to achieving radical life extension include the inability to use syngeneic, youthful mesenchymal stem cells (MSCs) and the anti-regenerative effects of senescence-associated secretory phenotype (SASP) factors. We aim to overcome this by a combination approach in which senescent cell burden is reduced utilizing SenoVax™ a dendritic cell based senolytic immunotherapy combined with syngeneic pluripotent stem cell derived MSC.
METHODS: We induced hepatic injury and accelerated aging using two established murine models: carbon tetrachloride (CCl₄) mediated liver injury and doxorubicin induced systemic senescence. Animals were treated with control, SenoVax, pMSCs or the combination. Outcomes included biochemical and histologic indices of liver injury, circulating and tissue biomarkers of senescence (IL-11, YKL-40, IL-6, IL-23 R) and regeneration (Klotho, FGF-2, neo-VEGF, GDF-11), RESULTS: Both CCl₄ and doxorubicin induced a robust senescent phenotype characterized by increased pro-inflammatory and pro-fibrotic mediators and downregulation of regenerative biomarkers. Combined senolytic and pMSC therapy outperformed mono therapies and produced clear synergistic benefits, including significant biochemical improvement of liver failure parameters, reversal of accelerated aging features, and restoration of regenerative signaling pathways. Senolytic monotherapy yielded partial improvements, while pMSCs alone showed limited activity in the presence of a high senescent-cell burden.
CONCLUSIONS: These findings support a mechanistic model in which senescent cells and SASP factors directly suppress MSC-mediated tissue repair. Targeted senolytic immunotherapy enhances the efficacy of regenerative interventions and represents a promising combinatorial strategy for chronic disease management and potentially for modifying biological aging itself.
CLINICAL TRIAL NUMBER: Not applicable.
METHODS: We induced hepatic injury and accelerated aging using two established murine models: carbon tetrachloride (CCl₄) mediated liver injury and doxorubicin induced systemic senescence. Animals were treated with control, SenoVax, pMSCs or the combination. Outcomes included biochemical and histologic indices of liver injury, circulating and tissue biomarkers of senescence (IL-11, YKL-40, IL-6, IL-23 R) and regeneration (Klotho, FGF-2, neo-VEGF, GDF-11), RESULTS: Both CCl₄ and doxorubicin induced a robust senescent phenotype characterized by increased pro-inflammatory and pro-fibrotic mediators and downregulation of regenerative biomarkers. Combined senolytic and pMSC therapy outperformed mono therapies and produced clear synergistic benefits, including significant biochemical improvement of liver failure parameters, reversal of accelerated aging features, and restoration of regenerative signaling pathways. Senolytic monotherapy yielded partial improvements, while pMSCs alone showed limited activity in the presence of a high senescent-cell burden.
CONCLUSIONS: These findings support a mechanistic model in which senescent cells and SASP factors directly suppress MSC-mediated tissue repair. Targeted senolytic immunotherapy enhances the efficacy of regenerative interventions and represents a promising combinatorial strategy for chronic disease management and potentially for modifying biological aging itself.
CLINICAL TRIAL NUMBER: Not applicable.