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Showing posts with label resveratrol. Show all posts
Showing posts with label resveratrol. Show all posts

Tuesday, 12 March 2013

Resveratrol increases sirtuins.

reposted from: NHS Choices
crabsallover highlights, key points, comments / links.

Further to the article by David Stipp in Scientific American blog, reviewed by me a few days ago...

Drugs that could help people 'to live to 150' could soon be a reality, according to headlines in The Daily Telegraph and the Daily Mail.
The news comes from molecular-level research into the compound resveratrol, which is found in red wine and dark chocolate, and has been shown to increase the activity of proteins called sirtuins.
These proteins are able to increase the lifespan of yeast, worms and flies, and it has been suggested that they may also play a role in human age-related diseases such as Alzheimer's disease.
This laboratory study looked at whether a synthetic version of resveratrol could stimulate the activity of sirtuins to such an extent that it could theoretically improve human life expectancy.  
Although the researchers found that these compounds directly activated the sirtuin proteins, it is far too early and optimistic to claim that a pill could be created that would allow people to live to 150.
This study was interested in biological processes in a laboratory, not the development of an anti-ageing pill. No pill has been made to improve life expectancy in humans, and the '150-year' claim seems to have been manufactured by the headline writers. Dreams of a pill that will allow you to live to 150 remain just that: dreams.

Red wine and resveratrol

Red wine only contains tiny amounts of resveratrol. Any hopes that a bottle of red will extend your lifespan are unfounded.

Where did the story come from?

The study was carried out by researchers from Harvard Medical School, the Massachusetts Institute of Technology, the US National Institutes of Health, the pharmaceutical company GlaxoSmithKline, and other institutions in Portugal and Australia.
The research was funded by research organisations throughout the US and Portugal. No funding support was reported for GlaxoSmithKline (GSK), although a GSK company (Sirtris) employs several of the researchers involved in the project, and one author is an inventor on patents licensed to this company.
Patents have also been filed by Harvard Medical School on the tests developed in their study, as well as by Sirtris and another company for some of the compounds tested.
The study was published in the peer-reviewed journal Science.
Headlines proclaiming that a pill has been developed that will help us live to 150 are highly flawed. It is also unclear what evidence these claims are based on, such as the Daily Mail stating that a pill could be "available within five years". Indeed, it is nearly two years since the last time the Mail ran a story on very similar news.
This laboratory research tested whether, and how, a class of compounds can increase the activity of a particular enzyme previously identified as being involved in a range of age-related diseases.
The research did not assess whether these compounds have the same effect when given to humans in a pill, if there is any effect on human disease or lifespan, or whether such a pill would be safe.
Much more research is needed before we know if these compounds could show any effect on human lifespan.

What kind of research was this?

This was a laboratory study that examined the ways that molecules called sirtuin-activating compounds (STACs) may increase the activity of the protein sirtuin-1 (SIRT1). 
Previous research has found that activating sirtuin proteins leads to a longer lifespan in yeast, flies and worms. It has been suggested that SIRT1 plays a role in many age-related conditions, including cancer, Alzheimer's disease, and type 2 diabetes.
Researchers report that SIRT1 has been shown to be involved in several processes surrounding these conditions, including controlling DNA repair and natural cell death, insulin secretion and inflammatory pathways, among others.
These findings make it an attractive drug target, as researchers hope that drugs that safely activate this protein could improve human health and extend our lifespan.
Previous research has shown that both synthetic and naturally occurring STACs (including resveratrol) can activate SIRT1 in the laboratory.
However, there has been debate as to whether this activation was a real, direct effect of STACs, or if it was caused by fluorescent chemical compounds called fluorophores, which are used to monitor the effects of STACs during experiments.
Fluorophores are widely used in laboratory research, as they make it easier to measure chemical changes to these proteins. However, they do not occur naturally in the human body and they may change what naturally happens in the reactions being tested.
There is the risk of a kind of biological Heisenberg Uncertainty principle: the act of observation could change the system you are trying to observe. This means that if the STACs cannot really directly activate SIRT1 in the body, and only do so in the laboratory due to the presence of the fluorophores, they would no longer be potential candidates for treating age-related diseases or extending lifespan.
The set of experiments described in the current study were designed to determine whether STACs were able to directly activate SIRT1, and to identify the precise way that such activation occurs.

What did the research involve?

The researchers carried out a series of complex laboratory experiments to determine whether a range of STACs were able to activate SIRT1. They developed a new way of measuring SIRT1 activation that did not require the use of fluorophores, so that these compounds could not affect the reactions.
The SIRT1 protein acts by modifying a range of different proteins, and the researchers tested whether the STACs enhanced the effect of SIRT1 across this range of proteins, or only on certain proteins. They also assessed how STACs might be having this effect.

What were the basic results?

The researchers found that STACs could activate SIRT1 in the laboratory, even if fluorophores weren't present.
They found that this increase in SIRT1 activity only affected proteins that had a specific type of amino acid in a particular position in the protein.
They found similar findings for all of the 118 STACs tested, including resveratrol.

How did the researchers interpret the results?

The researchers felt that their results meant that a range of STAC compounds can activate SIRT1, and that this process "remains a viable therapeutic intervention strategy for many diseases associated with ageing".

