Pronounced long-jev-in-ex
The Official Website
Pronounced long-jev-in-ex
The Official Website
February 19, 2010: by longevinex.com
When the race to produce a bona fide anti-aging pill began in 2003 with the now-tainted discovery that a red wine molecule, resveratrol (rez-vair-ah-trawl), activates a survival gene (Sirtuin1), who could have guessed the road to longevity would get stuck in reverse gear at times.
None of what is to be revealed below takes any luster off of resveratrol, which is a small molecule that has been remarkably demonstrated to exhibit broad biological action including anti-inflammatory, anti-depressant, anti-bacterial, anti-viral, anti-fungal, anti-cholesterol, anti-brain plaque, anti-blood clotting, anti-tumor activity. But the gene targets and doses required to produce beneficial biological effects are what is in question.
The road to produce a longevity pill seemed clear. Cutting caloric intake in half nearly doubles the lifespan of all living organisms and a molecular mimic of calorie restriction (CR) might prolong the human lifespan and healthspan beyond imaginable limits.
The gene target was initially identified as Sir2 in yeast cells, akin to Sirtuin1 in humans. Sirtuin1 is known as a survival gene, switched on when an organism nears starvation.
A developmental drug company began its pursuit of an anti-aging pill with the introduction of SRT501, which is nothing more than an amped-up resveratrol pill that is micronized, stabilized and emulsified. Replicas of such a pill are widely available in vitamin shops across the country. So an effort was made to instruct consumers that such a high dose of resveratol was needed to reproduce the same effects demonstrated in the laboratory that they had better wait for stronger “new chemical entities” — patentable molecules that had never been used in humans but which were alleged to activate the Sirtuin1 gene 1000-fold better than plain resveratrol.
News reports claimed it would take 1000 bottles of red wine to produce the same effects. This spawned neophyte makers of resveratrol pills who offered mega-dose resveratrol, at recommended doses ranging from 1000 to 7000 mg, doses that certainly could be harmful to humans over the long term.
Moreover, while high-dose resveratrol was initially shown to prolong the life of mice fed a high-fat diet, there was disappointment when it was shown the human equivalent dose of 360 mg and 1565 mg of resveratrol shortened the lifespan of laboratory mice fed a standard calorie diet.
Subsequent studies show over-activation of the Sirtuin1 gene may have adverse effects, and that high-dose resveratrol should be confined to the treatment of cancer as it may weaken otherwise healthy tissues in the body. In a landmark laboratory mouse study, mega-dose resveratrol (1750-3500 milligram human equivalent) worsened tissue damage in chemically-induced heart attack, but protected the heart from damage at relatively low dose (175-350 milligrams).
Critical articles published recently at Forbes.com and GeneNews.com have created a pause in the hoopla over resveratrol as an anti-aging pill. These critiques emanate from two published laboratory investigations, conducted by competing pharmaceutical companies, which conclusively show resveratrol does not activate the Sirtuin1 gene, a gene once referred to as the “holy grail” of anti-aging, nor do the man-made drugs (“new chemical entities”) activate this gene or significantly reduce blood sugar levels in animal studies.
But while high-tech reporters were airing this battle between pharmaceutical companies, a nutriceutical study was being overlooked. The mice in the nutriceutical study responded to an unprecedented low-dose of resveratrol in a biological experiment that has been ignored by the biotechnology industry.
Whereas the resveratrol SRT501 drug, at a human equivalent dose of 70,000 mgs, reduced blood sugar levels by 24% in a 3- week mouse study, the resveratrol-based nutriceutical mixture (Longevinex®) produced a 31.3% decline in blood sugar using a dose of 100 mg of resveratrol combined with other botanical extracts (250 mg total) in a 3-month study. The man-made molecule (“new chemical entity” SRT1720), reduced b blood sugar levels by 20%.
Furthermore, the nutriceutical matrix (Longevinex®) exerted a far broader genomic effect than plain resveratrol (Longevinex 1711 genes, resveratrol 225 genes).
Not only did pharmaceutical research scientists find that resveratrol and the “new chemical entities” did not activate the Sirtuin1 gene, the nutriceutical mixture also did not activate this gene in animal experiments.
The original 2003 study published in Nature Magazine, which showed resveratrol was the best activator of Sirtuin1, was later found to have utilized a fluorescent compound that apparently was responsible for the activation of Sirtuin1, and not resveratrol.
Furthermore, two years later an MIT professor who first reported a calorie restricted (CR) diet activates the SIR2 gene (akin to Sirtuin1 in humans) in yeast cells, noted that CR does not activate the SIR2 gene in all tissues and organs. Therefore, Sirtuin1 cannot be used as a universal marker for the mimicry of CR by resveratrol.
That the biological utility of a small molecule like resveratrol is being solely evaluated by its ability to activate a single gene, among 25,000 genes in the human genome, appears to be a misdirected gauge of its effectiveness.
