Low Dose Quercetin as a Geroprotector in Mice

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Quercetin is used in combination with dasatinib as a senolytic treatment capable of selectively destroying senescent cells, but quercetin used by itself is not meaningfully senolytic. Researchers here show that long term low dosage with quercetin modestly slows aspects of aging in mice, however, without extending life span. They evaluate a number of potential mechanisms, including possible reductions of the inflammatory signaling secreted by senescent cells. All in all an interesting paper, particularly for the investigation of effects on retrotransposons. I expect that most interventions shown to slow aging will turn out have some impact on retrotransposon activity, but that has yet to be investigated rigorously.

Quercetin (Que) is a natural bioflavonoid. Que (50 mg/kg) in combination with dasatinib (5 mg/kg) (abbreviated as D + Q) has been shown to effectively eliminate senescent cells via induction of apoptosis, thus alleviating senescence-related phenotypes and improving physical function and lifespan in mice. We recently identified Que as a geroprotective agent that counteracts accelerated and natural aging of human mesenchymal stem cells (hMSCs) at a concentration of as low as 100 nmol/L, which is 100 times lower than the concentration of Que (10 μmol/L) previously used in combination with dasatinib.

To explore the geroprotective effect of low-dose Que in rodents, we evaluated the in vivo effect of long-term low-dose Que administration under physiological-aging condition. Que was given to 14-month-old C57BL/6J male mice by weekly oral gavage at a concentration of 0.125 mg/kg body weight, which is 80-400 times lower than that of the previously tested D + Q (10-50 mg/kg body weight) regimens. After eight months of treatment, Que-treated mice showed decreased hair loss with normal food intake, body weight, blood glucose and bone mineral density. Compared to control mice, mice subjected to Que treatment showed markedly improved exercise endurance. However, the lifespan was not prolonged by low-dose Que treatment observed up to the age of 31 months. Taken together, these data indicate that long-term low-dose Que administration alone sufficiently improves multiple aspects of healthspan, but not lifespan, in mice.

To investigate how Que improved healthspan in mice, we collected 11 different kinds of tissues from 10-week young male mice (Y-Ctrl) and control (O-Veh) and low-dose Que-treated 22-month old male mice (O-Que). Given that exercise endurance and diastolic function were improved by Que, we particularly examined the changes in skeletal muscles (SKM), white adipose tissues (WAT), brown adipose tissues (BAT) and hearts. Upon Que treatment, the arrangement of muscle fibers became more regular and compact with less fibrosis and senescence. In WAT, the increases in adipocyte size and senescence-associated β-galactosidase (SA-β-Gal)-positive area during aging were both alleviated upon Que treatment.

We previously observed that Que alleviates hMSC senescence in part through the restoration of heterochromatin architecture in prematurely and physiologically aging hMSCs. Constitutive heterochromatins are predominantly comprised of repetitive elements (REs), including retrotransposable elements (RTEs). The expression of RTEs is repressed via epigenetic regulation under normal conditions but is elevated during physiological aging, eliciting active transposition. Accordingly, mobilization of RTEs is likely to be a key contributor to tissue aging innate immune responseand cell degeneration. To test whether Que treatment may also repress activation of RTEs in a mouse in vivo model, we compared the transcriptional levels of RTEs in multiple tissues of Y-Ctrl, O-Veh, and O-Que mice. Consistently, most RTEs were transcriptionally upregulated in the SKM and BAT of old mice compared to those of young mice and were repressed by Que treatment.

In senescent cells, the activation of RTEs leads to genome instability, which subsequently promotes senescence-associated secretory phenotype (SASP). Consistently, the inflammatory cytokine IL-6 was increased in old mice compared to young mice and Que antagonized the increase of IL-6 in both hMSCs and old mouse SKM and BAT. Thus, our data suggest that Que may block SASP through the axis of heterochromatin-RTEs-innate immune response pathway. Our data provide important evidence supporting the role of low-dose Que in safeguarding genomic stability (i.e. inhibition of retrotransposition), which at least in part contributes to its geroprotective activity in rodents.

Link: https://doi.org/10.1007/s13238-019-0646-8

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