Conclusion

As yet, there is no pill that allows us to live to 150 years old. The research these claims are based on actually aimed to resolve debate about whether STACs, such as the resveratrol found in red wine, can activate the ageing- and disease-related SIRT1 protein. The results suggest that these compounds do in fact directly activate this protein.
Compounds that can activate the SIRT1 protein are of great interest to longevity researchers. This is because they have found that activating similar sirtuin proteins in yeast, flies and worms extends their lifespan. It remains to be seen whether or not producing these compounds can increase the human lifespan. 
Researchers have pointed out that the amount of resveratrol in red wine is significantly lower than the amounts fed to mice in previous research. The lead researcher said that, "at least 100 glasses [of red wine] would be needed each day to get the levels shown to improve health in mice". Research is also being conducted into similar synthetic chemicals, as some of these seem to have greater effects in the laboratory.
This type of study is a necessary and useful early step in the development of drugs. On its own, however, it is certainly not sufficient evidence for us to be able to say that STAC compounds can reverse human ageing or help us live for 150 years.
Media claims that such a pill is five years around the corner are ludicrously optimistic. While researchers suggest that pre-clinical studies in mice have been initiated, these studies would need to prove effective and safe, and then be followed by furtherrandomised control trials in humans.
It is important to note that the media coverage of this research failed to highlight the fact that the best way to reap the benefits of sirtuins is to take regular exercise.
Rather than waiting for scientists to develop a wonder drug, why not go for a walk in your local park, go for a swim or have a leisurely bike ride? Read more about the importance of exercise for older adults.

Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter.

Links to the headlines

Pill to live to 150. The Daily Telegraph, March 10 2013

Links to the science

Hubbard BP, Gomes A, Dai H, et al. Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators. Science. Published online March 8 2013
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Saturday, 9 March 2013

Sirtuin mechanism, resveratrol & calorie restriction by David Stipp

reposted from: Scientific American Blogs
crabsallover highlights, key points, comments / links.


What is it about sirtuins? Few research topics have engendered fiercer controversy in recent years than these enzymes, channels through which the famous red-wine ingredient resveratrol appears to exert effects like those of calorie restriction, a reduction of food intake known to slow ageing in many species.

The most basic bone of contention is whether resveratrol really activates sirtuins. The idea that it revs up the enzymes dates from the first study that suggested it has anti-ageing power—a 2003 investigation led by Harvard University’s David Sinclair. Two years later, other researchers published studies suggesting that resveratrol only stimulates sirtuins in misleading test-tube assays—and probably not in living cells. The skeptics’ findings put a cloud over Sinclair’s research and raised questions about work at Sirtris Pharmaceuticals, a biotech he cofounded.

But now Sinclair’s group has marshalled evidence that sirtuin activators really do stimulate the enzymes as originally proposed—at least in certain situations. Their new findings are reported in the March 8 issue of Science in a study coauthored by Sirtris researchers. A second study led by Clemens Steegborn at the University of Bayreuth in Germany, published this week in Aging, supports the Harvard group’s analysis.

Together the studies “appear to elegantly resolve” the mechanism controversy, according to a commentary in Aging by Sita Kugel and Raul Mostoslavsky, researchers at Massachusetts General Hospital in Boston. Mostoslavsky is a member of Sirtris’s scientific advisory board.

The new data won’t end the sirtuins debate, which concerns issues besides the mechanism question—the most hotly contested one is whether sirtuins are centrally involved in calorie restriction’s anti-aging effects. But the studies should restore lost luster to Sinclair’s work on sirtuins. They’re also good news for GlaxoSmithKline, which bought Sirtris in 2008 for a hefty $720 million—the skeptics’ reports had suggested that Glaxo’s effort to develop sirtuin activators as drugs was based on a cracked foundation.

The mechanism debate began after Sinclair and colleagues discovered in 2003 that resveratrol sped up the action of SIR2, a yeast sirtuin thought to mediate calorie restriction’s effects, and of SIRT1, a mammalian version of SIR2, in test-tube assays. Using a fluorescent molecule called Fluor-de-Lys to flag the enzyme’s activity, their experiments indicated that resveratrol interacted with the sirtuins in a way that accelerated their normal function. (SIR2 and SIRT1 regulate the activity of various “substrate” molecules in cells by removing pieces from them called acetyl groups.) The sirtuin stimulation extended yeast cells’ lifespans by up to 60%, according to the report.

But in 2005, skeptics reported that resveratrol failed to boost sirtuins’ action without the presence of Fluor-de-Lys. (Attached to substrates, the fluorescent molecules generated a telltale glow when acetyl groups were removed by sirtuins.) That suggested Fluor-de-Lys inadvertently had played a central role in producing the sirtuin-boosting effect—and that the effect didn’t occur outside the test tube. 
In 2009 and 2010, respectively, researchers at Amgen and Pfizer reported similar findings.

Meanwhile, many studies in living organisms were reported that indicated resveratrol and other sirtuin activators induce calorie-restriction-like effects by stimulating the enzymes. But many observers found them suspect. Indeed, soon after the Pfizer report, a scientist tracking the debate emailed me that it seemed “sirtuins and resveratrol and the entire Sirtris enterprise are a house of cards that is in the process of crumbling badly.”

It appeared to the skeptics that purported sirtuin activators, at most, might indirectly boost the enzymes via unknown knock-on effects in cells. That led many to conclude that Glaxo had made a costly blunder when it bought Sirtris in hopes of turning its compounds into drugs targeting SIRT1 and other sirtuins.

But Sinclair theorized that the fluorescent molecules may have acted a lot like naturally-occurring parts of sirtuin substrates in the test-tube assay. If so, his team’s apparently misleading experiments with Fluor-de-Lys could have pointed, fortuitiously, to a correct conclusion: That resveratrol can rev up sirtuins in living cells.

The new studies support this theory. Both indicated that the fluorescent molecules, which are hydrophobic (repelling water molecules), mimic hydrophobic amino acids found at two locations in certain SIRT1 substrate molecules. In fact, sirtuin activators appear to rev up SIRT1 only when it is interacting with a limited number of substrates that contain hydrophobic molecules at one or both of the two locations.

