Resveratrol is getting rather confusing

Here, have another glass of this great Cabernet...

But hold on about jumping to conclusions. The resveratrol story keeps getting more complicated, according to the most recent research. This is in addition to what we just discussed here.

To begin with, there is additional confirmation that resveratrol does confer health benefits – at least in mice. However – and this is a major qualification – the research did not indicate there was a general extension of longevity in the mice.

Furthermore, the way that the research was announced introduced further confusion. In one press release (from the publisher, Cell Press, of Cell Metabolism) we have:

Red wine ingredient wards off effects of age on heart, bones, eyes and muscle (7/3/08)

Large doses of a red wine ingredient can ward off many of the vagaries of aging in mice who begin taking it at midlife, according to a new report published online on July 3rd in Cell Metabolism, a Cell Press publication. Those health improvements of the chemical known as resveratrol—including cardiovascular benefits, greater motor coordination, reduced cataracts and better bone density—come without necessarily extending the animals' lifespan.

Sinclair and de Cabo's team further show evidence that resveratrol mimics the beneficial effects of eating fewer calories. In mice, they found that resveratrol induces gene activity patterns in multiple tissues that parallel those induced by dietary restriction and every-other-day feeding.

But in another press release, from NIH's National Institute on Aging, we find:

Resveratrol found to improve health, but not longevity in aging mice on standard diet (7/3/08)

Scientists have found that the compound resveratrol slows age-related deterioration and functional decline of mice on a standard diet, but does not increase longevity when started at middle age. This study, conducted and supported in part by the National Institute on Aging (NIA), part of the National Institutes of Health, is a follow-up to 2006 findings that resveratrol improves health and longevity of overweight, aged mice. The report confirms previous results suggesting the compound, found naturally in foods like grapes and nuts, may mimic, in mice, some of the effects of dietary or calorie restriction, the most effective and reproducible way found to date to alleviate age-associated disease in mammals.

The findings, published July 3, 2008, in Cell Metabolism, may increase interest in resveratrol as a possible intervention for age-related declines, said NIA scientists. The authors emphasized, however, that their findings are based on research in mice, not in humans, and have no immediate and direct application to people, whose health is influenced by a variety of factors beyond those which may be represented in the animal models.

Keep in mind, this is all about the same research. Clearly, there are some differences of spin being offered here. The second announcement seems to be closer to what was actually found, as can be seen from the abstract of the actual journal article:

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span

A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging, including reduced albuminuria, decreased inflammation, and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started midlife.

(Aside: in discussions like this you will often see the terms "longevity" and "lifespan" used almost interchangably. Properly speaking, "longevity" is usually the better term, as it refers to average length of life, a statistical property, while "lifespan" refers to maximum potential length of life. For the most part, the distinction can be glossed over, though it isn't entirely unimportant.)

Confused yet? Let me try to boil this down a little. This is just my interpretation, but the conclusions I see are these:

1. Resveratrol fed to middle-aged mice can have health benefits, such as cardiovascular benefits, greater motor coordination, reduced cataracts and better bone density.
   
2. The health benefits and gene transcriptional changes resulting from resveratrol in the diet are similar to, though not quite the same as, those resulting from calorie restriction alone.
   
3. Resveratrol in the diet did not increase longevity of mice on normal diets, even though calorie restriction by itself has been shown to increase longevity (in mice), while resveratrol does increase longevity of mice on high-calorie diets.
   
4. In mice on high-calorie diets where resveratrol increased both health factors and longevity, the improvement occurred without decreasing actual body weight.
   
5. This research on mice may not be predictive of the effects that might be seen in similar experiments (which have not yet been done) on humans.
   

Putting this even more succinctly, in mice adding resveratrol to the diet slows down some undesirable side-effects of aging, but does not appear to actually increase longevity, whereas calorie restriction does slow aging and increase longevity somewhat. All bets are still off as to what effects resveratrol may have in humans.

How could it be that resveratrol had all these health benefits, but didn't increase longevity? The logical conclusion would be that resveratrol has little effect on conditions that usually cause mice to die. In particular, mice usually die of cancer, and resveratrol doesn't have much benefit in that regard, though calorie restriction does.

There might actually be good news for humans in this – if resveratrol did benefit cardiovascular health in humans, that would be great, since cardiovascular disease is the largest cause of human mortality. (Cancer's a big cause too, just not as big.)

