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 reports, phytoestrogens attenuate age‐related diseases; however, their pro‐longevity effects in healthy models in mammals remain unknown. As longevity research demonstrates age‐related transcriptomic signatures in human blood, the current study hypothesizes that phytoestrogen‐supplemented diet may induce changes in gene expression that ultimately confer pro‐longevity benefits. Methods and results In the present study, RNA sequencing is conducted to determine transcriptome‐wide changes in gene expression in whole blood of healthy rats consuming diets supplemented with phytoestrogens. Ortholog cell deconvolution is applied to analyze the omics data. The study 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 The 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. The study characterizes transcriptomic patterns in blood of healthy rats consuming diets supplemented with polyphenols. Supplementation with pterostilbene (PTS), a dietary bioactive compound from a group of phytoestrogens, resulted in gene expression changes that are functionally linked to hallmarks of aging. It suggests PTS action towards reduced inflammation and maintenance of homeostasis in the immune functions and cellular metabolism.