8 replies to this topic

[niner]

Our old pal David Sinclair was on TOTN Science Friday this afternoon. This was of course the fallout of this weeks sirtuin paper in Science. TOTN bungled it (typical) by hyping the red wine angle, although Sinclair, to his credit, pointed out that you'd need a hundred glasses a day to get a reasonable dose of resveratrol. He was a reasonably good proponent of the idea of anti-aging. The most interesting thing that I caught was his hinting that his lab had a rejuvenating compound that could take a two year old mouse and make it "metabolically young" in a week's time.

Edited by niner, 09 March 2013 - 01:10 AM.

[maxwatt]

Sinclair, ever the showman.

[maxwatt]

Sinclair gets all the publicity for his work with resveratrol, meanwhile tetrahydro-curcumin has shown better results in healthy mice, and we hear nothing about it in the press.

http://www.ncbi.nlm....les/PMC3249455/

Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor


Lan Xiang,^1,3,5 Yukiko Nakamura,³ Young-Mi Lim,² Yasutoyo Yamasaki,² Yumi Kurokawa-Nose,¹ Wakako Maruyama,¹ Toshihiko Osawa,³ Akira Matsuura,⁴ Noboru Motoyama,¹ and Leo Tsuda²

Author information ► Article notes ► Copyright and License information ►


This article has been cited by other articles in PMC.
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Abstract


The O-type forkhead domain transcription factor (FOXO) is involved in many biological processes such as aging, the oxidative stress response, and growth regulation. FOXO activity is tightly controlled within cells. In particular, growth factor signaling pathways and the oxidative stress response can both stimulate nuclear translocation of this transcription factor. Here, we show that tetrahydrocurcumin (THC), a curcumin metabolite, regulates the oxidative stress response and aging via FOXO. In NIH3T3 cells, THC induced nuclear accumulation of FOXO4, a member of the FOXO family of transcription factors, by inhibiting phosphorylation of protein kinase B (PKB)/Akt. In Drosophila melanogaster, THC attenuated the oxidative stress response, an effect that was blocked in a foxo mutant background. THC also extended the life span of Drosophila under normal conditions, and loss of either foxo or Sir2 activity eliminated this effect. Based on these results, THC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.

Biogerontology. 2007 Oct;8(5):567-73. Epub 2007 May 22.
The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice.

Kitani K, Osawa T, Yokozawa T.

Source

National Institute for Longevity Sciences, 36-3, Gengo, Moriokacho, Obu-shi, Aichi 474-8522, Japan. kitani@nils.go.jp

Abstract


The effect of feeding of two different antioxidants, tetrahydrocurcumin (TC) and green tea polyphenols (PPs) on the survival of male C57BL/6 mice was examined. Mice that started to receive diets containing TC (0.2%) at the age of 13 months had significantly longer average life spans (days, mean +/- SD) than control mice (797.6 +/- 151.2 vs.882 +/- 154.6, both n = 50, controls vs. TC treated, plus 11.7%, P < 0.01). The 10% longest survival was also significantly greater in TC-treated mice (plus 6.5%, P < 0.01). In contrast, in mice that started to receive TC in their 19th month of life, no significant difference from the control mice was found for either the average life span or the 10% longest survival. In mice that received water containing PPs (80 mg/l), the average life span was also significantly longer than in the control mice (801 +/- 121.5 vs. 852.7 +/- 88.2, plus 6.4%, P < 0.05), although the 10% longest survival was not significantly different from that in the control mice (P > 0.05). The body weights of the TC (but not PP) fed mice, were slightly (2-4%) but significantly (P < 0.05) lower than the values for the corresponding ages in the control mice in the first six months of treatment. Thereafter, the difference in average body weight between the control and the TC-fed animals was totally lost. Although an additional contribution of an unintended slight decrease in food intake due to TC feeding (suspected due to the difference in body weight) is not excluded, we suggest that the feeding of nutritional antioxidants such as TC and PPs may have the potential to beneficially modify the life spans of animals. PMID: 17516143

[Mind]

Sigh...."in mice".

[maxwatt]

Yes, in mice. You read "Hitchhiker's Guide to the Galaxy", perhaps?

If it works in mice, then maybe we should test in people. (Resveratrol did not extend lifespan of norma-diet mice, so everyone lost interest, Undeservedly so, there are a good many beneficial effects for health. But mice are not little people.)