In spite of the ambiguities, this is a very significant piece of research, in part because of the large team of experienced scientists – such as David Sinclair – who participated. Here are some additional news reports on the research:

• Resveratrol helps hearts in mice, but doesn’t reproduce all the benefits of low-calorie diets (7/3/08)
  
• Wine chemical improves health but not longevity (7/3/08)
  
• Fountain of youth? Red wine gives up secrets (7/3/08)
  

But wait. We're not done yet. There are additional complications, as some of these other reports point out. For one thing, it isn't at all clear how resveratrol is beneficial at a molecular level. (And it's just as unclear why calorie restriction is beneficial – which might be different in some ways from the reasons applicable to resveratrol.) It is known that resveratrol has antioxidant and anti-inflammatory properties. Both of those are positives.

However, resveratrol also seems to activate the sirtuin protein Sirt1. There's quite a bit of research – in model organisms like nematodes, yeast, fruit flies, and rodents – that shows sirtuins have beneficial properties of their own. In particular, sirtuins do increase longevity, as does calorie restriction, in the model organisms, even if the molecular mechanisms aren't quite the same. (This is more evidence that the beneficial effects of resveratrol are not largely due to sirtuin activation.)

Regarding Sirt1 specifically, there have been at least two other recent research results published. The results are mixed. In some ways Sirt1 is shown to be beneficial, while in at least one way, it may be harmful. To the extent that resveratrol does serve to activate Sirt1, is may have the same helpful or harmful properties.

Here's the bad news, first:

Life-extending Protein Can Also Have Damaging Effects On Brain Cells (7/1/08)

Proteins widely believed to protect against aging can actually cause oxidative damage in mammalian brain cells, according to a new report in the July Cell Metabolism, a publication of Cell Press. The findings suggest that the proteins can have both proaging and protective functions, depending on the circumstances, the researchers said.

"Sirtuins are very important proteins," said Valter Longo of the University of Southern California, Los Angeles. "Overexpression can protect in some cases, and in other cases, it may do the opposite. It has to do with the fact that they do so many things." ...

SirT1, the mammalian version of yeast Sir2, controls numerous physiological processes including glucose metabolism, DNA repair, and cell death, the researchers added. In mammalian cells, SirT1 also controls several stress-response factors.

Now, the researchers show that cultured rat neurons treated with a SirT1 inhibitor more often survived treatment with oxidative stress-inducing chemicals. They further show evidence to explain the mechanism responsible for that effect.

They also found lower oxidative stress levels in the brains of mice without SirT1. However, those SirT1 knockout mice didn't live as long as normal mice do on either a normal or a calorie-restricted diet.

In brief: lowering Sirt1 levels helps cells withstand oxidative stress, while higher levels make cells more vulnerable to oxidative stress. Nevertheless, mice without Sirt1 at all live shorter lives. Confusing, no?

This research, which was published in the same issue of Cell Metabolism as the de Cabo-Sinclair study, went on to investigate in more detail what Sirt1 inhibition was doing. Here's the research abstract to explain:

SirT1 Inhibition Reduces IGF-I/IRS-2/Ras/ERK1/2 Signaling and Protects Neurons

Sirtuins are known to protect cells and extend life span, but our previous studies indicated that S. cerevisiae Sir2 can also increase stress sensitivity and limit life-span extension. Here we provide evidence for a role of the mammalian Sir2 ortholog SirT1 in the sensitization of neurons to oxidative damage. SirT1 inhibition increased acetylation and decreased phosphorylation of IRS-2; it also reduced activation of the Ras/ERK1/2 pathway, suggesting that SirT1 may enhance IGF-I signaling in part by deacetylating IRS-2. Either the inhibition of SirT1 or of Ras/ERK1/2 was associated with resistance to oxidative damage. Markers of oxidized proteins and lipids were reduced in the brain of old SirT1-deficient mice, but the life span of the homozygote knockout mice was reduced under both normal and calorie-restricted conditions. These results are consistent with findings in S. cerevisiae and other model systems, suggesting that mammalian sirtuins can play both protective and proaging roles.

(Technical aside: Note, in particular, the conjectured effect of Sirt1 on IGF-1 signaling. Sirt1 promotes phosphorylation of IRS2, the "Insulin receptor substrate 2", which enhances IGF-1 signaling, and this makes cells more vulnerable to oxidative stress. Conversely, inhibition of Sirt1 reduces cell vulnerability. (We discussed many properties of IGF-1, including relations to calorie restriction and longevity, here.))

