The current state of evolving research on sirtuins and resveratrol is well detailed and referenced in the following article written by Bill Sardi. As Mr Sardi is the president of a resveratrol manufacturer, I want to make it clear that I do not endorse or offer any opinion on his product versus other resveratrol products. However, I believe his article is worth reading:
The science surrounding the sirtuin family of genes that control the rate of aging is changing so fast that it begs for a scientific update. Many health and longevity seekers are drinking a bit more red wine or taking resveratrol pills in hopes of prolonging their number of healthy years. Are they doing the right thing? Well, yes, it certainly appears so. But now there is greater understanding how small molecules found in nature actually produce longevity.
The discovery that a molecule commonly found in red wine, resveratrol, activates the Sirtuin 1 DNA-repair “survival” gene, a gene that is also activated by calorie restricted diets [Science. 2000 Sep 22; 289(5487):2126-8] brought immediate hope that a molecular shortcut could be utilized rather than having to deprive oneself of food to achieve healthy longevity.
Various small molecules were tested and it was found that resveratrol activates Sirtuin 1 to a greater extent than other small molecules like quercetin, fisetin, etc. Yeast cells lived far longer when given resveratrol. [Nature 425: 191-96, 2003] Then follow-up studies showed that resveratrol extended the life of fruit flies and roundworms. [Nature 430: 686-69, 2004]
And the resveratrol story only kept getting better. Researchers in Italy showed resveratrol prolonged the life of a cold-water fish. [Experimental Gerontology 2007 Jan-Feb; 42(1-2):81-9] And there was even more excitement among biologists when resveratrol prolonged the life of a warm-blooded mammal (lab mouse) and overcame the effects of a high-fat diet. [Nature. 2006 Nov 16; 444(7117):337-42]
The race was on to develop synthetic resveratrol-like molecules that can activate the Sirtuin 1 gene to an even greater extent than resveratrol by itself. Synthetically made Sirtuin 1 gene activators which could stimulate the Sirtuin 1 gene 1000-fold were unveiled. [Aging Cell 6: 35-43, 2006]
But now the picture isn’t so clear about greater and greater Sirtuin 1 gene activation, and more genes than just Sirtuin 1 may be involved here, and there is even (a) question as to the mechanism that produces in greater amounts of Sirtuin 1 gene-derived proteins.
In an animal study, modest increases of Sirtuin 1 gene protein improved cardiac health, while greater than a 7.5 fold increase in Sirtuin 1 gene protein induced heart failure in laboratory mice. [Circulation Research 100: 1512-21, 2007] This is certainly a red flag. Over-stimulation of Sirtuin1 needs greater scientific scrutiny before mega-sirtuin activator drugs are employed.
Within a year of the report showing resveratrol molecularly mimics a calorie restricted diet, researchers at the National Institutes of Health were reporting that food deprivation activates the Sirtuin 1 gene via another gene called FOXO3a. Elimination of the FOXO3a gene in animals inhibits the starvation-increased expression of Sirtuin 1 gene proteins. Furthermore, when the p53 tumor suppressor gene is eliminated, the Sirtuin 1 gene proteins are not upregulated. Thus resveratrol is now forced to share the limelight with the FOXO3a gene and the p53 gene. Biologists now claim in mammals, p53, Foxo3a and Sirtuin 1 all constitute a nutrient-sensing pathway. [Science 2004 Dec 17; 306 (5704):2105-8] That is to say, during periods of food deprivation, a number of genes are activated in defense of the organism.
Longevity seekers will be hearing more about the family of FOXO family of genes. The Sirtuin1 activator resveratrol works in tandem with the FOXO1 gene, whose proteins are translocated to the nucleus of living cells where they decrease the generation of free radicals and inflammation. So resveratrol is effective in this regard through the action of FOXO1 gene derived proteins. [American Journal Physiology Endocrinology Metabolism 2007 Jul;293(1):E159-64]
Biologists now recognize that one of the adverse effects of high insulin levels and high insulin-growth factor signaling is suppression of the FOXO gene family. Aging is accelerated by the suppression of the FOXO gene family, which results in generation of damaging free radicals. Here is how biologists explain it:
Biologists say “an understanding of the processes controlled by these FOXOs
should permit development of novel classes of agents that will more directly
counteract or prevent the damage associated with diverse life-threatening
conditions, and so foster a life of good health to a ripe old age. Just like caloric restriction, lifespan can be increased in various species by plant-derived polyphenols, such as resveratrol, via activation of sirtuins in cells. Sirtuins, such as SIRT1 in mammals, utilize FOXO and other pathways to achieve their beneficial effects on health and lifespan. Current progress bodes well for an ever-increasing length of healthy life for those who adapt emerging knowledge personally (so-called 'longevitarians')”. [Journal Hypertension 2005; 23: 1285-309]
Even more perplexing, however, is a Harvard study showing that inhibition of Sirtuin 1 gene activity results in a decrease rather than an increase in senescence. Harvard researchers suggest that inhibitors for Sirtuin1 may have anticancer potential. [Oncogene 25: 176-85, 2006] How so? Most lay persons following this story were led to believe the Sirtuin 1 gene needs to be up-regulated rather than down-regulated to produce longevity.