By a twist of fate, the substrate used by both Sinclair and his critics in their early test-tube experiments lacked the critical hydrophobic amino acids. That’s why resveratrol’s sirtuin-revving effect only occurred, as the skeptics reported, when that substrate was gussied up with Fluor-de-Lys—the fluorescent molecules substituted for the missing hydrophobic amino acids.

Importantly, according to the Sinclair group’s new data, substrates with such amino acids include ones thought to help induce some of calorie restriction’s key health-promoting effects, such as the “stress response,” which hardens cells against damage by DNA-mangling molecules.

In its latest study, Sinclair’s group also went beyond test-tube experiments to probe SIRT1’s action in living cells. This step was based on their discovery that the SIRT1 protein includes a single amino acid that’s critical for the boosting of the enzyme’s activity by resveratrol and other activators—when another amino acid is substituted for it, SIRT1 does its normal enzymatic thing but can’t be artificially revved up.
That enabled a revealing experiment: Sirtuin activators added to cells containing normal SIRT1 were found to enhance the cells’ mitochondrial function in a way reminiscent of calorie restriction’s effect. (Mitochondria, cells’ energy dynamos, are spruced up by calorie restriction.) But when the activators were added to cells whose SIRT1 lacked the critical amino acid, the mitochondrial boost didn’t occur. The results imply that SIRT1 serves as a key channel for inducing the mitochondrial effect, which the Sirtris compounds can amplify in cells.

Besides clearing up the mechanism issue, said Mostoslavsky, the new findings should aid drug development since they’ve illuminated how different sirtuin activators exert selective effects on SIRT1 substrates. That promises to lead to sirtuin-boosting medicines that confer specific therapeutic benefits, with few side effects, by targeting certain SIRT1 substrates and not others.



References:

Hubbard B.P. et al. (2013). Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science, 339, 1216-1219.

Kugel S., Mostoslavsky R. (2013). SIRT1 Activators: The Evidence STACKs Up. Aging, 5.
Lakshminarasimhan M., et al. (2013). SIRT1 activation by resveratrol is substrate sequence-selective. Aging, 5.

Yuan H., Marmorstein R. (2013). Red Wine, Toast of the Town (Again), Science, 339, 1156-1157.
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Thursday, 27 January 2011

Stop, rewind: the scientists slowing the ageing process

reposted from: http://www.bbc.co.uk/news/science-environment-12207953
crabsallover highlights, key points, comments / links.

26 January 2011 Last updated at 09:46

Stop, rewind: the scientists slowing the ageing process

By Neil BowdlerScience reporter, BBC News
woman and childThe ageing process has been linked with many biological mechanisms

Related stories

Scientists are slowly unlocking the secrets of ageing, and some suggest treatments may soon be at hand to slow or even reverse the ageing process.
But what can science really achieve, and what are the dangers of meddling with our biological clocks?
Could such treatments induce cancers in humans, for example, and what about the world's burgeoning population and the West's "pension time bomb"?
Chromosome tips
The ageing process is a complex one, and for long remained an impenetrable mystery, but progress is now being made.
Late last year, a team at the Dana-Farber Cancer Institute in Boston published a Nature paper in which they detailed the reversing of the ageing process in mice.
They targeted the chromosomes that reside within the nuclei of all cells, and specifically telomeres, caps at the tips of chromosomes. The telomeres protect the chromosomes from damage, but also shorten with age, until the cells are no longer able to replicate.

“Start Quote

By understanding the ageing process, we can help combat arthritis, diabetes and heart disease”
Professor Tim SpectorKing's College London
Professor Ronald DePinho and colleagues manipulated the enzyme that regulates these tips - known as telomerase - and witnessed dramatic results. Boost the enzyme, and the mice appeared to rewind the clock.
Click to play
The BBC's Neil Bowdler reports on the science of ageing
"What we were expecting was a slowing or stabilisation of the ageing process," he told the BBC. "Instead we witnessed a dramatic reversal in the signs and symptoms of ageing."
"These animals had their brains increase in size, they improved their cognition, their coat-hair was restored to a healthy sheen and their fertility was also restored."
Of course, this was a story of mice, not men, and applying such principles to humans could be an altogether bigger challenge. Telomerase has been linked with cancer, and there are likely to be many other mechanisms involved in ageing.
Many believe mitochondria may play a bigger role - genetic material contained within the cell but outside the nucleus. Mitochondria are the "power houses" of cells, but have also been seen to generate harmful chemicals linked with aging.
Then there is the role played by free radicals, highly reactive atoms or molecules that attack our bodies. Stem cells, primitive cells which play a key role in renewing the human body, are also likely to be involved.
Anti-ageing drug
But even though a comprehensive picture of how we age is still to be constructed, there are scientists who are already testing anti-ageing treatments on humans.
Chromosome with telomeres at tipsTelomeres (in red) are found at the ends of each chromosome, and shorten with age
Professor David Sinclair also works in Boston at an ageing laboratory at Harvard Medical School. He and his colleagues have been working on synthetic drugs called "Sirtuin activating compounds" or STACs.
Animal studies have indicated STACs can restore the health and life prospects of obese mice and early-stage trials in humans are now underway.
The research follows earlier work on resveratrol, a naturally-occurring ingredient of red wine. Both resveratrol and STACs appear to mimic the effects of restricting calorie intake, which has been seen to slow ageing in animals.
"This isn't going to be an excuse to eat French fries all day and watch TV but is a way to augment your healthy lifestyle and give you the ultimate benefits of perfect health which your body is capable of," Professor Sinclair told the BBC.
"It doesn't change food intake - the mice eat just normally or they get fatter, but their body doesn't seem to know they're fat and their organs and even their longevity is as good as a really healthy mouse."
But should we be experimenting with something so fundamental as ageing in the first place? And what of the ethical issues?
Professor Tim Spector of King's College London, who also works on the ageing process, says the focus is not on extending life, but on extending good health.
"If it means by living a long time you're crippled by arthritis and can't get out of the house that's not much use to anyone."
"But by understanding the ageing process, we can help combat arthritis, diabetes, heart disease, all these things which are age-related."
Professor James Goodwin, head of research at Age UK, believes access will quickly emerge as a key issue, should effective anti-ageing medical treatments be developed.
"Will everybody be able to get this technology which will give them a longer healthier life, or will it be restricted to the rich and wealthy?" he asks.
"Or how will the poorer countries regard the richer countries of the world where everyone is living well and living longer?"


