Leibniz Institute on Aging-Fritz Lipmann Institute, Jena, Germany.
Department of Reproduction Management, Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany.
PLoS Genet. 2018 Mar 23;14(3):e1007272. doi: 10.1371/journal.pgen.1007272. eCollection 2018 Mar.
The genetics of lifespan determination is poorly understood. Most research has been done on short-lived animals and it is unclear if these insights can be transferred to long-lived mammals like humans. Some African mole-rats (Bathyergidae) have life expectancies that are multiple times higher than similar sized and phylogenetically closely related rodents. To gain new insights into genetic mechanisms determining mammalian lifespans, we obtained genomic and transcriptomic data from 17 rodent species and scanned eleven evolutionary branches associated with the evolution of enhanced longevity for positively selected genes (PSGs). Indicating relevance for aging, the set of 250 identified PSGs showed in liver of long-lived naked mole-rats and short-lived rats an expression pattern that fits the antagonistic pleiotropy theory of aging. Moreover, we found the PSGs to be enriched for genes known to be related to aging. Among these enrichments were "cellular respiration" and "metal ion homeostasis", as well as functional terms associated with processes regulated by the mTOR pathway: translation, autophagy and inflammation. Remarkably, among PSGs are RHEB, a regulator of mTOR, and IGF1, both central components of aging-relevant pathways, as well as genes yet unknown to be aging-associated but representing convincing functional candidates, e.g. RHEBL1, AMHR2, PSMG1 and AGER. Exemplary protein homology modeling suggests functional consequences for amino acid changes under positive selection. Therefore, we conclude that our results provide a meaningful resource for follow-up studies to mechanistically link identified genes and amino acids under positive selection to aging and lifespan determination.
寿命决定的遗传学知之甚少。大多数研究都是在寿命短的动物身上进行的,目前还不清楚这些研究结果是否可以应用于人类等寿命较长的哺乳动物。一些非洲鼹鼠(非洲滨鼠科)的预期寿命是与其体型相似、亲缘关系密切的啮齿动物的数倍。为了深入了解决定哺乳动物寿命的遗传机制,我们从 17 种啮齿动物中获取了基因组和转录组数据,并在与增强长寿进化相关的 11 个进化分支上扫描了正选择基因(PSGs)。这表明与衰老有关的 250 个鉴定 PSGs 在长寿的裸鼹鼠和短寿的老鼠的肝脏中表现出与衰老的拮抗多效性理论相符的表达模式。此外,我们发现 PSGs 富集了与衰老相关的已知基因。这些富集包括“细胞呼吸”和“金属离子稳态”,以及与 mTOR 途径调节的过程相关的功能术语:翻译、自噬和炎症。值得注意的是,PSGs 中包括 RHEB,这是 mTOR 的调节剂,以及 IGF1,这两者都是与衰老相关的途径的核心成分,还有一些基因虽然尚未被证实与衰老有关,但却是有说服力的功能候选基因,例如 RHEBL1、AMHR2、PSMG1 和 AGER。典型的蛋白质同源建模表明,正选择下氨基酸变化具有功能后果。因此,我们得出结论,我们的研究结果为后续研究提供了有意义的资源,有助于将鉴定出的受正选择影响的基因和氨基酸与衰老和寿命决定联系起来。
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