Buck Institute for Research on Aging, Novato, CA, 94945, USA.
Davis School of Gerontology, University of Southern California, University Park, University Park, Los Angeles, CA, 90089, USA.
Nat Commun. 2024 Oct 29;15(1):9330. doi: 10.1038/s41467-024-52909-y.
Dietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species-random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.
饮食限制（DR）是一种增强寿命和健康跨度的有效方法，但个体反应受遗传变异的影响。了解与代谢相关的遗传差异如何影响长寿和健康跨度尚不清楚。为了研究这一点，我们使用代谢物作为标记物，揭示不同基因型如何对饮食做出反应，从而影响寿命和健康跨度特征。我们分析了在 AL 和 DR 条件下饲养的果蝇遗传参考品系（DGRP）菌株的数据，结合了代谢组学、表型和全基因组信息。我们在跨物种中使用了两种计算和互补的方法——在 DGRP 中使用随机森林建模作为主要分析，在人类队列中使用孟德尔随机化作为次要分析。我们确定了具有跨物种相关性的关键特征，以及影响寿命和健康跨度的潜在异质性和多效性。值得注意的是，在人类中，乳清酸盐与父母的死亡年龄有关，并且在果蝇中阻断了 DR 对寿命的延长，而苏氨酸补充剂以菌株和性别特异性的方式延长了寿命。因此，我们利用来自果蝇和人类的自然遗传变异数据，采用系统生物学方法阐明了潜在的治疗途径和代谢组学靶点，以研究饮食依赖性的寿命和健康跨度变化。
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