13 replies to this topic

[maxwatt]

J Nutr Biochem. 2013 Mar 18. pii: S0955-2863(13)00021-1. doi: 10.1016/j.jnutbio.2013.01.003. [Epub ahead of print]
Fisetin regulates obesity by targeting mTORC1 signaling.

Jung CH, Kim H, Ahn J, Jeon TI, Lee DH, Ha TY.

Source

Division of Metabolism and Functionality Research, Korea Food Research Institute, 1201 Anyangpangyo-ro, Bundang-Ku, Sungnam-Si, Gyeonggi-Do, 463-746, Republic of Korea.

Abstract


Fisetin, a flavonol present in vegetables and fruits, possesses antioxidative and anti-inflammatory properties. In this study, we have demonstrated that fisetin prevents diet-induced obesity through regulation of the signaling of mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth, cellular proliferation and lipid biosynthesis. To evaluate whether fisetin regulates mTORC1 signaling, we investigated the phosphorylation and kinase activity of the 70-kDa ribosomal protein S6 kinase 1 (S6K1) and mTORC1 in 3T3-L1 preadipocytes. Fisetin treatment of preadipocytes reduced the phosphorylation of S6K1 and mTORC1 in a time- and concentration-dependent manner. To further our understanding of how fisetin negatively regulates mTORC1 signaling, we analyzed the phosphorylation of S6K1, mTOR and Akt in fisetin-treated TSC2-knockdown cells. The results suggested that fisetin treatment inhibits mTORC1 activity in an Akt-dependent manner. Recent studies have shown that adipocyte differentiation is dependent on mTORC1 activity. Fisetin treatment inhibited adipocyte differentiation, consistent with the negative effect of fisetin on mTOR. The inhibitory effect of fisetin on adipogenesis is dependent of mTOR activity, suggesting that fisetin inhibits adipogenesis and the accumulation of intracellular triglycerides during adipocyte differentiation by targeting mTORC1 signaling. Fisetin supplementation in mice fed a high-fat diet (HFD) significantly attenuated HFD-induced increases in body weight and white adipose tissue. We also observed that fisetin efficiently suppressed the phosphorylation of Akt, S6K1 and mTORC1 in adipose tissue. Collectively, these results suggest that inhibition of mTORC1 signaling by fisetin prevents adipocyte differentiation of 3T3-L1 preadipocytes and obesity in HFD-fed mice. Therefore, fisetin may be a useful phytochemical agent for attenuating diet-induced obesity.
Copyright © 2013 Elsevier Inc. All rights reserved. PMID: 23517912

Aging Cell. 2011 Oct;10(5):908-11. doi: 10.1111/j.1474-9726.2011.00722.x. Epub 2011 Jun 14.
Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells.

Chen T, Shen L, Yu J, Wan H, Guo A, Chen J, Long Y, Zhao J, Pei G.

Source

Laboratory of Molecular Cell Biology and Center of Cell Signaling, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, China.

Abstract


Reprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency-associated transcription factors. This seminal work was followed by numerous studies reporting alternative (noninsertional) reprogramming methods and various conditions to improve the efficiency of reprogramming. These studies have contributed little to an understanding of global mechanisms underlying reprogramming efficiency. Here we report that inhibition of the mammalian target of rapamycin (mTOR) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF-1 signaling pathway, which like mTOR is involved in control of longevity, also enhances reprogramming efficiency. In addition, the small molecules used to inhibit these pathways also significantly improved longevity in Drosophila melanogaster. We further tested the potential effects of six other longevity-promoting compounds on iPSC induction, including two sirtuin activators (resveratrol and fisetin), an autophagy inducer (spermidine), a PI3K (phosphoinositide 3-kinase) inhibitor (LY294002), an antioxidant (curcumin), and an activating adenosine monophosphate-activated protein kinase activator (metformin). With the exception of metformin, all of these chemicals promoted somatic cell reprogramming, though to different extents. Our results show that the controllers of somatic cell reprogramming and organismal lifespan share some common regulatory pathways, which suggests a new approach for studying aging and longevity based on the regulation of cellular reprogramming.
© 2011 The Authors. Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland. PMID: 21615676

Edited by maxwatt, 27 June 2013 - 12:56 PM.

[YOLF]

Very interesting. Anything that suggests this would work in vivo?

[maxwatt]

If we can get the full papers, we can see the concentrations used. Then, with some pharmokinetic data we can see if we can obtain such concentration in blood serum.
Fisetin is a lot less toxic than rapamycin.

[gavino]

Bump.

Anything come of this? Niner, have you deemed fisetin worthwhile as a supplement? Or do you have any idea as to dosing?

[Darryl]

Significant effect on obesity at feeding levels of 0.25% and 0.50% in diet. Rodent chow is about 3 kcal/g, so scaled up to a 2000 kcal adult human diet, that's 1700-3300 mg fisetin. That's only 17-33 Japanese wax tree extract capsules.

