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

New drug being developed using compound found in red wine 'could help humans live until they are 150'. Daily Mail, March 10 2013

Cheers! Red wine pills will beat killer diseases. Daily Express, March 8 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

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.

Worm lifespan doubled - Cynthia Kenyon

reposted from: http://www.facebook.com/ajax/sharer/?s=99&appid=2309869772&p%5B0%5D=680125715&p%5B1%5D=239216616142237

Refs: Unlocking the Secrets of Longevity Genes; March 2006; Scientific American Magazine; by David A. Sinclair and Lenny Guarente; 8 page(s)

crabsallover highlights, key points, comments / links.

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.

The new biology of ageing

reposted from: Royal Society by Linda Partridge
doi:10.1098/rstb.2009.0222Phil. Trans. R. Soc. B 12 January 2010 vol. 365 no. 1537 147-154

Abstract

Human life expectancy in developed countries has increased steadily for over 150 years, through improvements in public health and lifestyle. More people are hence living long enough to suffer age-related loss of function and disease, and there is a need to improve the health of older people. Ageing is a complex process of damage accumulation, and has been viewed as experimentally and medically intractable. This view has been reinforced by the realization that ageing is a disadvantageous trait that evolves as a side effect of mutation accumulation or a benefit to the young, because of the decline in the force of natural selection at later ages.

However, important recent discoveries are that mutations in single genes can extend lifespan of laboratory model organisms and that the mechanisms involved are conserved across large evolutionary distances, including to mammals. These mutations keep the animals functional and pathology-free to later ages, and they can protect against specific ageing-related diseases, including neurodegenerative disease and cancer. Preliminary indications suggest that these new findings from the laboratory may well also apply to humans. 

Translating these discoveries into medical treatments poses new challenges, including changing clinical thinking towards broad-spectrum, preventative medicine and finding novel routes to drug development.

• ageing
 
• lifespan
 
• ageing-related disease
 
• geriatrics
• preventative medicine
 
• nutrient-sensing pathways

Previous SectionNext Section

1. Introduction

The increase in life expectancy in human populations worldwide is a triumph of biomedical research. Survival rates started to increase in the mid-nineteenth century, because of improvements in public health, particularly clean water, immunization and antibiotics, and also because of other improvements in lifestyle such as better housing. The rate of increase in life expectancy in most countries does not yet show any sign of slowing and, indeed, is greatest in older age classes; we cannot yet see what any intrinsic limit to human life expectancy will be (Wilmoth 2000; Oeppen & Vaupel 2002).

For a given age, health now is better than it was 150 years ago, but this welcome change is also producing great challenges. Many of these are socio-economic, concerning issues such as work force participation and affordability of pension schemes. Paradoxically, there is also a major medical problem. The improvement in individual health means that larger numbers of individuals reach older ages, and hence live long enough to suffer from ageing-related disease and loss of function. All of the major killer diseases, including cardiovascular disease, cancer and dementia, are strongly age related. The predominant burden of ill-health is now falling on the older section of the population and, both for health benefits to ageing individuals and economic benefits to the societies in which they live, we urgently need to discover means of improving health during ageing. Fortunately, major scientific opportunities have opened up in research into ageing and bring with them the enticing prospect of a broad-spectrum, preventative, medicine for diseases of ageing. However, taking the fruits of these scientific discoveries to the ageing human population may not be straightforward.

From the biological standpoint, the major features of ageing are an intrinsic decline in function during adulthood, leading to a drop in fecundity and increased likelihood of death (Finch 1990). Ageing is not inevitable and, indeed, some organisms seem not to age at all or to do so very slowly. Some even show an increase in fecundity or survival rate over at least part of adulthood.

Ageing is particularly apparent in organisms where growth is completed before reproduction commences, such as insects, birds and many mammals, including humans (Vaupel et al. 2004; Baudisch 2005). The major laboratory model organisms used for research into ageing, namely budding yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans, the fruitfly Drosophila melanogaster and the mouse Mus musculus, all fall into this category and, in this sense at least, are good models for human ageing.