Now researchers at MIT and Harvard show that a calorie-restricted diet does not uniformly activate the Sirtuin 1 gene in all organs of the body. In the liver, a high-calorie diet activates Sirtuin 1 and a low-calorie diet inhibits Sirtuin 1, which runs contrary to what was anticipated.
The researchers themselves explain it this way:
In summary, we show that the regulation of SIRTUIN1 by the diet is more
complicated than originally imagined. While it has been assumed that SIRTUIN1
activity increases generally during calorie restriction, we show that in the
liver the activity of this gene actually decreases. The regulation of SIRTUIN1
activity during calorie restriction is not only tissue-specific, but even
region-specific in non-homogeneous tissues, such as the brain. [Genes &
Development, published online June 11, 2008]
Do any of these revelations take the luster off of resveratrol? Hardly. But certainly the explanation of how resveratrol works is itself a work in progress. And while there may be momentary concern that resveratrol could in fact have the unwanted effect of inducing, or at least failing to prevent, the synthesis of fat and cholesterol in the liver, in fact, resveratrol-fed mice placed on a high-fat diet do not develop fatty liver and actually exhibit improved liver physiology and metabolic function. [Nature 444: 337-42, 2006; Cell 127: 1109-22, 2006]
And for all the followers of this unfolding discovery concerning molecularly-induced longevity who were initially introduced to the Sirtuin1 gene and seek to activate it via red wine or resveratrol pills, there is yet another revelation. At least two of the family of seven sirtuin genes share the role of lifespan regulation via nutrient availability, Sirtuin1 and Sirtuin6.
Furthermore, these same researchers who report on the role of Sirtuin6 also report that food deprivation doesn’t increase Sirtuin1 gene activity, but rather stabilizes this gene-derived protein which results in more of this protein being available. In other words, a calorie-restricted diet doesn’t increase the activity of Sirtuin6, but rather helps preserve it once it is produced. Here is how the researchers describe it:
These findings raise the possibility that, in mammals, several sirtuins mediate
the beneficial effects of calorie restriction on life span in a combinatorial
manner. Hence, a systematic approach is required when studying the role of
sirtuins in aging and calorie restriction. Furthermore, we propose that in order
to develop small molecules which could mimic the ability of calorie restriction
to prolong healthy life-span, one should search for master regulators with the
ability to promote the activities of multiple sirtuins. [FEBS Letters, In Press,
Corrected Proof, Available online 9 June 2008]
Well, there you have it, Sirtuin1 has a brother, Sirtuin6, and they are sharing the scientific limelight now with other genes, including FOXO and the p53 gene, with likely more to come. Furthermore, the activation of Sirtuin1 is not uniform in all tissues and organs and that in vitro studies (in test tubes) which measure activation of the Sirtuin1 gene may not provide a complete nor accurate picture of what is actually going on inside a living organism.
It is this author’s opinion that there is too much reductionist thinking here. Genes do nothing in themselves, they react to biological stressors, such as excess food, food deprivation, radiation, heat, cold, etc. Genes can also be targeted by molecules in the diet, but apparently in not such a narrow way, but rather more broadly. Albeit, the very advantage these small natural molecules like resveratrol have is that they affect a broad array of genes. [Journal Nutritional Biochemistry 2005 Aug; 16(8):449-66]
The human genome consists of 30,000 genes. Upcoming global gene array studies will provide a broader picture of how dietary-derived molecules affect the genome. Cherry-picking a single gene to describe it as “the holy grail” of aging may have been a bit premature. How many genes does a calorie restricted diet significantly upregulate? Around 200.
The next round of scientific discoveries will soon compare the effect of a calorie restricted diet, a resveratrol-supplemented diet, and a diet where multiple small molecules have been employed.
These are challenging studies because calorie restriction induces hundreds (if not hundreds of thousands) of biological changes, making it difficult to identify those that are causal, say researchers. [Journal of Nutrition 2001; 131:918S-923S]
However, aging results in different gene expression patterns specific to each tissue in the body, and the good news is that most alterations produced by aging can be completely or partially prevented by caloric restriction in both heart and skeletal muscle. [Cardiovascular Research 66: 205-12, 2005] Therefore, calorie restriction mimics with small molecules are very promising.
The small molecules that exert the greatest effect over the genome in regard to aging will all be found to be mineral chelators or controllers. [Neurobiology Aging. 2008 Jul; 29(7):1052-9; FEBS Letters 2003 Sep 11; 551(1-3):58-62; Ageing Research Reviews 2003 Jan;2(1):25-37] The gradual accumulation of minerals in the body, once full childhood growth has been achieved, explains the progressive aging experienced by humans. Removal of these minerals (chelation) holds the promise of restoring a youthful state to aging cells, tissues and organs, with the prospect of a biologically unlimited lifespan. –Copyright Bill Sardi, June 21, 2008.
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