GNU-Darwin Distribution Posts about calorie restriction and the resveratrol
Resveratrol: a biochemical mechanism

Michael L. Love Ph.D
Fri Jun 2 16:23:48 PDT 2006

  
Posted By: proclus
Date: 2006-04-08 23:42
Summary: Nature's way: resveratrol supplement

I am very impressed with your product line. In my opinion, we need 
a high potency (500 mg) resveratrol supplement now. You should have a 
look at the work of the Sinclair lab at Harvard HMS. Here is a link. 
 
http://www.hms.harvard.edu/pathol/sinclair/index.html 
 
It appears that resveratrol-like compounds are CR-mimetics, which will 
be future cures for cancer, diabetes, and other degenerative diseases. 
 
Moreover, CR-mimetics are virtually certain to extend human lifespan 
by decades. It appears to me that information about calorie restriction 
and resveratrol is currently being suppressed, but that situation can't 
go on forever, and you should get a jump on the pharmas while you 
still can. 
 
BTW, I found out about your products via the Nutrition Geeks website.  
I am a Utah native, born in Ogden. Please feel free to pass along this 
message as you like. 
 
Regards, 
Michael L. Love Ph.D 
Department of Biophysics and Biophysical Chemistry 
School of Medicine 
Johns Hopkins University 
725 N. Wolfe Street 
Room 608B WBSB 
Baltimore MD 21205-2185 
 
Interoffice Mail: 608B WBSB, SoM 
 
office: 410-614-2267 
lab: 410-614-3179 
fax: 410-502-6910 
cell: 443-824-3451 
http://www.gnu-darwin.org/

By: proclus realm - proclus
molecular mechanism post  
2006-05-27 14:15
From the email list: 
 
From: proclus@gnu-darwin.org 
Subject: resveratrol molecular mechanism (the longevity pill) 
Date: Tue, 23 May 2006 19:40:48 -0400 (EDT) 
To: proclus@gnu-darwin.org 
 
 
After some thought, I believe that I have the molecular mechanism of 
resveratrol. It is an NAD-hydrogenase inhibitor. Here is a reference. 
 
http://www.proteinscience.org/cgi/reprint/6/10/2084
 
In it, you will find the binding configurations of NAD within 
various dehydrogenase enzymes. It is apparent that resveratrol, 
a planar molecule, inhibits the enzymes that bind NAD in the semi- 
planar near-syn or near-anti rotations of the ribose-1'-nicotinamide 
bond. Thus, resveratrol would stack on the adjacent bulky hydrophobic 
residues like a flat board to cover up the active site. It is possible 
that this binding accounts for all of resveratrol's CR-memetic 
properties, such as down regulation of the tca cycle and various lipid 
pathways. With the NAD-binding sites blocked, the activity of sirtuin 
rises with the rising NAD/NADH ratio, producing the CR-memetic effect. 
 
Contrarily, enzymes that bind NAD in the apo (relaxed) configuration 
would not be inhibited substantially by resveratrol. Notably, these 
enzymes include catalase, whose always-on activity is required for free 
radical detoxification in the cell. Another notable exception are 
enzymes like sirtuin itself, which eliminate nicotinamide from NAD by 
stressing the bond in a syn or anti configuration. Clearly, resveratrol 
must not inhibit the NAD apo binding or nicotinamide eliminating 
enzymes, or else it would not promote the observed extension of longevity. 
 
I would also like to point out that this general mechanism is prior art 
in any CR-memetic related patent ;-}. Resveratrol is freely available 
from grapes. Please feel free to pass that along as you like. 
 
Of course, NAD-dependent metabolism is a heavily researched topic, and 
it is likely that other noted NAD enzyme inhibitors are also CR- 
memetics. Cheers! 
 
Regards, 
Michael L. Love Ph.D 
Department of Biophysics and Biophysical Chemistry 
School of Medicine 
Johns Hopkins University 
725 N. Wolfe Street 
Room 608B WBSB 
Baltimore MD 21205-2185 
 
Interoffice Mail: 608B WBSB, SoM 
 
office: 410-614-2267 
lab: 410-614-3179 
fax: 410-502-6910 
cell: 443-824-3451 
http://www.gnu-darwin.org/
 
 
 
 
 
--  
Visit proclus realm! http://proclus.tripod.com/
-----BEGIN GEEK CODE BLOCK----- 
Version: 3.1 
GMU/S d+@ s: a+ C++++ UBULI++++$ P+ L+++(++++) E--- W++ N- !o K- w--- !O 
M++@ V-- PS+++ PE Y+ PGP-- t+++(+) 5+++ X+ R tv-(--)@ b !DI D- G e++++ 
h--- r+++ y++++ 
------END GEEK CODE BLOCK------ 

    From: proclus@gnu-darwin.org
 Subject: Re: Life extension happens
    Date: Mon, 5 Jun 2006 20:41:53 -0400 (EDT)
      To: gnu-darwin-ports@lists.sourceforge.net
      Cc: gnu-darwin-distribution@lists.sourceforge.net,     James Love 


For those of you who are grokking the resveratrol postings...