[maxwatt]

The price of the extract is several times most other such extracts.

[PWAIN]

Significant effect on obesity at feeding levels of 0.25% and 0.50% in diet. Rodent chow is about 3 kcal/g, so scaled up to a 2000 kcal adult human diet, that's 1700-3300 mg fisetin. That's only 17-33 Japanese wax tree extract capsules.

Has anyone got a source to buy this stuff by the Kg? Seems like spending $13 for 30 x 100mg caps that works out at one dose per bottle is not going to be affordable.

[Darryl]

For perspective, rapamycin extends longevity at 14 ppm (0.0014%) in rodent chow, or scaled to humans as above, 90 mg / day. Injectable rapamycin has 10-50 times the bioavailability, and 9 mL of a 1 mg/mL injectable solution starts at $US 25.

I'd halve all those amounts, as the maximum tolerated oral dose for rapamycin is 40 mg, and I suspect fisetin at those doses may be hepatotoxic (its a polyphenol, hence a redox cycler). A 1500 mg / day fisetin megadose would be $US 2300 / year, while the 4.5 mg / d injectable rapamycin dosing would be $US 4600 / year. These costs are not insurmountable obstacles for many with the intellectual wherewithal to understand the past's decade's aging science, especially considering that it might reduce health costs from other sequellae of the aging process.

[maxwatt]

Rapamycin does not extend mouse life span unless they are raised under pathogen-free conditions. It tends to destroy their immune systems. Fisetin not so much.

[Darryl]

I wouldn't be so sure - anything that knocks down mTOR enough to effect known aging pathways (protein synthesis, autophagy, FoxA regulated oxidative stress response, etc), can also be expected to interfere with immune cell proliferation in response to infection. Though I don't have access to the paper at present, I wouldn't be surprised if these mice also had antibiotics in their chow.

There's a large body of literature on fisetin and immune response, mostly dealing with its ability (common to most flavonoids) to suppress NF-κB mediated inflammation. However, it can also just prevent T-cell activation:

Song, Bocui, et al. "Suppressive effects of fisetin on mice T lymphocytes in vitro and in vivo." Journal of Surgical Research (2013).

...and about 50 prior papers which attribute the immunosuppression by fisetin to interfering with inflammatory cytokine production, etc.

Immunosuppression appears to be a normal side effect of mTOR inhibition, both pharmacological and through dietary restriction. This is one reason considerable attention has been given to mTOR-independent modulators in autophagy research.

Edited by Darryl, 21 January 2014 - 12:25 AM.

[Darryl]

Aha, here's the review I really needed to make the point, "messing with mTOR necessarily messes with immunity".

Yang, Hui, et al. "Modulation of TSC–mTOR Signaling on Immune Cells in Immunity and Autoimmunity." Journal of cellular physiology 229.1 (2014): 17-26.

Take enough fisetin to mimic rapamycin's effect on mTORC1, and similar immunosuppression can be expected, along with numerous other effects due to fisetin's lesser selectivity. This isn't bad, per se, but it does suggest there are times, like hospitalization for infection, when it will be wise to cease mTORC1 inhibiting supplements.

Edited by Darryl, 23 January 2014 - 05:10 PM.

[YOLF]

Significant effect on obesity at feeding levels of 0.25% and 0.50% in diet. Rodent chow is about 3 kcal/g, so scaled up to a 2000 kcal adult human diet, that's 1700-3300 mg fisetin. That's only 17-33 Japanese wax tree extract capsules.

 

How does this conversion compare to allometric scaling?

[maxwatt]

Mouse weighs typically 20 grams, and eats 5 grams a day.  At 0.5% of diet, the amount of fisetin in the study was 25 mg, times 50 = 1250 mg / kg. 

 

For a 70 kg human this would be a over 70 grams, all other things being equal, which they are not.  Difference in metabolic rate implies a scaling factor based on relative body surface area.  The FDA publishes a table (http://www.fda.gov/d...s/UCM078932.pdf) for determining starting doses in clinical trials using such an algorithm, and for mice one multiplies the mouse dose of 1250 mg/kg by 0.08.  So the equivalent human dose would be 100 mg/kg.    Around 7 grams, still somewhat high.  Half that (some of the mice got .25% fisetin diets) would be 3.5 grams.  And maybe their mice weighed more, like 30 grams, so you might get by with 3 grams a day,

 

Another wrinkle is mouse pharmokinetics are different than human.  We may clear a xenobiotic like fisetin more efficiently than a mouse, and would need more.  Or maybe less?  If our metabolic pathways are even more different.

 

Resveratrol also targets M-TOR, though perhaps not as efficiently as fisetin.

Edited by maxwatt, 26 April 2016 - 12:49 AM.

[YOLF]

Wow, so 1.7g to 7g, that's alot of the stuff and we'd probably have to take it longer... Yeah, I think I'll be focusing my hopes on gene therapy. Though there are some new weight loss products that promise to be fairly effective.