Pterostilbene targets hallmarks of aging in the gene expression landscape in blood of healthy rats

Scope: Polyphenols from the phytoestrogen group, including pterostilbene (PTS), are known for their antioxidant, anti-inflammatory and anti-cancer effects. In recent studies, phytoestrogens attenuate age-related diseases, however their pro-longevity effects in healthy models in mammals remain unknown. As longevity studies demonstrate age-related transcriptomic signatures in human blood, we propose that phytoestrogen-supplemented diet may induce changes in gene expression that ultimately confer pro-longevity benefits. Methods and Results: In the present study, we conducted RNA sequencing to determine transcriptome-wide changes in gene expression in whole blood of healthy rats consuming diets supplemented with phytoestrogens. Ortholog cell deconvolution was applied to analyze the omics data. We discovered that PTS leads to changes in the gene expression landscape and PTS-target genes are associated with functions counteracting hallmarks of aging, including genomic instability, epigenetic alterations, compromised autophagy, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular interaction, and loss of proteostasis. These functions bridge together under anti-inflammatory effects through multiple pathways, including immunometabolism, where changes in cellular metabolism (e.g., ribosome biogenesis) impact the immune system. Conclusion: Our findings provide a rationale for pre-clinical and clinical longevity studies and encourage investigations on PTS in maintaining cellular homeostasis, decelerating the process of aging, and improving conditions with chronic inflammation.研究范围：属于植物雌激素（phytoestrogen）类的多酚（polyphenols）物质，包括紫檀芪（pterostilbene，PTS），已知其具有抗氧化、抗炎及抗肿瘤活性。近年研究表明，植物雌激素可缓解年龄相关性疾病，但其在哺乳动物健康模型中的延寿效应仍未明确。鉴于延寿相关研究已在人类血液中鉴定出与年龄相关的转录组特征，本研究提出，摄入补充植物雌激素的膳食可能诱导基因表达改变，最终带来延寿益处。 方法与结果：本研究通过RNA测序（RNA sequencing），分析了摄入植物雌激素补充膳食的健康大鼠全血中全转录组水平的基因表达变化，并采用直系同源细胞解卷积（ortholog cell deconvolution）方法对组学数据进行解析。研究发现，紫檀芪可改变基因表达谱，其靶基因所参与的生物学功能可对抗衰老的标志性特征，包括基因组不稳定性、表观遗传修饰改变、自噬功能受损、线粒体功能障碍、营养感知失调、细胞间相互作用异常及蛋白质稳态失衡。这些功能可通过免疫代谢（immunometabolism）等多条通路协同发挥抗炎作用：细胞代谢（如核糖体生物发生）的改变可对免疫系统产生调控影响。 结论：本研究结果为临床前及临床延寿相关研究提供了理论依据，并为紫檀芪在维持细胞稳态、延缓衰老进程及改善慢性炎症相关病症中的应用研究提供了科学指引。