Resveratrol, the life-extending supplement, is the GNU/Linux, nay, the
GNU-Darwin of CR-memetics, and right now, we have anchored it to the
public common, never to be removed.  I have more to tell you about the
molecular mechanism of resveratrol (resV) now.

For those who are just jumping in, I have posted the thread at
Celestrialism.  Here is the link.

http://proclus.gnu-darwin.org/gdposts.html

It is also on the SF website.

http://sourceforge.net/forum/forum.php?forum_id=560492
http://sourceforge.net/mailarchive/forum.php?forum_id=6042

It is noteworthy that some NAD-binding enzymes are likely to selectively
bind two resveratrol molecules, each adding to the inhibition activity
in the active site.  In this case, resveratrol would bind like a flat
board to cover the adenyl-ribosyl site which holds the compound in
semi-flat, relaxed, syn or anti conformation, precisely like the
previously stated mechanism for the ribosyl-nicotinamide site.

I find it confirmational to note that such NAD-binding enzymes form a
narrow sub-class, which clusters in the crucial metabolic core reactions
of the cell, reaching from (but not including)
glyceraldehyde-3-phosphate dehydrogenase, though to many targets in and
adjacent to the citric acid cycle and mitochondrial energy transfer
apparatus.  

It is clear then that by binding doubly to these enzymes, resV is able
to clamp down hard on the TCA cycle, reducing free radical production,
as well as producing the many other beneficial effects of CR memetics.

For example, it is quite obvious that many cancer cells will simply
starve themselves to death under these conditions.  Similar arguments
can be made for diabetes, and several brain degenerative diseases as
well.  It also becomes clear why calorie restriction is good for you. 
We can continue to build on this prior art archive, if you like!

The molecule of the day is resV, but other compounds that come from
common roots, fruits, and vegetables are the free and open source of the
future, and I hope that these posts help all of us to continue in that
public spirited tradition.

Regards,
Michael L. Love Ph.D
Department of Biophysics and Biophysical Chemistry
School of Medicine
Johns Hopkins University
725 N. Wolfe Street
Room 608B WBSB
Baltimore MD 21205-2185

Interoffice Mail: 608B WBSB, SoM

office: 410-614-2267
lab:    410-614-3179
fax:    410-502-6910
cell:   443-824-3451
http://www.gnu-darwin.org/




-- 
Visit proclus realm! http://proclus.tripod.com/
-----BEGIN GEEK CODE BLOCK-----
Version: 3.1
GMU/S d+@ s: a+ C++++ UBULI++++$ P+ L+++(++++) E--- W++ N- !o K- w--- !O
M++@ V-- PS+++ PE Y+ PGP-- t+++(+) 5+++ X+ R tv-(--)@ b !DI D- G e++++
h--- r+++ y++++
------END GEEK CODE BLOCK------
 
    From: proclus@gnu-darwin.org
 Subject: Re: Bootstrapping your body towards maximum life span
    Date: Tue, 15 May 2007 14:19:45 -0400 (EDT)
      To: proclus@gnu-darwin.org
      Cc: gnu-darwin-distribution@lists.sourceforge.net,     gnu-darwin-ports@lists.sourceforge.net



Here is a little more obvious prior art in the resveratrol story.

I was reading the latest from Biochemistry about bioflavinoids as
possible cancer treatment agents.  Here is the link, although some of
the material is unfortunately not public access ;-}.

http://dx.doi.org/10.1021/bi7000664

I cribbed below some references that indicate the action of the
bioflavinoid molecules against tyrosine kinase activity.  It is obvious
and clear prior art that resveratrol will also act against tyrosine
kinase activity, because it is similar in structure to the bioflavinoids
as well as to the substrate, tyrosine.  Ultimately, this interferes with
the protein kinase C cascade, which leads to many of the anti-cancer,
health inducing, and life extending benefits.  To my knowledge, this
activity of resveratrol remains unpublished until _now_.

As always, please feel free to pass along my messages as you like.  In
particular, this message should be considered as a prior art declaration
against any CR-memetic related patent.  Resveratrol is freely available 
from grapes, roots, nuts, and berries; and it is widely available as a
supplement in the dosage required to produce beneficial effects.  At
this time, choose the highest dosage supplement that you can find, but
this situation may change in the future ;-}>.