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Saturday, 22 January 2011

Charlie Rose - Calorie Restriction

reposted from:
crabsallover highlights, key points, comments / links.




Part 2


Part 3

- monkeys on CR (30% calorie reduction) have reduced type 2 diabetes, reduced colon cancer, body fat reduced by 70%, 55 genes involved in inflamation have lowered expression

Part 4

- humans on CR have reduced heart disease
- nematode worms live 2 weeks
- resveratrol effects activity of sirtuins (anti-ageing genes)

Part 5

- polyphenols
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Sunday, 12 December 2010

Could the secret to a longer, healthier life lie in popping a little pill every day?

reposted from: http://www.thetimes.co.uk/tto/health/article2839553.ece

Could the secret to a longer, healthier life really lie in popping a little pill every day? The news this week that taking low-dose aspirin could cut your risk of cancer by a quarter will send plenty of us rushing to the chemist.

Indeed, we are rapidly entering an era where everyone is taking some kind of preventive drug or supplement every day. For drug companies, the potential profits from preventive pills are huge; healthy people make far more sustainable customers than seriously ill ones.

But none of these pills is without its side-effects, and some of these can be serious. It is up to each of us to weigh the risks and benefits.
Aspirin 
This week an Oxford University study revealed that a 75mg aspirin tablet a day substantially cuts death rates from common cancers. The Lancet study found that people taking it had a 25 per cent lower risk of death from cancer and a 10 per cent reduction in death from any cause, compared with patients who were not given the drug. Aspirin is already known to cut the risk of heart attack and stroke among those at increased risk. Professor Peter Rothwell, the lead researcher, is not urging healthy middle-aged adults to start taking aspirin immediately, but he says that the evidence on cancer “tips things towards it being well worth it”. His reticence is due to aspirin’s main side-effect, stomach bleeding.

A British study last year found that daily aspirin can increase the risk of dangerous internal bleeding by a third. It can also cause haemorrhagic strokes.

The complication rate means that if aspirin were submitted today as a new drug to clinical trials, it would fail. Some experts suggest that taking aspirin with milk reduces stomach irritation. Others, such as the scientists behind a review in the Drug and Therapeutics Bulletin, say the drawbacks may outweigh the benefits.

Cod liver oil 
Cod liver oil has been revived in the past decade as a one-a-day golden wonder for healthy hearts, supple joints and sparky brains. Critics have suggested recently that there is a dearth of large-scale study evidence to support this. But in September, doctors at Imperial College London and the Royal Brompton Hospital in London, studied nearly 7,000 people with chronic heart failure and found that 1g of fish oil capsules a day cut the death rate by 9 per cent. Hospital admissions also fell.

A recent study by the University of California may help to explain why: omega-3 fatty acids in the oil switch on receptors in blood that prevent harmful inflammation in the heart and arteries. There are worries about harmful mercury contamination, particularly for pregnant women.

But Dr Jeremy Pearson, of the British Heart Foundation, says: “If people feel they can tolerate fish oil, I don’t think there is any suggestion that they might be doing themselves harm.”

Vitamins 
We spent £398 million on vitamins last year, but there is alarmingly little medical research on them. Most studies say they are of little or no use, especially if you have a normal healthy diet. Some multivitamin supplements can even be dangerous. For example, Swedish researchers warn that an overdose of multivitamins increases the risk of breast cancer.

However, vitamin D shines through. It is essential for healthy bones and to protect against a range of diseases including cancer, heart disease, diabetes and multiple sclerosis. With most of us leading increasingly indoor lives, increasing numbers of us are becoming deficient.

For pregnant mothers, the balance of evidence indicates that taking a multivitamin may benefit their babies. A study in the Clinical Pharmacology & Therapeutics journal found a reduced risk for paediatric brain tumours, neuroblastoma, and leukaemia, though it’s not known why.

Statins 
Statins lower cholesterol levels and have been hailed as wonder drugs. A Lancet study last year said that daily statins cut the risk of strokes by about a fifth. They have also been shown to prevent arteries ageing prematurely. Statins may also protect against arthritis and help the body to combat serious infections by activating bacteria-killing white blood cells.

Such is their promise that more than five million people take them. They were developed for people with high cholesterol, but drug industry-backed research recently concluded that they lower the death risk for everyone, even those with low cholesterol. One British cardiac consultant even said that they should be put in the water supply. This has sparked a huge academic row over accusations of research hype.

Certainly statins can have side-effects, including muscle problems, sexual dysfunction, serious depression, sleep disturbance and memory loss. Critics also fear that people wrongfully believe that statins can enable them to carry on overeating and under-exercising.

Sex hormones 
Some studies estimate that hormone replacement therapy (HRT) extends life by three years because it cuts the risk of heart attack in women by 50 per cent. It also helps to beat osteoporosis. But in 2001 a large study in America showed that HRT considerably increases the risk of breast cancer. After that, use of HRT halved in Britain, to below 20 per cent of menopausal women. But it still has its proponents. Last month Durham University researchers reported that HRT can rejuvenate the brains of women in their fifties and sixties. The general expert consensus is that HRT remains an effective short-term treatment for menopausal symptoms.

