The mammalian target of rapamycin（哺乳动物雷帕霉素靶蛋白，mTOR）是一种参与调控真核细胞生长和代谢的丝氨酸/苏氨酸蛋白激酶。研究发现，mTOR信号通路与细胞对营养和生长因子的响应密切相关，调控包括蛋白质合成、自噬等多个细胞过程。mTOR信号通路的失调与多种疾病的发生发展有关，如癌症、糖尿病和衰老，因此成为了一个重要的研究热点。
The quantity of nutrients present tells our cells if it’s a good time for them to grow or not. Our cells’ ability to tell this difference is crucial for our wellbeing. But unfortunately, this ability declines with time. This decline is called “deregulated nutrient sensing”, and is one of the nine hallmarks of ageing. Nutrient sensing by our cells happens via four pathways, IGF-1, mTOR, sirtuins and AMPK.
2. mTORC1和mTORC2
mTOR 形成了两个不同的蛋白质复合体：mTORC1和mTORC2。
mTORC1 主要通过促进蛋白质、脂质和核苷酸合成来控制细胞生长，同时抑制自噬等分解代谢过程。
mTORC2 则参与细胞存活和增殖，主要通过磷酸化和激活 Akt 和其他AGC 家族激酶来发挥作用。
mTORC1 和 mTORC2 信号通路
mTORC1 亚基和 mTOR 上的相应结合位点。mTORC1 与 FKBP12-雷帕霉素复合物（不含 DEPTOR 和 PRAS40，PDB：5FLC）复合的 5.9-A° 低温电子显微镜结构被描绘为空间填充模型，并按亚基着色。
mTORC2 亚基和 mTOR 上的相应结合位点
3. mTOR的下游信号通路
mTORC1 通过两大关键效应物 p70S6K 和 4EBP 调节蛋白质合成。mTORC1 还通过调控脂质和核苷酸合成、糖代谢，维持细胞生长所需的能量和物质供应。此外，mTORC1 抑制自噬，调控蛋白质的降解平衡。
mTORC2 通过磷酸化 AGC 家族的多种激酶，尤其是 Akt，调控细胞存活和代谢。Akt 的激活促进细胞增殖，并通过抑制 TSC2 进而激活 mTORC1，形成一种反馈调控机制。
4. 上游调控机制
When mTOR is high, it promotes growth in the body and can even stimulate the growth of cancer and tumor cells. When mTOR is low, it works on repair and maintenance for the body. Low mTOR stimulates autophagy (recycling of damaged and old proteins into new amino acids to build new tissues). This slows down the ageing process.
While activation of the mTOR pathway is great for growth and energy, it's the opposite for longevity! Tissue growth and extended lifespans are mutually exclusive. This is clearly observable in animals. Animals that grow quickly, like mice, worms and insects, have very short lifespans. And animals that grow slowly, like elephants and whales, have very long lifespans.
Thus, mTOR pathway is a hallmark of ageing and too much activity in this pathway can also contribute to a number of chronic diseases like: Cancer, Obesity, Type-2 diabetes, Neurodegeneration.
mTOR has been linked to multiple hallmarks of aging: nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.
Inhibiting the mTOR pathway improves insulin sensitivity and promotes autophagy. Inhibiting mTOR in older mice has shown increased longevity.
6. 结论与展望
mTOR 信号通路在细胞代谢和生长调控中扮演核心角色，其失调与多种人类疾病密切相关。未来的研究方向包括开发更精准的 mTORC1 特异性抑制剂，以用于代谢疾病、神经退行性疾病和癌症的治疗。
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