Modern pharmacology likes single molecules to target single disease or aging genes. Cancer drugs like Erbitux and Gleevex are single-gene targeted drugs, but they are only modestly effective. Researchers point out the tremendous advantage that small molecules like resveratrol offer is their ability to exert influence over a broad array of genes. Since chronic age-related diseases and aging itself involve a myriad of genes, the broad genomic action exerted by resveratrol would be advantageous.
The nutriceutical study is worthy of note because of its groundbreaking discoveries. Not only was it demonstrated that a dose of resveratrol 17-320 times lower than used in prior experiments was able to “strikingly” mimic the genomic response seen in calorie restriction, this short-term study produced a broad genomic effect in mouse heart tissue that had only been seen in prior experiments after long-term calorie restriction. This would mean the biological action of CR could be set in motion without years of adherence to a deprivation diet.
Whatever the role of Sirtuin1 or resveratrol in promoting longevity, their net effect is to reinvigorate a cellular mechanism called autophagy that rids the cell of debris (lipofuscin) that accumulates over time. It is also worth noting that the Longevinex® nutriceutical matrix has been shown to eradicate cellular debris (lipofuscin) in the aged human retina which produced measurable improvements in vision of an 80-year old male. So the quest for an anti-aging pill is fast moving from dream to reality.
The current available evidence points to lower doses of resveratrol, which can be readily achieved through dietary supplementation, provided in combination with other botanical-derived molecules, to achieve a synergistic effect, which can mimic the genomic effects of a limited calorie diet.
Posted in Resveratrol
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[...] SRT1720 is not a resveratrol-like molecule in structure. It may be similar in activity, but probably narrower in its ability to target genes. You can read our report about it here: [...]
I don’t understand the gene differentiation argument 198 for CR, 225 for Resveratrol and 1711 for Longevinex. If CR is the gold standard for increasing lifespan, how do we know the additional genes being activated are also increasing lifespan and not shortening it? And do we even know that genes affected by CR are a subset of the genes activated by Resveratrol and Longevinex? Perhaps you can explain that point more clearly?
Longevinex.com:
at issue is exactly what is the genomic goal line for a calorie restriction mimic? Calorie restriction is the unequivocal practice that doubles the healthspan and lifespan of living organisms. The idea is to employ small molecules that switch genes in the same manner as CR without having to deprive oneself of food.
If CR is practiced life long, then 832 genes are differentiated in rodent heart tissue (significantly up or down-regulated, or more simply, switched on or off). In the short-term only 198 genes are affected by CR. This says something.
First, it appears that the idea of focusing solely on a single gene, like SIrtuin1 (SIRT1), may be a misdirection.
Second, there may be marginal benefit in taking plain resveratrol pills in the short-term.
Third, we know that Longevinex switched 633 genes in the same direction as CR (633 out of 832).
Fourth, researchers showed that the primary action of Longevinex was via its influence over FOXO1, not SIRT1. See diagram below. NCM = nutriceutical mix (Longevinex). Longevinex exerts gene expression of FOXO1, then downstream, over PGC1a and mTOR, with mTOR (target of rapamycin) also considered another key anti-aging target.
Fig. 1: Proposed model explain mechanism by which NCM mimics the expression of the genes and metabolic pathways affected by long-term CR. NCM uniquely increases the expression of Foxo1 which subsequently induces a shift in gene expression reminiscent of LTCR.
Now, in analysis of key genes, as tested by Affymetrix gene array and by real-time polymerase chain reaction (RT-PCR),
(see the two sets of bar charts below), you can compare the effect of Longevinex versus CR and plain resveratrol.
Note that in the Affymetrix gene array Longevinex down-regulated SIRT1, whereas in the RT-PCR there was only marginal influence over SIRT1 by Longevinex. Other gene assays conducted in rodent heart tissue show Longevinex upregulates SIRT1 (soon to be published).
Fig. 2: Expression of selected genes relevant to the effects of CR. Data represent average signal sensitivity (+ standard error) from the microarray. Significant (P<0.01) differences from CO mice are indicated with an asterisk.
Fig. 3: RT-PCR confirmation of genes shown in Fig. 2. Data represent fold change in expression (+standard error) compared to CO mice. Significant differences are indicated with P<0.05 or *P<0.01.
It is better to visualize the global effect of short-term calorie restriction, plain resveratrol and Longevinex (NCM) in a bar line chart, compared against aging in normal-fed animals (short-term), and long-term calorie restriction. Genes are grouped into pathways involving known biological mechanisms, such as glucose metabolism, fatty acid metabolism, oxidative phorphorylation, etc. (See below)
Only long-term CR and Longevinex exerted significant effect over these four groupings of genes. Pay particular attention to the long-term calorie restriction (LTCR) and Longevinex (NCM).