The polypill 
The idea of a single pill that wraps up the life-saving benefits of several other preventive drugs was mooted in 2003. Now scientists at Imperial College London are beginning a worldwide trial on it. The two-year trial tests a cheap pill that contains low-dose aspirin, a statin and two drugs to lower blood pressure. The test will see if it can cut heart attacks and strokes in 2,000 people who are thought to be at risk. A trial of one formulation has already proved disappointing at lowering blood pressure. And there is always a chance that a polypill might combine all the bad side-effects with few of the benefits. But researchers hope that within a few years they will have a proven, low-cost formula that millions will be taking every day.

Holy grail 
The ultimate goal of researchers is to find a natural substance (after all aspirin comes from willow bark) that has no side-effects but protects against a primary cause of disease — ageing cells. Scientists thought they had got it in resveratrol, found in grape skins and red wine. Early tests indicated that it may act as a serum of cellular youth, preventing Alzheimer’s in mice. GlaxoSmithKline bought the patent off its developers, then trialled it on cancer patients. But it caused kidney damage and the trial had to be stopped earlier this year. GlaxoSmithKline says it won’t do any further trials.

Never mind, say the seekers of medicine’s ultimate one-a-day holy grail — there are many more natural candidates to try.
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Sunday, 10 October 2010

Is science on the brink of creating the elixir of life?

reposted from: Daily Mail

Is science on the brink of creating the elixir of life?

By MICHAEL HANLON Last updated at 5:00 AM on 9th October 2010

Once I had a very odd dinner with an elderly and distinguished scientist who told me how he planned to live for ever - or at least for a very long time indeed. We ate in his beautiful house by the sea in California. Our meal consisted of one bowl of rice each and a glass of water. With this extreme diet, my host said - limiting himself to 800-1,000 calories a day (the average male is recommended to consume 2,500) - he hoped to stave off death for many more decades.

Such a regime was based on the well-established theory that by reducing calorie intake, people can dramatically increase their lifespans. This had been shown, after numerous scientific investigations, to work in animals from fruit flies to mice. Professor Roy Walford, a biologist at UCLA, was 74 years of age when I met him. He had no doubt that extreme calorie restriction would work in people, too. However, despite his punishing diet, he was to die five years later from the auto-immune disorder Lou Gehrig’s disease. Seventy-nine years was a little better than the three score years and ten which have been approximated as the human lot since Biblical times - but his innings only matched the average lifespan for an educated, middle-class white California male of his generation. It is tempting, then, in the light of this story, to write off the theory that by eating the bare minimum we can slow the ageing process. But it seems Professor Walford was probably on to something, even if the fates conspired to ensure that he personally did not benefit from his diet thesis.

For there is a growing scientific consensus that ageing - against which humanity has been battling for millennia - might not be inevitable.


Of course, the quest for eternal youth has been led by charlatans, frauds and snake-oil salesmen through the ages. There is money to be made by promising the Holy Grail - as the questionable claims on the labels of countless anti-ageing beauty products will attest. For centuries, lotions and potions have been touted as elixirs of longevity. These have ranged from products containing monkey glands to injections of minced dog testicles. Unsurprisingly, all have failed. Still, the search continues.

We have been told that exercise, red wine, chocolate, Vitamin C and various cocktails of antioxidants are the answers. The latest elixir claim comes from scientists in Italy, who announced this week that mice given dietary supplements rich in three amino acids (similar to the concoctions favoured by human bodybuilders) lived on average 12 per cent longer than mice fed on ordinary food (see: ScienceLongLife). For humans, this would mean about an extra ten years of life. And yet the world still awaits its first 125-year-old. The record stands at 122 years - achieved by Frenchwoman Jeanne Calment, who died in 1997. But the truth is, charlatans apart, the ageing process may be more amenable to change than was thought.

For a start, life expectancy (the number of years a newborn is predicted to live) is increasing by five hours a day in Britain. This means a baby born in five years’ time should live a year longer than a baby born today. This is, for the most part, simply a result of better healthcare. For evidence we need only look at the first big jump in life expectancy, which took place in the 19th century when infant mortality rates dropped because of improved diets, better medicine and proper sanitation. We haven’t conquered age, it’s just that more and more of us are living to our full potential. But we may now be nearing a surprising breakthrough.

According to a new book, The Youth Pill, by health journalist David Stipp (Amazon.co.uk) with a selection of reviews on his book at DavidStipp.com, in a few decades a number of pills may be available, which will help delay the onset of most serious illnesses by up to ten years. This would give us at least five extra years of healthy old age and allow the 122-year barrier to be breached.

Until recently, those scientists working on increasing the longevity of fruit flies or mice have shied away from making claims that humans could benefit from their work on genetics. But now, as Stipp points out, this attitude seems to be changing; more and more experts now say that human lifespan can be increased - and what’s more, they agree that it would be a good idea.

How we grew old, and why, was a mystery until recently. It was commonly supposed that our bodies simply wore out, like machines. But this wasn’t a good analogy. Unlike most machines, our bodies are equipped with efficient repair systems that keep our cells healthy for decades. In fact, we do not really start to ‘age’ at all until we are into our 20s. So, discovering why these mechanisms stop working as we enter middle and old-age is the key to understanding the ageing process. Ageing is, after all, not entirely inevitable. Several organisms appear to hardly age at all and live for centuries.

Humans are among the longest-lived of all species, but our longevity is exceeded by some giant tortoises which can live for nearly 200 years. Bowhead whales have recently been found, alive and well, with antique harpoons embedded in their skulls which can be dated back to the 1790s. Some of these animals may be more than 300 years old. There is a pattern in all this. Big creatures tend to live longer than small ones. Anything that can fly or swim tends to live longer than animals stuck on the ground. Understanding these differences gives us our first clue as to how ageing works - and to what might be done to delay it.