As you recall, Sirt1 is what's called a histone deacetylase (HDAC) enzyme. (Some discussion here.) As such, one of the main properties of Sirt1 is that it can silence a bunch of genes at the same time, by removing acetyl groups from the histones to which the genes are normally bound. Clearly, that is why Sirt1 affects many diverse processes, and why it can be risky to mess with.

That's the cautionary news on Sirt1. But again on the positive side of the ledger for Sirt1 (and hence perhaps resveratrol also), there is one more study that did not receive as much media attention. The study, was published July 3 in the Proceedings of the National Academy of Sciences. Its authors included Matthias Tschöp and Paul Pfluger.

Here's the abstract (via BioInfoBank):

Sirt1 protects against high-fat diet-induced metabolic damage

Here, we report that mice with moderate overexpression of Sirt1 under the control of its natural promoter exhibit fat mass gain similar to wild-type controls when exposed to a high-fat diet. Higher energy expenditure appears to be compensated by a parallel increase in food intake. Interestingly, transgenic Sirt1 mice under a high-fat diet show lower lipid-induced inflammation along with better glucose tolerance, and are almost entirely protected from hepatic steatosis. We present data indicating that such beneficial effects of Sirt1 are due to at least two mechanisms: induction of antioxidant proteins MnSOD and Nrf1, possibly via stimulation of PGC1-α, and lower activation of proinflammatory cytokines, such as TNF-α and IL-6, via down-modulation of NF-κB activity. Together, these results provide direct proof of the protective potential of Sirt1 against the metabolic consequences of chronic exposure to a high-fat diet.

From this news story already mentioned, here's a little more explanation:

Increasing levels of the mouse sirtuin, SirT1, prevents mice from developing heart problems and fatty livers even when they are fed high-fat diets, researchers at the University of Cincinnati College of Medicine and the Spanish National Cancer Research Center in Madrid reported June 30 in Proceedings of the National Academy of Sciences. These mice with higher levels of SirT1 eat more but also burn more calories than do mice with normal levels of the enzyme.

If you haven't had enough punishment yet, here's a more detailed report on all the research already discussed, and a bit more:

SIRT1, Resveratrol and More: Moving Closer to Anti-aging Elixir? (7/8/08)

One of the additional bits is this:

Working independently and publishing 4 June in PLoS ONE, researchers led by Tomas Prolla at the University of Wisconsin, Madison, report similar results in their microarray analysis comparing transcription profiles induced by CR and resveratrol. First author Jamie Barger and colleagues fed mice from middle age (14 months) to old age (30 months) a control diet, CR diet, or resveratrol-supplemented control diet. The researchers report a “striking transcriptional overlap” of CR and resveratrol (99.7 percent of gene expression changes correlating by direction) in heart, skeletal muscle, and brain (neocortex), and show that both regimens prevent age-related cardiac problems.

And here's the journal article, in full, being referred to:

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice (6/4/08) - also here

Resveratrol in high doses has been shown to extend lifespan in some studies in invertebrates and to prevent early mortality in mice fed a high-fat diet. We fed mice from middle age (14-months) to old age (30-months) either a control diet, a low dose of resveratrol (4.9 mg kg⁻¹ day⁻¹), or a calorie restricted (CR) diet and examined genome-wide transcriptional profiles. We report a striking transcriptional overlap of CR and resveratrol in heart, skeletal muscle and brain. Both dietary interventions inhibit gene expression profiles associated with cardiac and skeletal muscle aging, and prevent age-related cardiac dysfunction. Dietary resveratrol also mimics the effects of CR in insulin mediated glucose uptake in muscle. Gene expression profiling suggests that both CR and resveratrol may retard some aspects of aging through alterations in chromatin structure and transcription. Resveratrol, at doses that can be readily achieved in humans, fulfills the definition of a dietary compound that mimics some aspects of CR.

If that sounds a bit familiar, it's because not only does it parallel the research reported by Sinclair and de Cabo discussed above, but in fact we're already written about it here, as it was described in this press release.

To summarize this whole thing, resveratrol has benefits for both general health and longevity. The benefits are similar to, but not quite the same as, those of either sirtuins or calorie restriction. Further, sirtuins, and hence resveratrol, may also have detrimental side effects. A lot more research, which must eventually include human studies, is needed.

There have also been a couple of other recent reports on completely different possible mechanisms to explain the benefits of calorie restriction, but we'll save those for another time.

Additional reading:

The Ongoing Saga of Sirtuins and Aging – overview in Cell Metabolism of the research by Li, et al (sub rqd)

Tags: resveratrol, sirtuins, aging, longevity, calorie restriction, biogerontology