Department of Molecular, Cellular, and Developmental Biology, University of Michigan College of Literature, Science, and the Arts, USA.
Department of Pathology, University of Michigan School of Medicine, USA; University of Michigan Geriatrics Center, Ann Arbor, MI 48109, USA.
Life Sci. 2023 Sep 1;328:121904. doi: 10.1016/j.lfs.2023.121904. Epub 2023 Jul 3.
Long-lived mouse models and treatments that extend lifespan, such as Rapamycin, acarbose and 17α- -estradiol, lead to reduction in mTORC1 activity, declines in cap-dependent translation and increases in cap-independent translation. In addition, these treatments reduce the MEK-ERK-MNK (ERK1-2) signaling cascade, leading to reduction in eIF4E phosphorylation, which also regulates mRNA translation. Here, we report that Canagliflozin, a drug that extends lifespan only in male mice reduces mTORC1 and ERK1-2 signaling in male mice only. The data suggest reduction in mTORC1 and ERK pathways are common mechanisms shared by both genetic and pharmacological models of slowed aging in mice. Our data also reveal a significant sexual dimorphism in the ERK1-2 signaling pathway which might help to explain why some drugs can extend lifespan in males but have no effects in female mice.
长寿的老鼠模型和能够延长寿命的治疗方法，如雷帕霉素、阿卡波糖和 17α-雌二醇，会降低 mTORC1 的活性，降低帽依赖性翻译，增加帽非依赖性翻译。此外，这些治疗方法还会降低 MEK-ERK-MNK（ERK1-2）信号级联反应，导致 eIF4E 磷酸化减少，从而调节 mRNA 翻译。在这里，我们报告称，卡格列净是一种仅能延长雄性小鼠寿命的药物，它只能降低雄性小鼠的 mTORC1 和 ERK1-2 信号。数据表明，降低 mTORC1 和 ERK 通路是遗传和药理学模型减缓小鼠衰老的共同机制。我们的数据还揭示了 ERK1-2 信号通路的显著性别二态性，这可能有助于解释为什么有些药物可以延长雄性小鼠的寿命，但对雌性小鼠没有影响。
