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.wisepoqder Quercetin powder
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.
