In Vino Vita?

By Vivienne Baillie Gerritsen

For many, a prolonged - but of course healthy - life is a tempting prospect. Especially, in a day and age where there seems so little time to fulfill our ever-growing aspirations and the gift of an extra few hours a day is just not on. Researchers have been giving a lot of their time to the problem of longevity since the 1930s when it was first discovered that calorie restriction actually lengthened life expectation in mammals. It took many more years of research before scientists got a glimpse of the molecular pathway underlying such a process. And, for the time being, it really is just a glimpse but an encouraging one. A family of proteins, known as sirtuins (sir-too-ins) or SIRS, an abbreviation of Silent Information Regulators, known to exist from bacteria to humans, seem to have a definite role in the ageing process of cells, and hence the ageing process of organisms.

 

 

Fig. 1 Bacchus, Hermitage, St. Petersburg, Peter Paul Rubens (1610-1695)

 

It is now clear that the ageing pathway in different organisms is different. In yeast, for example, an accumulation of what is known as toxic extrachromosomal rDNA circles (ERCs) is a cause of cell senescence. Whilst in worms, interference in the insulin signaling pathway have an effect in the organism's longevity. The exciting discovery is that sirtuins have a direct effect in these different ageing processes. They may act in different molecular pathways but their mode of action is the same. Sirtuins are NAD-dependent protein deacetylases. What they do is remove acetyl groups from specific target proteins. Their function however depends on the intracellular concentration of nicotinamide adenine dinucleotide (NAD), which in the oxidized form greatly enhances sirtuin activity. In yeast for example, genomic instability and hence the accumulation of ERCs, stakes its fate. Sirtuins can brake this fate by acting on certain histones. Through deacetylation of the said histones, chromatin structure is modified, the lecture of rDNA disrupted and the formation of ERCs hindered.

What kind of event would delay cell senescence? Calorie restriction for one. It is thought that calorie restriction either shifts the ratio of oxidized/reduced NAD or alters its level, thereby having an effect on sirtuin activity. How? Well, a number of proteins which are also NAD-dependent may become less active and release their NAD which is then free to activate the sirtuins. Another hypothesis for an increase in NAD is a metabolic shift to respiration. Indeed, when glucose is limiting, respiration is preferred. An increase in respiration yields a higher rate of electron transport thereby increasing the overall cellular NAD/NADH ratio. Either way, an increase in NAD activates sirtuin activity and as a result, in the event of environmental stress, such as less food but also fungal infection for instance, organisms would be given a better chance to survive.

So, sirtuins do seem to have an overall role as regulators of programmed cell death and cell differentiation. As we have seen, they are more heavily summoned during environmental stress. In the quest for eternal youth and health, scientists set about to find out if they could pin down a molecule or two which could trigger off sirtuin activity, instead of just counting on calorie restriction. A number of chemical compounds were examined amongst which a few polyphenols, which are metabolites found in plants. The most potent activator turned out to be resveratrol, a plant metabolite found in the skins of red and white grapes for instance…. and in the eyes of the convivial 'grapes' spells 'wine'…. Another plant metabolite, quercetin, is also an activator of sirtuins, but to a lesser degree and is found in olive oil for example. Both compounds are synthesized in response to environmental stress and are already known for their health benefits, namely their antioxidant properties, their capacity to lower cholesterol levels and decrease blood clot formation.

There is a theory that, when there is a lack of nutrients, plants may have the power to 'say' so to other organisms via resveratrol for example. Various animals feeding on plants would assimilate the increased ratio of resveratrol and thereby transfer the warning message to their own organism; i.e. that reproduction has to be halted and survival means undertaken. However, there is no reason not to believe that organisms other than plants do not have their own sirtuin activity enhancers which have simply not been identified yet. Time will tell.

So should we all take to drinking a glass of red wine or two per day? Or adding olive oil to our diet? Certainly, statistics have shown that the French, who are generous drinkers of red wine, suffer less from the side effects of overweight than do the Americans for example. A Mediterranean diet, which includes not only red wine but also ample amounts of olive oil as well as fresh fruit and vegetables, is also statistically far kinder to humans than a more Western diet of coke, hamburgers and chips. Let us make a finer comparison for the gourmet readers: wines produced in cooler regions or areas where grapes are more prone to disease often have more resveratrol. Hence Pinot Noir, for instance, has rather high doses of the chemical while a Cabernet-Sauvignon is not so rich in the compound. What is more, resveratrol is unstable on exposure to air and goes off within 24 hours. Would it be wiser then to drink a bottle a day?

Well no. In fact, it has been shown that high doses of resveratrol stunts its effect on sirtuins - so no point in overdrinking. Nothing has been proved yet. No one can say whether even one glass of wine a day keeps the doctor away or not. Furthermore, in human cells, resveratrol - via sirtuin activity - ultimately deactivates a tumor suppressor, thus fueling concerns that increasing resveratrol levels may predispose humans to cancer. Though a number of scientists disagree since calorie restriction per se has never proved to do so. Much more has to be done, sirtuin's 3D structure for one, before any conclusions can be made. Naturally, a lot of money could be involved in this kind of discovery. Yet another miracle diet: eat your cake and swill it down with a glass of wine enriched with resveratrol. Just imagine. However scientists insist that the findings are not so much to prolong life than to avoid the bothersome effects of ageing such as neurodegeneration, carcinogenesis and atherosclerosis. Well, the message is always the same isn't it? Just eat a healthy varied diet: some wine, some olive oil, fresh fruit and vegetables, cereals and even chocolate. Just don't eat too much of it and you should be all right.

Cross-references to Swiss-Prot

P06700: Saccharomyces cerevisiae (Baker's yeast) NAD-dependent histone deacetylase SIR2

References

1. Finkel T.
Ageing: a toast to long life
Nature 425:132-133(2003).
PMID: 12968159.

2. Howitz K.T., Bitterman K.J., Cohen H.Y., Lamming D.W., Lavu S., Wood J.G., Zipkin R.E., Chung P., Kisielewski A., Zhang L.-L., Scherer B., Sinclair D.A.
Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Nature 425:191-196(2003).
PMID: 12939617.

3. Hall S.S.
In vino vitalis? Compounds activate life-extending genes
Science 301:1165-1165(2003).
PMID: 12947168.

Protein Spotlight (ISSN 1424-4721) is published by the SWISS-PROT group at the Swiss Institute of Bioinformatics (SIB). Authorization to photocopy or reproduce this article for internal or personal use is granted by the SIB provided its content is not modified. Please enquire at spotlight@isb-sib.ch for redistribution or commercial usage.