Feature: The science of longevity: Resveratrol and beyond

This feature appeared in the November/December 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

It’s a most perplexing phenomena: if you restrict the caloric intake of any of a wide range of organisms – from yeast to nematode worms to rats or even primates – instead of them being hampered by the lack of energy in their diet, their lifespan can be actually increased significantly.

They also often enjoy a number of other health benefits, such as lower levels of cholesterol, a reduction in the incidence of age-related diseases and general improvements in health and stamina. It even appears as though such a diet, called calorie restriction (CR), works in humans as well.

Clearly, harnessing such an effect would be of tremendous benefit to health. However, not many organisms – particularly humans – respond well to the prospects of cutting caloric intake by 30-40 per cent indefinitely.

As such, there’s been a great deal of effort focused on uncovering the mechanisms underlying longevity and CR with the hope that we might one day be able to produce drugs that trigger a similar effect, boosting longevity and improving health.

One of the pioneers in this field is Australian researcher, David Sinclair, who is currently professor of pathology at Harvard Medical School in the US. Sinclair first entered the headlines in 2003 when he discovered that resveratrol – a chemical found in red wine – can mimic the effects of CR and increase longevity in a variety of organisms.

His research has continued apace since then, and in he spoke this week at the Australian Health & Medical Research Congress about his latest insights into the mechanisms of longevity and the search for drugs that might capitalise on our body’s natural repair mechanisms.

Age old questions

Why do we age? It’s a surprisingly simple question with a deceptively complex answer. It was once thought that aging was controlled by genes tasked with managing senescence – so-called ‘aging genes’. But the problem with this approach is it’s difficult to see how natural selection could select for aging genes, because aging after reproduction, itself, isn’t adaptive.

On the other hand, it is entirely plausible that the body does possess genes that maintain a healthy body, enacting repairs to tissue and staving off disease – so-called ‘longevity genes’. Yet, after reproductive age is reached, there’s less reason, in an evolutionary sense, for these genes to continue working, thus beginning the slow decline to the grave.

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But then how to explain the CR phenomenon? It was originally believed that CR acted in a passive way, such as by slowing the metabolic rate due to lack of energy, which meant less toxic by-products of metabolism were also produced. Yet many organisms undergoing a CR diet actually exhibited an increased metabolic rate, so that explanation went out the window.

Another explanation was that CR delayed development of the organism, thus slowing aging. However, CR works just as effectively in older as in younger organisms, suggesting it’s independent of developmental mechanisms.

As, one by one, the passive explanations of CR were eroded, this led Sinclair and others to speculate that CR actually triggers an active longevity mechanism. They theorised that CR acts like a form of biological stressor, triggering our longevity genes to fire up and boost our natural defences – suggesting a natural survival mechanism that enables organisms to ride out tough times.

What appears to be most striking about this process is that it is governed by a relatively small number of genes. This opens the possibility of finding particular molecules that might trigger those genes, giving the beneficial effects of CR – without the ‘R’.

This is where Sinclair has had his biggest breakthroughs by discovering a range of molecules that boost the activity of the Sir2 family of genes – the ‘sirtuins’ – which appears to mimic the effects of CR in yeast and other organisms.

“It’s clear now that these sirtuins are ancient survival genes that evolved to keep organisms alive during times of adversity, like when food supply was very low,” says Sinclair. “They’re triggered when we diet and exercise, and their job is to make the body fitter and healthier in order to survive the adversity. What we’re trying to do in making these drugs is to activate our body’s natural defences against disease without having to undergo these bodily stresses – which you can’t really ask an elderly person or a sick person to do.”

Chief among these sirtuin-stimulating molecules is resveratrol. When Sinclair’s 2003 paper in Nature made the link between red wine and longevity, wine sales in the United States experienced a significant jump. Since 2003, sales of resveratrol in supplement form have also skyrocketed.

However, there’s little supporting evidence to suggest that taking resveratrol supplements or drinking red wine will have any significant positive impact on health; you’d have to drink so much wine each day to see the beneficial effects of resveratrol that the negative effects of the wine would more than compensate for them.

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Beyond resveratrol

Sinclair’s quest over the past several years has been to uncover new molecules that have greater potency than resveratrol, molecules that might be made into treatments for many of the diseases for aging.

If these drugs actually work, they could potentially treat a slew of age-related diseases, everything from Type 2 diabetes to neurodegenerative, cardiovascular and inflammatory disease, as well as that holy grail of medicine: they might even significantly extend our lifespan and improve general health throughout our lives (although, no companies are currently touting full blown anti-aging drugs because US Food and Drug Administration has no regulatory framework for such treatments.)

You’d be forgiven for thinking the manifold benefits of sirtuins almost sound too good to be true. “It does sometimes seem too good to be true, but the data’s the data,” says Sinclair. “There are now hundreds of labs coming up with papers showing how these genes are beneficial. It’s hard to argue with the hundreds of papers that have come out.” It’s now just a matter of getting the right molecules to trigger the right genes, with a potentially multi-billion dollar market awaiting the results.