Regards,
Michael L. Love Ph.D
Department of Biophysics and Biophysical Chemistry
School of Medicine
Johns Hopkins University
725 N. Wolfe Street
Room 608B WBSB
Baltimore MD 21205-2185

Interoffice Mail: 608B WBSB, SoM

office: 410-614-2267
lab:    410-614-3179
fax:    410-502-6910
cell:   443-824-3451
http://www.gnu-darwin.org/


18. Akiyama, T., Ishida, K., Nakagawa, S., Ogaara, H., Watanabe, S., Itoh, N. M., Shibuya, M., and Fukami, Y. (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases, J. Biol. Chem. 262, 5592-5595. [ChemPort] [Medline] 
19. Hagiwara, M., Inoue, S., Tanaka, T., Nunoki, K., Ito, M., and Hidaka, H. (1988) Differential effects of flavonoids as inhibitors of tyrosine protein kinases and serine/threonine protein kinases, Biochem. Pharmacol. 37, 2987-2992. [ChemPort] [Medline] [CrossRef] 
20. Geahlen, R. L., Koonchanok, N. M., McLaughlin, J. L., and Pratt, D. E. (1989) Inhibition of protein-tyrosine kinase activity by flavonoids and related compounds, J. Nat. Prod. 52, 982-986. [ChemPort] [Medline] 
21. Cushman, M., Nagarathnam, D., Burg, D. L., and Geahlen, R. L. (1991) Synthesis and protein-tyrosine kinase inhibitory activities of flavonoid analogues, J. Med. Chem. 34, 798-806. [ChemPort] [Medline] 
22. Yang, E. B., Guo, Y. J., Zhang, K., Chen, Y. Z., and Mack, P. (2001) Inhibition of epidermal growth factor receptor tyrosine kinase by chalcone derivatives, Biochim. Biophys. Acta 1550, 144-152. [ChemPort] [Medline] 
23. Hollosy, F., and Keri, G. (2004) Plant-derived protein tyrosine kinase inhibitors as anticancer agents, Curr. Med. Chem.: Anti-Cancer Agents 4, 173-197. [ChemPort] 



On  9 Feb, To: proclus@gnu-darwin.org wrote:
> 
> I thought that you might like a little essay I wrote about caloric
> restriction as a war protest.  It is a sort of HOWTO for the general
> public.  Feel free to pass the link along, or write back as you like.
> 
> http://proclus.gnu-darwin.org/~proclus/bootstrap.html
> 
> Regards,
> proclus
> http://www.gnu-darwin.org/
> 

-- 
Visit proclus realm! http://proclus.tripod.com/
-----BEGIN GEEK CODE BLOCK-----
Version: 3.1
GMU/S d+@ s: a+ C++++ UBULI++++$ P+ L+++(++++) E--- W++ N- !o K- w--- !O
M++@ V-- PS+++ PE Y+ PGP-- t+++(+) 5+++ X+ R tv-(--)@ b !DI D- G e++++
h--- r+++ y++++
------END GEEK CODE BLOCK------



    From: proclus@gnu-darwin.org
 Subject: Re: [Gnu-darwin-distribution] Bootstrapping your body towards	maximum life span
    Date: Fri, 25 May 2007 12:45:21 -0400 (EDT)
      To: gnu-darwin-distribution@lists.sourceforge.net
      Cc: gnu-darwin-ports@lists.sourceforge.net, mamzel1@jhmi.edu,	bianchet@juliet.med.jhmi.edu



More support for the NAD-based resveratrol (resV) mechanism and prior
art here...

I'm studying quinone reductase 1 & 2 enzymes (QR1 & QR2), which have
received alot of attention from our department here at Hopkins, so I
am cc'ing a couple of people here.  I was happy to learn that quinone
reductase 2 is known to bind resV at high affinity (nM range), which is
quite unusual, and there is a structure to look at, if you like.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Citation&list_uids=15350128

I've been looking at the binding of some other quinone reductase
inhibitors, and it appears to me that these enzymes obey the syn/anti v.
apo rule stated in our prior art statements on resV.  This rule
would explain why resV strongly inhibits QR2, but QR1 only very weakly.

If this is true, then it is an superb example of the rule, because the
FAD molecule provides a flat table-like surface for the planar resV to
bind and block access to NAD, which apparently also adopts a roughly
flat conformation in order to activate QR2.  This would be in contrast
to QR1 which because of some steric hindrance would prefer the
activating group of NAD in the apo conformation.