I know of only one person using tetrahydro-curcumin, but it is a major metabolite of curcumin,

[bixbyte]

Sinclair gets all the publicity for his work with resveratrol, meanwhile tetrahydro-curcumin has shown better results in healthy mice, and we hear nothing about it in the press.

http://www.ncbi.nlm....les/PMC3249455/

Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor
Lan Xiang,^1,3,5 Yukiko Nakamura,³ Young-Mi Lim,² Yasutoyo Yamasaki,² Yumi Kurokawa-Nose,¹ Wakako Maruyama,¹ Toshihiko Osawa,³ Akira Matsuura,⁴ Noboru Motoyama,¹ and Leo Tsuda²

Biogerontology. 2007 Oct;8(5):567-73. Epub 2007 May 22.
The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice.

Kitani K, Osawa T, Yokozawa T.

I read to warnings for people playing the role of test mice:

1. TC may regulate the aging process via an evolutionarily conserved signaling pathway that includes both foxo and Sir2.
.........

2. The body weights of the TC (but not PP) fed mice, were slightly (2-4%) but significantly (P < 0.05) lower than the values for the corresponding ages in the control mice in the first six months of treatment. Thereafter, the difference in average body weight between the control and the TC-fed animals was totally lost. Although an additional contribution of an unintended slight decrease in food intake due to TC feeding (suspected due to the difference in body weight) is not excluded, we suggest that the feeding of nutritional antioxidants such as TC and PPs may have the potential to beneficially modify the life spans of animals. PMID: 17516143

I am not capable of communication with mice.
How did the Mice "feel" dosing on TC?
Sounds like they did not "feel" like eating much food.
What is a human dose?
Therefore, IMHO, human experimental dosing should be extremely cautious.

Edited by Michael, 17 March 2013 - 12:43 PM.

[Michael]

Our old pal David Sinclair was on TOTN Science Friday this afternoon. This was of course the fallout of this weeks sirtuin paper in Science. TOTN bungled it (typical) by hyping the red wine angle, although Sinclair, to his credit, pointed out that you'd need a hundred glasses a day to get a reasonable dose of resveratrol.

I'm not sure to what account this should be credited: it's not at all clear that any dose of resveratrol is genuinely beneficial to normal, healthy animals (an issue that is elided repeatedly in the interview), and we know even less (and likely will continue to know even less) about the novel sirtuin-activating compounds from GSK. There is a lot more reason to think that people not predisposed to alcoholism will be better off drinking a glass or two of red wine than that they will be benefitted by taking resveratrol or its analogs.

Sinclair gets all the publicity for his work with resveratrol, meanwhile tetrahydro-curcumin has shown better results in healthy mice, and we hear nothing about it in the press.

http://www.ncbi.nlm....les/PMC3249455/

Tetrahydrocurcumin extends life span and inhibits the oxidative stress response by regulating the FOXO forkhead transcription factor
Lan Xiang,^1,3,5 Yukiko Nakamura,³ Young-Mi Lim,² Yasutoyo Yamasaki,² Yumi Kurokawa-Nose,¹ Wakako Maruyama,¹ Toshihiko Osawa,³ Akira Matsuura,⁴ Noboru Motoyama,¹ and Leo Tsuda²

There's no result here from oral administration in any mammal species; I don't think it really tells us anything worthy of press coverage.

Biogerontology. 2007 Oct;8(5):567-73. Epub 2007 May 22.
The effects of tetrahydrocurcumin and green tea polyphenol on the survival of male C57BL/6 mice.
Kitani K, Osawa T, Yokozawa T.

... Mice that started to receive diets containing TC (0.2%) at the age of 13 months had significantly longer average life spans (days, mean +/- SD) than control mice (797.6 +/- 151.2 vs.882 +/- 154.6, both n = 50, controls vs. TC treated, plus 11.7%, P < 0.01). The 10% longest survival was also significantly greater in TC-treated mice (plus 6.5%, P < 0.01). In contrast, in mice that started to receive TC in their 19th month of life, no significant difference from the control mice was found for either the average life span or the 10% longest survival. ... The body weights of the TC (but not PP) fed mice, were slightly (2-4%) but significantly (P < 0.05) lower than the values for the corresponding ages in the control mice in the first six months of treatment.

In addition to the issue raised by bixbyte (the unintended weight loss, suggesting a possible crypto-CR effect -- also seen in the NIA's ITP study(1)), this actually isn't a result worth paying attention to: it's yet another case of partially normalizing the lifespan of a colony of short-lived mice. As I keep hammering at, a normal, well-husbanded, well-fed, genetically-normal, non-toxin-fed colony of mice will live 900 d on average, 1100 max. The controls here lived just 800 d, and the TC group 12% longer -- ie, about what a colony of mice should have lived in the first place. At a guess, I'm going to say that the control group was given unlimited chow access, developed metabolic syndrome, and died early, while the TC group ate less because curcumin is pretty powerful-tasting stuff, were less overfed, got less metabolic disease, and lived more or less normal lives. Unfortunately, the authors did not monitor food intake.

