Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction.
Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction.
复制标题
DOI：
10.1111/acel.12489
复制
发表时间：
2016-08
期刊：
影响因子：
7.8
通讯作者：
Simons MJ
中科院分区：
文献类型：
--
作者：
Garratt M;Nakagawa S;Simons MJ
减少雷帕霉素（mTOR）信号机制靶点可延长酵母、线虫、果蝇和小鼠的寿命，凸显了可以调节进化差异生物体衰老的生理途径。据推测，该信号系统在通过饮食限制延长寿命方面发挥着核心作用。通过整理 48 项已发表研究的数据，这些研究检查了 mTOR 信号传导减少的寿命，我们发现，mTOR 信号传导减少可以使不同物种的中位寿命有类似的延长，而基因 mTOR 操作始终比雷帕霉素药物治疗提供更长的寿命延长。然而，与中位寿命变化的一致性相反，寿命延长的人口原因具有高度的物种特异性。减少 mTOR 信号传导可显着降低死亡率随年龄增长（衰老率）而增加的程度，从而延长线虫的寿命。相比之下，小鼠和酵母的寿命延长主要是通过推迟衰老的开始来实现的，但一旦衰老开始，死亡率曲线的形状就不会改变。重要的是，在小鼠中，mTOR 信号传导减少引起的死亡率改变模式不同于饮食限制引起的死亡率改变，后者降低了衰老速度。 mTOR 信号传导的影响也具有性别依赖性，但仅限于小鼠，而不是果蝇，因此又具有物种特异性。与年龄相关的死亡率的减轻并不是模型生物体中 mTOR 信号传导减少的共同特征，也不能复制饮食限制所带来的与年龄相关的生存益处。
Reduced mechanistic target of rapamycin (mTOR) signalling extends lifespan in yeast, nematodes, fruit flies and mice, highlighting a physiological pathway that could modulate aging in evolutionarily divergent organisms. This signalling system is also hypothesized to play a central role in lifespan extension via dietary restriction. By collating data from 48 available published studies examining lifespan with reduced mTOR signalling, we show that reduced mTOR signalling provides similar increases in median lifespan across species, with genetic mTOR manipulations consistently providing greater life extension than pharmacological treatment with rapamycin. In contrast to the consistency in changes in median lifespan, however, the demographic causes for life extension are highly species specific. Reduced mTOR signalling extends lifespan in nematodes by strongly reducing the degree to which mortality rates increase with age (aging rate). By contrast, life extension in mice and yeast occurs largely by pushing back the onset of aging, but not altering the shape of the mortality curve once aging starts. Importantly, in mice, the altered pattern of mortality induced by reduced mTOR signalling is different to that induced by dietary restriction, which reduces the rate of aging. Effects of mTOR signalling were also sex dependent, but only within mice, and not within flies, thus again species specific. An alleviation of age‐associated mortality is not a shared feature of reduced mTOR signalling across model organisms and does not replicate the established age‐related survival benefits of dietary restriction.