Resveratrol and Sirtuins

A study this week helps to establish a relationship between resveratrol (the anti-aging tonic refined from red wine) and a family of genes known as SIRT, which seems to extend life span in some lab species by turning genes off.  But the results may be moot if resveratrol cannot be shown to extend life span in mammals, including humans.

 

Seldom do arcane questions about detailed mechanisms of gene expression make headlines in science news, but a hard-fought debate over sirtuins and resveratrol has attracted public attention since 2003. Once again this week, the debate burst onto news pages. The prospect of anti-aging drugs only partially explains the special notice; other factors are major investments in the field from Big Pharma, and some flamboyant personalities.

Science Magazine has a section labeled Perspectives where technical articles from the back of the magazine are summarized for non-specialists. But the Perspective piece on Friday was clear as mud, explaining

that natural SIRT1 substrates with a large hydrophobic residue (Trp, Tyr, or Phe) at positions +1 and +6 [such as the substrate peroxisome proliferator-activated receptor γ coactivator 1α, acetylated on lysine at position 778 (PGC-1α-K778)] or +1 [such as the substrate forkhead box protein O3a acetylated on lysine at position 290 (FOXO3a-K290)], as well as other peptides that conformed to this substrate signature, were selectively activated by several STACs.

Ever wise and patient, Len Guarente did a far better job.  In an off-the-cuff interview for the MIT news service, he explains that the crux of the question is whether compounds in the resveratrol family act through the SIRT family of genes, or whether the SIRT genes are activated indirectly as a side-effect.

This paper, I think, provides findings that are very difficult to interpret in any way other than direct activation by the [resveratrol] compounds. The strongest evidence in the paper is that they found they could change one amino acid of the [SIRT] protein, from glutamate to lysine, and that change had no effect at all on the catalytic properties of the enzyme – the enzyme still works the same way as far as you can measure, there’s no difference between the mutant and the control. However, the mutant is completely dead with regard to activation by resveratrol. They also tested some of the newer compounds – I believe it was about 100 of them – and found the same thing. The mutant enzyme was either inactive or much less active than the normal version. 

Resveratrol trials in animals

Back in 2003 when the question about the action of resveratrol and its connection to SIRT-1 first sparked a debate, it seemed crucially important because compounds in the resveratrol family seemed head-and-shoulders the best candidates for quick development as anti-aging drugs.

The benefits of resveratrol were first discovered in the early 1990s in yeast cells, where it was found to prolong life span dramatically. Next, resveratrol was tested in worms and flies, short-lived species that are easy to grow in the lab. Both these species – evolutionarily miles apart from each other as each is from yeast – responded dramatically to resveratrol. In 2006, a visionary Italian grad student made expeditions to East Africa to introduce a new lab model for aging research: a killifish that thrives in seasonal wetlands. With a life span of just four months, it is the shortest-lived known vertebrate. Once again, resveratrol performed swimmingly, extending life spans up to 80% more than 50% (at the highest dosage), and helped to launch the career of Dario Valenzano. All this pointed to an evolutionarily-conserved mechanism for modulating life span.

With life spans of 2-3 years, mice were next in line for testing. (Compared to yeast and worms, mice are practically human.)  Expectations were high, and the tests were performed by genuine enthusiasts for resveratrol, who were looking for positive results. But we were all disappointed: Life span of the mice was not increased. Puzzling, tantalizing were observations that the mice seemed healthier in so many ways.

• Inflammation and oxidative damage was down
• Arteries were healthier
• Cataracts were delayed
• Insulin sensitivity was better
• Stamina was improved

Gene expression in the resveratrol mice also seemed in some ways to mimic gene expression of younger mice, or mice on a calorie-restricted diet. Why didn’t they live longer? These results were reported with positive spin, but it was confirmed in subsequent trials: life span was extended only for that branch of the experiment working with mice that were made obese with a high-calorie diet.

Here we present a long-term evaluation of resveratrol as a CR [calorie-restriction] mimetic in mice. In agreement with a concurrent study, we show that resveratrol induces changes in the transcriptional profiles of key metabolic tissues that closely resemble those induced by CR. In liver and muscle, these changes can also be correlated to the gene expression patterns in younger animals, while in adipose tissue, the trend is reversed. Overall health was improved under all dietary conditions, as reflected by the reduction of osteoporosis, cataracts, vascular dysfunction, and declines in motor coordination; however, longevity was increased only in the context of a high-calorie diet, as reported previously… In conclusion, long-term resveratrol treatment of mice can mimic transcriptional changes induced by CR, and allow them to live healthier, more vigorous lives.  (Harvard Med study, 2008)

 

What does SIRT-1 do?

Recently, I wrote about gene regulation and aging. A different subset of genes becomes active later in life. Curiously, there is generally more gene activity at older ages. Think of this extra gene expression as haphazard and damaging to the cells’ delicate chemical poise. A smart effective anti-aging strategy would be to change the set of genes that are expressed back to a youthful profile. But there is evidence from worms and flies that the dumb strategy of cutting back gene expression across the board might also work to some extent.

SIRT-1 turns genes off in a broadly dumb way. This is done via a chemical process called histone de-acetylation. Histones are wide protein spools, around which  DNA winds to keep itself compact. Where there are acetyl groups added to the histone, the DNA winds more loosely, and is more available for expression. What SIRT-1 does is to remove acetyl groups from the histones, which has the effect of broadly dialing down gene expression.

(To turn a gene on, either subtract a methyl group from the chromosome itself or add an acetyl group to the histone.  Methylation is the other principal way that gene expression is controlled.  Methylation is directly on the chromosome itself, not on the histone, and it is both more specific and more long-lasting than de-acetylation.)

 

The search for a resveratrol-based drug product continues

David Sinclair was the most ambitious and flamboyant of Guarente’s students. He went on to run his own lab at Harvard Med School, and to found a for-profit company called Sirtris, whose mission was to explore engineered variations on the theme of resveratrol. In 2008, Sirtris was bought by Glaxo SmithKline for an eye-popping $720 million, leading to widespread speculation that Sirtris had developed a promising candidate age-retarding drug. But in 2011, Glaxo announced that it was discontinuing trials of all the Sirtris drug candidates.

A recent short-term study of resveratrol in middle-aged women found none of the metabolic benefits reported for animals. These researchers from Washington University reported that resveratrol failed even to raise levels of sirtuins. Still, human trials are continuing for a handful of the hundreds of sirtuin-activators that Sirtris has identified. Science journalist David Stipp has written about positive results in humans and mice

And if I were an obese mammal with hypertension, I’d be sorely tempted at this point to try taking modest daily doses of a resveratrol supplement for a month to see whether it brings down my blood pressure. While I wouldn’t expect such an experiment to make me live a lot longer, I think I could justifiably entertain the hope that it just might help me age more gracefully.