Schoenfeldt Lucas, Paine Patrick T, Picó Sara, Kamaludeen M Nibrasul H, Phelps Grace B, Mrabti Calida, Desdín-Micó Gabriela, Del Carmen Maza María, Perez Kevin, Ocampo Alejandro
Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Vaud, Switzerland.
EPITERNA SA, Epalinges, Switzerland.
EMBO Mol Med. 2025 Jun 30. doi: 10.1038/s44321-025-00265-9.
The dedifferentiation of somatic cells into a pluripotent state by cellular reprogramming coincides with a reversal of age-associated molecular hallmarks. Although transcription factor induced cellular reprogramming has been shown to ameliorate these aging phenotypes in human cells and extend health and lifespan in mice, translational applications of this approach are still limited. More recently, chemical reprogramming via small molecule cocktails have demonstrated a similar ability to induce pluripotency in vitro, however, its potential impact on aging is unknown. Here, we demonstrated that chemical-induced partial reprogramming can improve key drivers of aging including genomic instability and epigenetic alterations in aged human cells. Moreover, we identified an optimized combination of two reprogramming molecules sufficient to induce the amelioration of additional aging phenotypes including cellular senescence and oxidative stress. Importantly, in vivo application of this two-chemical combination significantly extended C. elegans lifespan and healthspan. Together, these data demonstrate that improvement of key drivers of aging and lifespan extension is possible via chemical-induced partial reprogramming, opening a path towards future translational applications.
通过细胞重编程将体细胞去分化为多能状态与年龄相关分子特征的逆转相吻合。虽然转录因子诱导的细胞重编程已被证明可改善人类细胞中的这些衰老表型，并延长小鼠的健康寿命和寿命，但这种方法的转化应用仍然有限。最近，通过小分子混合物进行的化学重编程已证明在体外具有类似的诱导多能性的能力，然而，其对衰老的潜在影响尚不清楚。在这里，我们证明化学诱导的部分重编程可以改善衰老的关键驱动因素，包括老年人类细胞中的基因组不稳定和表观遗传改变。此外，我们确定了两种重编程分子的优化组合，足以诱导改善包括细胞衰老和氧化应激在内的其他衰老表型。重要的是，这种双化学组合的体内应用显著延长了秀丽隐杆线虫的寿命和健康寿命。总之，这些数据表明，通过化学诱导的部分重编程改善衰老的关键驱动因素和延长寿命是可能的，为未来的转化应用开辟了一条道路。
