Low Dose Quercetin as a Geroprotector in Mice

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

Comments

Quercetin is also a CD38 inhibitor, eh? Decreases NADase activity, increases NAD levels.

Posted by: cacarr at October 30th, 2019 5:43 AM

I take a 250mg quercetin capsule daily and ~5 grams/day of fisetin during my 4-day monthly water fasts. I wonder if I through the quercetin into the blender for a minute with the fisetin before I drank it, if the turbulence would be enough to break it down to nano size. In general, does anyone know a standard procedure for breaking something like quercetin down to nano size?

Posted by: Tom Schaefer at October 30th, 2019 7:26 AM

That part is all you need to know

"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"

Posted by: Glenn at October 30th, 2019 8:40 AM

Hi Glenn, Just a 2 cents.

Sometimes I think that we should say anti-health degrading...rather than anti-aging...I mean it,s anti-aging alright...but 'not really'...it's more 'anti-healthdegradation' or put another way 'pro-health'...which is is very good. But, still, not anti-aging in the real sense of the term. Aging, is the accumulation of years/damage that all, mostly, irreversible and make you 'Advanced' in your (life) time and 'Closer' to your death. That is what should be understood. But, there has been so much ambiguity between health and aging (since they are co/inter independent and co-Dependent, also). They depend on each other but can be separable/classifiable as disctinct (yet related), too. That makes confusion, so we simplified it by the large umbrella term 'anti-aging'. Which is simpler in that sense (a good thing). But, can be deceiving...just like:

''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''

These study results show that senolytics are mostly acting on the the health state and, surely, it must slow down 'some' aging and thus, you can live a fuller/healthier life...and, of course, longer....but NOT longer than the maximum/or so...of this specie.

I think most people (here) know that senolytics/remove senescence is not a max. lifespan extender (or a little bit...not that much; where some studies showed lifespan extension both avg and max using senolytics...but it is hard to replicate them in mouse). Rather, it is a avg lifespan extender (health). Thankfully this is just 1 thing...and there are many other things (everyone one knows by know that it's probably not 1 single SENS/other therapy that will save you, it's, most likely, a Multitude of combined approaches for all the many categories of damages, jink & whatnot...that May increase maximal lifespan (the May is important here)). Avg lifespan extension is nearly assured...if we get a 20 years lifespan extension in our 120 years max..it's good (avg lifespan) extension and was worth it. The more I see lifespan extension in mouse, the more I put it at like 5 years lifespan extension or so in humans in terms of 'weight' (mouse-to-human translation wise).

Just a 2 cents.

Posted by: CANanonymity at October 30th, 2019 1:13 PM

Leaving aside the specific issue of the lack of life extension, the actual lifespan of bothcontrol and Q mice was ridiculously short (all animals dead by a little over 900 days - Figure S1(I)). Sickly, prematurely-dying animals often benefit from antioxidants because of the stress they're under; the benefits have yet to translate when tested in otherwise-healthy (nonobese, non-mutant, well-cared-for, pathogen-protected, clean, well-nourished) animals.

Posted by: Michael at October 30th, 2019 6:01 PM

Hi Michael, Just a 2 cents.

True, I agree... I wonder sometimes if it's done on purpose (most likely), and like they went out of their way to 'get sick mice'....like couldn't they get less sick ones in there too. I understand that the major goal of most research, right now, is to cure illnesses..so it makes sense to target/use sick/fragile/unhleathy/disease-ridden/fast-aging mice...Because, the most Imperative right now, is the sick people needing our help (as their time is counted). That is not to say that lifespan/longevity research and solving is not important; it is..but I think, as of late, it's abit on the backburner (for about the last 2 years); yes, you have certain things like biogerontological studies (like epireprogramming...but besides...that..) not all that much happening (I remember 5 years ago, it was like the Boom of antioxidants, finding the 'cure' to aging, and whatnot...now not so much anymore) because researchers/scientists have calmed their 'ardeurs'...about things and because of so many failed studies/results...they might have lost a tiny bit of hope there.
Nothing is stopped, just slacking a bit. So, I think there is 'resource relocation' right now..towards 'Curing Bad Health/Diseases'...because so many people die of diseases; and after trillions of dollars we still can't cure many diseases. Maybe, we are more realistic (if pessimistic) about it now because there is hope and progress (such as SENS of course and other new stuff coming) but, I think, the general 'Feeling' right now is 'toned'. (down a bit). Thus, why you see studies using sick mice...and less focus on healthy mice/wild type controls to Extend their Maximal lifespan (to make Healthy People live Much Longer...right now, the attention seems shifted to older/sick/disease people...because of imperativity/priority/time is lacking for them, these must be solved right away to prevent millions of deaths of diseases).

And, as you said, these mice lifespan was short...and generally, sicker animals, get more benefit from the therapies...so, what about the healthy ones? Most likely...it'S redundant or very little effect in them (because they are already healthy and living 'their maximum')....so it's deceiving with new studies always using these sick animals and trying to fool people (healthy people who will feel left out 'because their are Too Healthy Already'). It may have to do with that and kind of 'keep it dead'/'Under the Lid'...they don'T want you to 'seek that' information too much...the point of them being sick is not the important point they want you to focus on. But, rather, the gains they obtained, despite were sick, So I think, they kind brush it aside...and may have been down/lost hope...they kind of know that 'only sick animals got gains'...so they go for that (and forgot about 'extending healthy animals' lifespan..gave nothing' and barely mention it (hoping it flies under your radar/who reads the 'materials/methods'???...almost no one except curious people into biology/or the scientists; the 99% don't read that (just like microscropic legalese at the bottom of a website or in a EULA. Heck when I go to groceries...99.999% people do not read the labels 'nutritious facts'etc....they simply pick and shove in their kart...and then wonder why get sick later).

Just a 2 c.

Posted by: CANanonymity at October 30th, 2019 8:14 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.