The other thing is that to the extent that it worked, it was only effective in animals initiated on treatment at age 13 mo -- say, in their mid- to late- thirties in human years. That's an awfully long time to run an experiment, whether you're waiting for results or experimenting on yourself -- and an awful long time to be unwittingly doing something harmful to yourself or your patients.

Meanwhile, the baby boomers are already older than "19-mo-old mice." If it's not going to be effective in them, and if it's going to require a six decade clinical trial to test, it's not worth anyone's attention from a practical POV.

-Michael


1. Randy Strong, Richard A. Miller, Clinton M. Astle, Joseph A. Baur, Rafael de Cabo, Elizabeth Fernandez, Wen Guo, Martin Javors, James L. Kirkland, James F. Nelson, David A. Sinclair, Bruce Teter, David Williams, Nurulain Zaveri, Nancy L. Nadon, and David E. Harrison.
Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice. J Gerontol A Biol Sci Med Sci first published online March 26, 2012 DOI: 10.1093/gerona/gls070
PMID: 22451473

[maxwatt]

...
In addition to the issue raised by bixbyte (the unintended weight loss, suggesting a possible crypto-CR effect -- also seen in the NIA's ITP study(1)), this actually isn't a result worth paying attention to: it's yet another case of partially normalizing the lifespan of a colony of short-lived mice. As I keep hammering at, a normal, well-husbanded, well-fed, genetically-normal, non-toxin-fed colony of mice will live 900 d on average, 1100 max. The controls here lived just 800 d, and the TC group 12% longer -- ie, about what a colony of mice should have lived in the first place. At a guess, I'm going to say that the control group was given unlimited chow access, developed metabolic syndrome, and died early, while the TC group ate less because curcumin is pretty powerful-tasting stuff, were less overfed, got less metabolic disease, and lived more or less normal lives. Unfortunately, the authors did not monitor food intake.

The other thing is that to the extent that it worked, it was only effective in animals initiated on treatment at age 13 mo -- say, in their mid- to late- thirties in human years. That's an awfully long time to run an experiment, whether you're waiting for results or experimenting on yourself -- and an awful long time to be unwittingly doing something harmful to yourself or your patients.

Meanwhile, the baby boomers are already older than "19-mo-old mice." If it's not going to be effective in them, and if it's going to require a six decade clinical trial to test, it's not worth anyone's attention from a practical POV.

-Michael
...

Thank you Michael for the much needed splash of cold water. I don't believe I claimed that TetraHydroCurcumin (THC) would extend lifespan in humans, only that the evidence was a bit stronger than resveratrol in mice on a (putatively) healthy diet. NB: unlike curcumin, tetrahydrocurcumin does not have such a strong taste. I doubt that is responsible for the reduced food intake seen in that study. I do think it is worthy of investigation, but somewhat neglected. Curcumin has proven benefits for multiple myeloma, and THC might work even at lower doses. But no one knows.

Shooting the moon, looking for the magic supplement that would make one immortal - that is not going to happen, as you rightly point out, and is too much to ask for. I think all we are going to get from supplements is false hope, and an occasional incremental benefit. The incremental benefits are sometimes worth it. Let us not belittle a lesser benefit because it doesn't deliver everything at once.

[niner]

Shooting the moon, looking for the magic supplement that would make one immortal - that is not going to happen, as you rightly point out, and is too much to ask for. I think all we are going to get from supplements is false hope, and an occasional incremental benefit. The incremental benefits are sometimes worth it. Let us not belittle a lesser benefit because it doesn't deliver everything at once.

No supplement is going to make anyone immortal, that is certain. I think that 'false hope' is going a little too far, save for the deluded or hopelessly naive. Along with some distinct medical benefits in the case of various disease states, some supplements and gray-area compounds like c60-oo hold the promise of a little (or maybe even a lot) of curve-squaring. That's nothing to sneeze at, particularly if one considers the bazillions of dollars spent giving cancer patients a few extra months.

The fact remains that resveratrol received a curiously large amount of media attention, due, I believe, to its narrative that tied together the French "paradox" and CR, and held out the false promise of attaining the benefits of CR without the work.