The evolutionary theory of ageing states that animals age at a rate commensurate to their likely survival time in the wild. Mice age quickly because - being small and feeble - they are likely to be eaten, starve or perish due to cold before too long. Evolution has given the mouse a body that literally lives fast and dies young. It’s full of sex hormones turbocharging its chances of reproducing before it is eaten by predators. It makes little sense for a mouse to be equipped with, say, anti-cancer mechanisms, if the chances are that it will be an owl or cat’s dinner within a year or two.

On the other hand, elephants age slowly because, being big, they are hard to kill. It takes a long time for them to die of starvation and they cope well when times get tough. So elephant bodies have evolved complex DNA repair systems which can keep them going for half a century or more.

Birds also live a long time because, although small, they can fly and thus avoid predators. Bats live longer than mice for the same reason, and porcupines and tortoises are long-lived simply because they make a difficult meal. In each case, their bodies age slowly to make the most of their potential life spans. Still, knowing why we age tells us little about how we age - and even less about what we might be able to do about it. There is growing evidence, however, that the very hormones that enable us to reproduce - those which produce eggs and sperm - may in themselves contribute to the ageing process. ‘Death,’ said one biologist, ‘is the price we pay for sex.’

Advances in DNA analysis - reading the entire genetic codes of organisms - have opened up exciting new areas in ageing research, allowing scientists to pinpoint individual genes which may be be responsible for the breakdown in our bodies over time. Yet the reality is that many of the resulting ‘breakthroughs’ have proved to be dead ends. For decades, ‘free radicals’ (waste chemicals produced by our bodies as by-products of respiration, digestion and the action of muscles) have been suggested as possible drivers of the ageing process.

Big creatures tend to live longer than small ones. Anything that can fly or swim tends to live longer than animals on the ground.

Some scientists have claimed that we should take large quantities of free-radical neutralisers called antioxidants (which include Vitamin C and are best found in fruit and vegetables). Yet Vitamin C, it turns out, may actually increase free-radical damage and very large doses can interfere with the body’s natural repair mechanisms.

It is such contradictions that have led researchers to focus, instead, on calorific restriction. Mice placed on near-starvation diets have seen their life expectancies increase 20-35 per cent. If such results were achievable in humans, the average Briton’s life expectancy would rise to almost 100 - with the potential to carry on to 150. This is precisely what Professor Roy Walford was trying to achieve with his grimly tedious rice and water diet in California. And the truth is that research into whether calorie restriction will greatly extend our lifespans would take decades to reach firm conclusions - simply because we are so much larger than mice.

Even so, research on rodents has uncovered how extreme calorie restriction appears to switch on a genetic mechanism called a stress response. This has evolved to allow animals to survive tough conditions (such as a very hard winter when little food is available). It seems the bodies of mice - and possibly those of humans, too - react to starvation by boosting their repair mechanisms, triggering anti-inflammatory responses which slow the damage done to vital organs as they age.

The problem for humans is that near-starvation is unlikely to catch on. What people are much more likely to turn to are drugs which mimic the effects of extreme calorie restriction, without having to live on lettuce. And such drugs may soon be available. One could be based on the chemical resveratrol which is a plant compound found in red wine. In 2006, Harvard scientist David Sinclair found that this could activate a stress-response gene called Sir2 in mice which extended their lives.

Vast fortunes are being spent by the big drug firms on anti-ageing drugs

The happy fact that the elixir of youth is found in wine was suggested as the possible reason why the French, who eat a lot of supposedly unhealthy meat and cheese, smoke too much and drink a lot of alcohol, have one of the world’s highest life expectancies.

Then, last year, three teams of researchers in the U.S. reported that another chemical which mimics the effects of starvation, called rapamycin, makes mice live longer by suppressing the onset of cancer. The chemical was isolated from a fungus found on Easter Island in the Pacific. Unsurprisingly, the big drug firms are trying to exploit these discoveries. Vast fortunes are being spent on anti-ageing drugs which mimic calorie restriction. The problem, sceptics point out, is that the ageing mechanism in rodents may be quite different to the one in humans.

Therefore, resveratrol and similar chemicals may not prove to be the answer (the same may be true of the Mr Universe protein supplements trumpeted this week). But the likelihood is that, in a few years, pills will be developed that will be able chemically to copy the effects of a near-starvation diet and that may well increase lifespan in humans.

If this happens, what would a world of 130-year-olds be like? Of course, there is a big difference between being a healthy 130-year-old and someone who has spent the last 40 years of their life suffering from dementia. So what about the anti-ageing pioneer Roy Walford? Ironically, his death was caused by a rare disease that is exacerbated, not ameliorated, by a low-calorie diet. But if he was right, then by helping publicise what was once an obscure field of scientific research, his last, hungry years by the Pacific may not have been in vain.
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Saturday, 9 October 2010

Eat less, live longer? Or Just eat less protein or methionine (become a Vegan) and live longer?