It was with this end in mind that he co-founded with Christoph Westphal the US-based biotech, Sirtris, which is exploring various sirtuins as possible drug candidates. GlaxoSmithKline was so impressed with the company’s prospects that it paid a staggering $US720 million dollars to acquire it in 2008. Not bad for a start-up.

But the big question that remains is how the sirtuins actually work. Uncovering the details of how molecules like resveratrol activate the longevity genes will be crucial to developing new, more efficient, molecules. And there’s recently been somewhat of a stoush between researchers at GSK/Sirtris and their rivals at Pfizer and Amgen over the efficacy of certain sirtuins.

In a paper in late 2009, Amgen researchers reported that the apparent activation of the key human SIRT1 gene is an artefact from Sirtris’s experimental method, particularly its choice of fluorescent peptide used in its assays. They suggested that SIRT1 was only activated indirectly in the presence of a particular flurophore, and not in native substrates.

Then, in January of this year, researchers from Pfizer published a paper in the Journal of Biological Chemistry reinforcing Amgen’s claims and also finding that one of Sirtris’s new sirtuin activators, SRT1720, failed to provide any benefits to diabetic mice.

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GSK even released a paper in JBC in August acknowledging that the structure of the substrate and the fluorescent peptide used impact the activation of SIRT1. Together, these papers dealt a significant blow to confidence in sirtuins.

But that’s not the end of the story. When speaking at the AH&MR Congress, Sinclair will reveal some new research that might shed light on this dispute, perhaps even going some way to settling it once and for all. “We’ve found the missing piece to the puzzle that will make sense of all the data they’re arguing about,” he says. “A piece people haven’t realised was missing.”

Sinclair has found that, in vitro, the sirtuins work under some conditions, but not under others, and the problem has been understanding why. “Pfizer says that because it doesn’t work under every condition, then it’s an artefact. GSK says the reason it doesn’t work under every condition is the system is complicated and we don’t understand everything.

“We agree with the latter, and it turns out there’s a protein partner that is part of the mechanism, and that, until now, people haven’t realised needs to be in the reaction to mimic what happens in the body. That explains why people are getting different results, because we need this protein-binding partner for the enzyme, which is naturally present. People didn’t know you needed to add it for it to be physiologically relevant. But in the cell SIRT1 isn’t naked, it’s bound up with this protein partner that we’ve figured out is important.”

Sinclair is keeping the details of this protein partner close to his chest at this stage, but he’ll be covering it more comprehensively at the Congress in November. As for the so-called ‘storm’ over sirtuins between rival big pharma companies, it’s all been blown out of proportion, says Sinclair.

“It’s a fairly typical debate in academia, it’s just a couple of papers. But the media reaction has been overheated. It’s just not unusual to argue over assays and how drugs work. But because there’s a lot at stake, it’s amplified the academic debate.”

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The next step

It could be that this present debate is but a minor speed bump in developing new therapies based on sirtuin activating compounds (STACs). That’s GSK and Sirtris’s main focus at the moment, with the former bringing its not inconsiderable expertise in disease to bear on the problem.

“They’ve had a lot of success in animal studies,” says Sinclair. “They’ve also done safety studies in human with a couple of the most promising STACs. Right now, they understand a lot about where they could be used in trials, and some of the early results are coming back from early human studies in diseases of aging. The areas they’re particularly interested in are metabolism and inflammation, including emphysema, arthritis and even sepsis. There are a lot of potential applications.”

The good news is that many of these STACs appear to be very well tolerated. “The first molecule being looked at, SIT2104, has shown no sign of toxicity or negative side effects. So the good news is tweaking the sirtuin pathway doesn’t seem to be overtly dangerous in humans. We don’t know for sure yet in thousands of people, but there’s nothing that is raising red flags or making us worried about side effects.” The good news is that this means phase II trials may not be far off.

Sinclair is also continuing his research into the underlying mechanisms of aging, with him recently focusing his attention on the role of mitochondria. “Mitochondrial activity key for keeping organs healthy, and it’s one of the biggest differences between a young person and an old person, or a healthy and a diseased one. We’ve found that the SIRT3 protein is master protector of mitochondria. If we boost its function, we can protect the heart and protect the brain, yet if you do the opposite and delete the gene, you see accelerated aging.”

He has also found that the activity of this enzyme drops off as people reach around 40 or 50 years of age. “I think this is probably a major cause in decline in memory and energy and fitness as we age.”

It also appears as though the various sirtuins work together, reinforcing each other. “One day it would be very interesting to find a molecule or a drug that enhances both their activity at the same time. But for now we’re excited about uncovering what we think is a new cause for aging.”

And Sinclair, who only turns 40 this year, has plenty of time left to make more pioneering discoveries in the mechanisms of aging. And if his research does lead to a new generation of longevity drugs, he could be conducting his research for many years yet.

This feature appeared in the November/December 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.