You can find copies of our prior art work in our email archive, and I
have provided copies at the POLARIS project site.  There are plenty of
background references listed there, including the wonderful survey of
NAD binding conformations from David Eisenberg's lab.  

http://proclus.gnu-darwin.org/gdposts.html

Regards,
Michael L. Love Ph.D
Department of Biophysics and Biophysical Chemistry
School of Medicine
Johns Hopkins University
725 N. Wolfe Street
Room 608B WBSB
Baltimore MD 21205-2185

Interoffice Mail: 608B WBSB, SoM

office: 410-614-2267
lab:    410-614-3179
fax:    410-502-6910
cell:   443-824-3451
http://www.gnu-darwin.org/




-- 
Visit proclus realm! http://proclus.tripod.com/
-----BEGIN GEEK CODE BLOCK-----
Version: 3.1
GMU/S d+@ s: a+ C++++ UBULI++++$ P+ L+++(++++) E--- W++ N- !o K- w--- !O
M++@ V-- PS+++ PE Y+ PGP-- t+++(+) 5+++ X+ R tv-(--)@ b !DI D- G e++++
h--- r+++ y++++
------END GEEK CODE BLOCK------


Posted By: proclus 
Date: 2008-05-07 13:44 
Summary: A product for Thailand's new pharmacutical industry 

Thai black rice has the highest anthocyanin content of any cereal grain 
that I have been able to find. Anthocyanin shares many properties with 
resveratrol and Sirtris' product, SRT501, and it is likely to be a drop 
in replacement for them. This rice, which is abundantly produced in 
Thailand, is so rich in anthocyanin content, that it will be cheap and 
easy to extract it for pharmaceutical uses by the local industry there. 
It is also likely to have a very wide range of beneficial medicinal 
uses, in contrast to narrowly targeted SIRT501. Here below is the 
reference that I used. It includes an extraction protocol (which needs 
some optimization). Cheers! 
 
http://www.ncbi.nlm.nih.gov/pubmed/16787017?ordinalpos=3&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum 
 
It is also very tasty indeed! 
 
Regards, 
Michael L. Love Ph.D 
Department of Biophysics and Biophysical Chemistry 
School of Medicine 
Johns Hopkins University 
725 N. Wolfe Street 
Room 608B WBSB 
Baltimore MD 21205-2185

Interoffice Mail: 608B WBSB, SoM 
Shipping Dock: 1915 E. Madison St. 
 
office: 410-614-2267 
lab: 410-614-3179 
fax: 410-502-6910 
cell: 443-824-3451 
http://www.gnu-darwin.org/ 



[Gnu-darwin-distribution] GNU-Darwin: an important source of supplements
From:  - 2008-06-21 05:03

Attachments: Message as HTML      
I wanted to pass along an important source of high quality information
and supplements. They are the best that I have been able to find.

NSI / Vitacost
http://www.vitacost.com/

This is where I get my polyphenol supplements, fruit concentrates,
L-Carnosine, Lipoic acid, Acetyl-carnitine, Omega-3 fatty acids, CoQ10,
Probiotics, Red yeast rice, and hunger suppressants. This is hacking at
its best in my opinion, longevity hacking. Even if you spend a little
more at Vitacost than other places, it might be worth the money.

Here is another source that I use for my retinol cream, folic acid,
Vitamins C and E, beta carotine, melatonin, and multi-vitamins.

Vitamin World
http://www.vitaminworld.com/

I have no axe to grind, and I have no stake in the above companies
other than to assure that quality supplements remain legal and on the
market. I have sought to find the best supplements for the lowest cost
using my biochemical insights, and this is what I came up with for my
own benefit. As some of my associates know, I can write at length
about these subjects, and I thought that many others could benefit from
this bit of information as well. As always, please feel free to pass it
along as you see fit. Cheers!

Regards,

-- 
Michael L. Love Ph.D
Department of Biophysics and Biophysical Chemistry
School of Medicine
Johns Hopkins University
725 N. Wolfe Street
Room 608B WBSB
Baltimore MD 21205-2185

Interoffice Mail: 608B WBSB, SoM

office: 410-614-2267
lab: 410-614-3179
fax: 410-502-6910
cell: 443-824-3451
http://www.gnu-darwin.org/

Visit proclus realm! http://proclus.tripod.com/
-----BEGIN GEEK CODE BLOCK-----
Version: 3.1
GMU/S d+@ s: a+ C++++ UBULI++++$ P+ L+++(++++) E--- W++ N- !o K- w--- !O
M++@ V-- PS+++ PE Y+ PGP-- t+++(+) 5+++ X+ R tv-(--)@ b !DI D- G e++++
h--- r+++ y++++
------END GEEK CODE BLOCK------ 








Dr. Love is a biochemist and staff scientist at Johns Hopkins School of Medicine protein crystallography lab. As founder of The GNU-Darwin Distribution, he is attempting to advance free software for the benefit of the user community at large.



Related Links for further reading

Celestrialism



For further ideas about the POLARIS project, how to stop the war, check here.

If you have comments or suggestions, email me at proclus@gnu-darwin.org