reposted from: New Scientist


IN GREEK mythology, the tale of the Trojan prince Tithonus is a tragic one. His lover, the goddess Eos, asks Zeus to grant him eternal life, but forgets to specify eternal youth. Time passes, and while the goddess of dawn stays young and beautiful, Tithonus degenerates into bedridden senility. Eventually Eos shuts him in a chamber of her celestial palace, where his feeble voice can be heard begging for death.
Dreams of eternal youth feature in many cultures throughout history, but it was only in the 20th century that research into longevity really began. Much about ageing is still mysterious - we don't even know the underlying reasons why we journey into old age. There are many lines of enquiry into how to live longer, though, with one of the most intriguing being calorie restriction: in effect, going on a lifelong diet.
Calorie restriction dramatically extends not only the lifespan of laboratory animals, but also their "healthspan" - how long they live free of disease. On the assumption that it has the same effect in people, some individuals have already adopted a restricted diet. The latest evidence suggests that while calorie restriction is indeed beneficial for humans, when it comes to lifespan extension, it may not be the whole story.
The good news is that we might be able to delay ageing without cutting our food intake. "There's a definite possibility that if you balance the diet correctly, a longer lifespan can be achieved without full food restriction," says Matthew Piper, a researcher into ageing at University College London.
There is a definite possibility that if you balance the diet correctly, a longer lifespan can be achieved without full-on food restriction
Interest in calorie restriction began in 1935, when scientists made the surprising discovery that rats on a reduced-calorie diet lived longer, provided they were supplemented with sufficient vitamins and minerals. The idea sounds counter-intuitive; after all, a state of starvation is not usually conducive to health. But there seems to be a window of benefit. While lifespan is reduced if calories are cut too drastically, it can be extended by cutting them moderately (see graph).

Calorie restriction has since been shown to extend the lives of other organisms including yeast, nematode worms, fruit flies and mice. Mice, for example, live up to 50 per cent longer if their calorie intake is cut by 30 to 50 per cent. What's more, mammals are protected from a number of age-associated maladies such as cancer, heart disease, type 2 diabetes and Alzheimer's disease.
It is unclear why eating less should make animals live longer. While a restricted diet triggers numerous changes at the molecular and genetic levels, only some of these are common across all the species tested. 
However, there does seem to be a general principle that a dearth of nutrients causes organisms to divert resources away from growth and reproduction and towards basic survival functions. From an evolutionary perspective, these adaptations could help an organism survive famine.

Longevity pioneers

The million-dollar question is whether calorie restriction has a similar effect in people. Humans are longer-lived and clearly harder to study than flies or mice, but recently two sources of evidence have hinted that it does.
The first comes from a 20-year study of rhesus macaques, a species obviously closer to humans than worms and mice. When the macaques were about 10 years old, equivalent to young adulthood in humans, half the group were placed on a diet in which they received 30 per cent fewer calories than the others. While none has yet beaten the record for the longest-lived macaque in captivity (about 40 years), the latest results, reported last year, look promising. 
About 80 per cent of the calorie-restricted monkeys were still alive when the study was published, beating the control group's survival rate of 50 per cent. And the dieting animals were one-third less likely to have died from an age-related disease (Science, vol 325, p 201).

The second strand of evidence comes from studying people who are practising calorie restriction. The first enthusiasts banded together through an email forum in the early 1990s. The group has since evolved into the Calorie Restriction Society International, which now has over 3000 members who refer to themselves as "CRONies", short for Calorie Restriction with Optimal Nutrition.
Needless to say, this lifestyle is not for everyone. Some people report struggling with hunger pangs, and the society warns on its website that side effects can include feeling cold, poor wound-healing and temporary infertility. But many CRONies insist that hunger is not a big problem and that they actually feel happier and healthier on their frugal diet (see "A day in the life of a CRONie").
CRONies typically cut calories by 10 to 30 per cent of the recommended intake, and most hover around the lower limit of "normal" body mass index, at 18.5 kilograms per height-in-metres squared. 

To ensure they get all the nutrients they need without busting their calorie quota, their diet is mainly vegetable-based and must be carefully planned, often with the help of a computer program. "People think calorie restriction involves tiny portions, but these people are eating huge amounts of low-calorie, nutrient-dense food," says Luigi Fontana, a professor of medicine at Washington University in St Louis and head of the Division of Nutrition and Aging at the Italian National Institute of Health, who has studied CRONies for the past eight years.
As with the macaques, it is too soon to tell if calorie restriction extends lifespan. The oldest people in Fontana's studies are only in their 70s - the average life expectancy for Americans. But there is evidence suggesting that it extends healthspan. In 2007, Fontana showed that CRONies have optimal metabolic profiles, and low blood pressure and cholesterol levels (Experimental Gerontology, vol 42, p 709). "They have hearts that are 15 years younger than those of typical Americans their age," he says.
So far, so good. But Fontana has found a notable difference in the way people and animals respond to calorie restriction, and it is not great news. It involves a hormone made by the liver called insulin-like growth factor 1.
IGF-1 (wikipedia) has emerged as an important promoter of ageing. IGF-1 levels are lower than normal in worms, flies and mice on a restricted diet, and this is thought to be at least partly responsible for their longer lifespan. When it comes to people, however, CRONies have the same IGF-1 levels as the rest of us.
The explanation for this anomaly may lie in a new theory about how diet affects ageing. This says that it may not only be the drop in calories that is responsible for lifespan extension - in some species at least, perhaps it is also the accompanying drop in dietary protein.
One piece of evidence for this idea comes from studies in fruit flies and rodents. If these animals are fed special diets with less amino acids - the building blocks of proteins - they can eat as many calories as they want and still live longer. "These results clearly show that you don't need to restrict calories as a whole to get lifespan extension," says Piper, an author of the study on flies (Nature, vol 462, p 1061).
Further support for this idea comes from studying the molecular pathways inside cells that affect lifespan. A molecule called TOR (TOR in wikipedia) has been found to set off a chain of reactions that boost cell growth at the expense of longevity. Blocking TOR increases lifespan in all organisms studied to date, including yeast and mice (Aging Cell, vol 9, p 105). Crucially, the most potent activators of TOR are amino acids.
Where does the protein theory leave the CRONies? Fontana noticed that the people in his study group were eating high levels of protein, about 1.7 grams per kilogram of body weight per day. This is more than the US government-recommended intake of 0.8 g/kg/day, and higher than that in a typical American's diet, about 1.2 g/kg/day.

