Ibrahim Rita, Bahilo Martinez Maria, Dobson Adam J
School of Molecular Biosciences, University of Glasgow, Glasgow, UK.
Aging Cell. 2024 Dec;23(12):e14328. doi: 10.1111/acel.14328. Epub 2024 Sep 3.
The macrolide drug rapamycin is a benchmark anti-ageing drug, which robustly extends lifespan of diverse organisms. For any health intervention, it is paramount to establish whether benefits are distributed equitably among individuals and populations, and ideally to match intervention to recipients' needs. However, how responses to rapamycin vary is surprisingly understudied. Here we investigate how among-population variation in both mitochondrial and nuclear genetics shapes rapamycin's effects on lifespan. We show that epistatic "mito-nuclear" interactions, between mitochondria and nuclei, modulate the response to rapamycin treatment. Differences manifest as differential demographic effects of rapamycin, with altered age-specific mortality rate. However, a fitness cost of rapamycin early in life does not show a correlated response, suggesting that mito-nuclear epistasis can decouple costs and benefits of treatment. These findings suggest that a deeper understanding of how variation in mitochondrial and nuclear genomes shapes physiology may facilitate tailoring of anti-ageing therapy to individual need.
大环内酯类药物雷帕霉素是一种具有代表性的抗衰老药物，它能显著延长多种生物的寿命。对于任何健康干预措施而言，至关重要的是要确定其益处是否在个体和人群中公平分配，理想情况下是使干预措施与接受者的需求相匹配。然而，令人惊讶的是，关于雷帕霉素反应如何变化的研究却很少。在这里，我们研究线粒体和核基因在种群间的变异如何塑造雷帕霉素对寿命的影响。我们表明，线粒体和细胞核之间的上位性“线粒体-核”相互作用调节了对雷帕霉素治疗的反应。差异表现为雷帕霉素不同的人口统计学效应，以及特定年龄死亡率的改变。然而，雷帕霉素在生命早期的适应性成本并未显示出相关反应，这表明线粒体-核上位性可以使治疗的成本和益处脱钩。这些发现表明，更深入地了解线粒体和核基因组的变异如何塑造生理学，可能有助于根据个体需求定制抗衰老疗法。
