Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy.
SYSBIO Centre for Systems Biology, 20126 Milano, Italy.
Int J Mol Sci. 2023 Jul 31;24(15):12223. doi: 10.3390/ijms241512223.
Quercetin (QUER) is a natural polyphenolic compound endowed with beneficial properties for human health, with anti-aging effects. However, although this flavonoid is commercially available as a nutraceutical, target molecules/pathways underlying its pro-longevity potential have yet to be fully clarified. Here, we investigated QUER activity in yeast chronological aging, the established model for simulating the aging of postmitotic quiescent mammalian cells. We found that QUER supplementation at the onset of chronological aging, namely at the diauxic shift, significantly increases chronological lifespan (CLS). Consistent with the antioxidant properties of QUER, this extension takes place in concert with a decrease in oxidative stress. In addition, QUER triggers substantial changes in carbon metabolism. Specifically, it promotes an enhancement of a pro-longevity anabolic metabolism toward gluconeogenesis due to improved catabolism of C2 by-products of yeast fermentation and glycerol. The former is attributable to the Sir2-dependent activity of phosphoenolpyruvate carboxykinase and the latter to the L-glycerol 3-phosphate pathway. Such a combined increased supply of gluconeogenesis leads to an increase in the reserve carbohydrate trehalose, ensuring CLS extension. Moreover, QUER supplementation to chronologically aging cells in water alone amplifies their long-lived phenotype. This is associated with intracellular glycerol catabolism and trehalose increase, further indicating a QUER-specific influence on carbon metabolism that results in CLS extension.
槲皮素 (QUER) 是一种天然多酚化合物，对人类健康具有有益的特性，具有抗衰老作用。然而，尽管这种类黄酮可作为营养保健品商业化，但仍未完全阐明其潜在的延长寿命的目标分子/途径。在这里，我们研究了 QUER 在酵母时序老化中的活性，这是模拟静止后哺乳动物细胞衰老的既定模型。我们发现，QUER 在时序老化开始时（即在双重营养期转变时）补充，可以显著延长时序寿命（CLS）。与 QUER 的抗氧化特性一致，这种延长伴随着氧化应激的减少。此外，QUER 会引发碳代谢的重大变化。具体来说，它通过改善酵母发酵和甘油的 C2 副产物的分解代谢，促进有利于长寿的合成代谢向糖异生的增强，从而导致糖异生增强。前者归因于磷酸烯醇丙酮酸羧激酶的 Sir2 依赖性活性，后者归因于 L-甘油 3-磷酸途径。这种协同增加的糖异生供应导致储备碳水化合物海藻糖的增加，从而确保 CLS 延长。此外，将 QUER 补充到单独用水的老化细胞中，会放大它们的长寿表型。这与细胞内甘油分解代谢和海藻糖增加有关，进一步表明 QUER 对碳代谢有特定的影响，从而导致 CLS 延长。