Accelerated ageing

So Fontana asked six CRONies to cut their protein intake to 0.95 g/kg/day while maintaining their usual calorie intake. After only three weeks on the low-protein diet, the CRONies showed a 25 per cent drop in their levels of IGF-1 (Aging Cell, vol 7, p 681). "Even if the CRONies are restricting their calories severely, if they're eating a high-protein diet, they're probably negating some of the most important beneficial effects," says Fontana.
If the new theory is right, then the whole concept of calorie restriction needs to be rethought. The very term would be misleading; Fontana and others have started referring to dietary restriction instead. As news of the study has spread, some CRONies have already reduced their protein intake.
The protein theory is bad news for people on low-carbohydrate weight-loss plans like the Atkins diet. "I'd be wary of diets that put a heavy emphasis on protein," says Piper. "It's hard to see how that could be healthy." Fontana goes one step further, saying that high-protein diets could risk accelerated ageing and cancer.
It's good news, however, for people already on low-protein diets, like vegans, who avoid eating meat, eggs and dairy products. In 2007, Fontana showed that vegans have lower levels of IGF-1 than meat-eaters (Rejuvenation Research, vol 10, p 225).
There may be another reason for vegans to celebrate. Studies on flies and rodents suggest that cutting intake of one particular amino acid, called methionine, lengthens life to a similar degree as calorie restriction. Proteins in meat and other animal products have high levels of methionine, so a vegan diet would score well by that measure, too (Medical Hypotheses, vol 72, p 125).
If calorie restriction would be hard for most people, calorie and protein restriction would be doubly so. Those determined to live to 130 may want to give it a shot, but for the rest of us, simply sticking to recommended dietary protein levels could have benefits for both lifespan and healthspan. "Protein restriction is much less difficult to maintain than [calorie] restriction and may be more powerful in reducing IGF-1 in humans," Fontana said in a recent review (Science, vol 328, p 321).
For those who don't fancy changing their diet, a more tempting prospect is a pill that replicates the effects without the hard work. Drug firms have taken a keen interest in trying to find such calorie-restriction mimetics, as they are sometimes called.
A decade ago the main focus was on signalling molecules called sirtuins (wikipedia) that reduce the expression of several ageing-related genes. Reports that resveratrol (wikipedia), a compound found in red wine, extended lifespan in some species by activating sirtuins boosted sales of red wine and resveratrol supplements. Resveratrol still has supporters, but inconsistent animal data have since dampened much of the enthusiasm.
The focus has lately switched to finding compounds that block TOR. One such agent is a drug called rapamycin (wikipedia), an immunosuppressant given to recipients of organ transplants. Last year rapamycin was found to extend the lifespan of mice, even in those started on the drug in later life, equivalent to 60-year-old humans (Nature, vol 460, p 392). However, because people don't live in a sanitised lab environment, rapamycin's strong immunosuppressive effects make it an unlikely candidate for a practical anti-ageing drug. Similar compounds that are less toxic would be more promising.
Another candidate is a drug called metformin (wikipedia), already used to treat type 2 diabetes. Metformin also blocks TOR, and lengthens lifespan in worms and mice (Cell Metabolism, vol 11, p 390). Does metformin slow ageing in people too? Studies published earlier this year suggest that diabetics taking metformin do get less cancer (Diabetes Care, vol 33, p 322). "The major risk factor for cancer, above all others, is ageing," says David Gems at University College London. He calls the studies a "smoking gun of a more generalised effect of metformin on ageing, rather than just strictly diabetes".
While metformin is less toxic than rapamycin, it, too, can have side effects, such as nausea and diarrhoea. So researchers may have a way to go before they find the perfect longevity pill.
And it would be premature to consider the case proven for the protein theory of lifespan extension. Even Fontana acknowledges there may be other nutrients that play a role, such as fatty acids or cholesterol. Others have speculated that it may be the ratio of calories to protein that is key.
In the meantime, the best bet for warding off ageing and disease could still be the time-honoured advice to eat your greens. Perhaps if vegetables had been the food of the gods, Tithonus could have enjoyed a few more quality years with Eos.

A day in the life of a CRONie

Paige Collins-Rideout, a 39-year-old medical transcriptionist in Blue Ridge, Georgia, does not look like she needs to diet, but that is exactly what she is doing. Collins-Rideout is a CRONie (which stands for Calorie Restriction with Optimal Nutrition), a member of a group who believe that eating a carefully controlled diet with 10 to 30 per cent fewer calories than recommended is key to a longer, healthier life.
For the past year-and-a-half, Collins-Rideout has been limiting her food intake to 1500 calories per day. At 1.7 metres (5 feet, 6 inches) tall, she weighs only 50 kilograms (110 pounds = 7st 12 pounds).
Vitamin-rich foods such as sweet potatoes, broccoli, spinach, eggs and whole grains are staples of Collins-Rideout's diet. Perhaps surprisingly, she says she is rarely hungry, although she admits to occasionally succumbing to unhealthy snacks like fried jalapeños. "Once in a great while I'll have something like that," she says. "Then I'm ready to go back to healthy eating."
There are downsides. Because it is hard to get the recommended levels of vitamins and minerals without supplements, which CRONies generally avoid, calorie restrictors often invest a great deal of time in planning and tracking their diet. To avoid becoming too underweight, Collins-Rideout has also cut back on her running - she used to jog 5 kilometres per day. She also says that social eating can be difficult.
But she says benefits of her diet include improved mood, sleep, mental clarity and memory. She has no desire to live to be 100, though. "My goal is to slow the ageing process so that when I get to retirement, I'll have the energy and vitality to actually live," she says. "I can't imagine going back to any other way of life."
Laura Cassiday is a science journalist based in Denver, Colorado
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