Chen Jiexian, Berg Joshua, Burns Calvin M, Jia Hanyi, Li Xinna, Miller Richard A, Endicott S Joseph, Garcia Gonzalo
Department of Chemical Biology, University of Michigan College of Literature, Science, and the Arts, Ann Arbor, MI, United States.
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI, United States.
Front Aging. 2025 Jun 25;6:1621808. doi: 10.3389/fragi.2025.1621808. eCollection 2025.
The availability of multiple slow-aging mice allows a search for possible shared mechanisms that affect the rate of aging. Previous work has shown downregulation of the MEK1-ERK-MNK kinase cascade, which regulates protein translation through eIF4E, in response to four anti-aging drugs. Here we show that decreased protein abundance of enzymes involved in hepatic lipogenesis (DNL) is characteristic of mice exposed to two anti-aging drugs that modulate glucose homeostasis (acarbose and canagliflozin), as well as in calorically restricted mice and in two long-lived mutant models. The same pattern of changes in the lipogenesis enzymes can be produced, in cultured cells or in intact mice, by trametinib, a drug that inhibits the MEK-ERK kinase cascade, and which has been shown to extend mouse lifespan. The trametinib effect on DNL enzymes is, unexpectedly, not related to transcriptional changes, but depends on selective protein degradation through chaperone-mediated autophagy. Our data support models in which chaperone-mediated proteomic alterations, triggered through the MEK1-ERK-MNK kinase pathway, may collaborate with mTORC1 changes to slow aging and extend mouse lifespan.
多种慢衰老小鼠的存在使得寻找影响衰老速率的可能共同机制成为可能。先前的研究表明，四种抗衰老药物会导致MEK1-ERK-MNK激酶级联反应下调，该级联反应通过eIF4E调节蛋白质翻译。在此，我们表明，参与肝脏脂肪生成（DNL）的酶的蛋白质丰度降低，是暴露于两种调节葡萄糖稳态的抗衰老药物（阿卡波糖和卡格列净）的小鼠、热量限制小鼠以及两种长寿突变模型小鼠的特征。在培养细胞或完整小鼠中，抑制MEK-ERK激酶级联反应且已被证明可延长小鼠寿命的药物曲美替尼，能够产生与脂肪生成酶相同的变化模式。出乎意料的是，曲美替尼对DNL酶的作用与转录变化无关，而是取决于伴侣介导的自噬导致的选择性蛋白质降解。我们的数据支持这样的模型，即通过MEK1-ERK-MNK激酶途径触发的伴侣介导的蛋白质组学改变，可能与mTORC1的变化协同作用，以延缓衰老并延长小鼠寿命。