The phenotypes associated with ageing have been best studied in humans and are complex (Martin 2002). Within single tissues, multiple types of damage and pathology increase in incidence with age, and the spectrum of changes differs between tissues. The precise phenotypes of ageing are also notably variable between individuals (Finch & Kirkwood 1999). This complexity and variability have led to a picture of the ageing process as intractable, for both experimental analysis and medical intervention. Indeed, it could be concluded that there is no single ageing process; rather, during ageing, a large number of independent and stochastic processes of damage accumulation occur in parallel, with little or no common causality. Amelioration of the impact of one type of ageing-related damage would, if this scenario is correct, leave the majority unaffected and would hence have little impact on overall ageing-related decline. This view of ageing permeates medicine to the present day.

Geriatrics is largely a primary care medical speciality, with little input from basic and clinical research, unlike specific ageing-related diseases such as cancer, cardiovascular disease and neurodegeneration, which are all associated with sizeable and well-funded research communities. Specific diseases of ageing are generally viewed as medically tractable, unlike the ageing process itself.

The idea that ageing is difficult to modify has until recently been reinforced by work on its evolution. Evolutionary biologists have long been intrigued by ageing, because it is a deleterious trait, but it nonetheless shows great diversity in the natural world. After various ideas of a possible benefit of ageing to family groups or whole species were largely discredited (Kirkwood & Cremer 1982), the key insight came with the realization that, because of extrinsic causes of mortality such as disease, predation and accidents, the force of natural selection weakens for older age classes, because fewer individuals succeed in reaching them (Haldane 1941; Medawar 1946, 1952). A substantial body of theoretical analysis, experimentation and comparative work led to the conclusion that ageing can hence evolve as a side effect, either of pressure of new mutations that reduce fecundity or survival probability later in life or of mutations that have beneficial effects in the young (Medawar 1952; Williams 1957; Hamilton 1966; Hughes & Reynolds 2005; Partridge & Gems 2006; Moorad & Promislow 2008). As far as we know, no genes have evolved to cause ageing. Unlike development, there is no well-oiled hierarchy of genetic regulation to ensure that ageing happens in the right tissues and at the right times. Instead, it is an unregulated side effect of the failure of natural selection to maintain function at the later ages that few individuals reach in nature (Partridge & Gems 2002a). These theoretical and practical insights have led to the conclusion that ageing is likely to be a highly polygenic trait, since many genes are involved in assurance of survival during adulthood and in promoting fecundity.

The complexity of the ageing phenotype and the realization that it is an evolutionary side effect, rather than an adaptive process, led to the widespread assumption that mutations in single genes were unlikely to be capable of slowing down ageing. Furthermore, it seemed improbable that mechanisms of ageing would be the same in different kinds of organisms. If different human tissues acquire such different forms of damage and pathology during ageing, presumably as a result of the different types of insults of daily living that they encounter then, by the same token, organisms with very different life styles would be expected to encounter different sources of damage (Partridge & Gems 2002b).

Previous SectionNext Section

2. Single-gene mutations that extend the lifespan of laboratory animals

Perhaps the single most important advance in ageing research in recent years has been discovery of mutations in single genes that extend the lifespan of laboratory animals. 

They first came to light as a result of a systematic chemical mutagenesis screen for lifespan-extending mutations in C. elegans (Klass 1983). Subsequent work with these mutations (Friedman & Johnson 1988), and further screening (Kenyon et al. 1993), revealed that it was possible to double the lifespan of the worm with a mutation in a single gene. Furthermore, rather than solely prolonging the moribund period at the end of the life, the mutations caused the worms to remain healthy and youthful for longer (Kenyon et al. 1993).

The mutated genes were discovered to encode components of an invertebrate insulin/insulin-like growth-factor-like signalling (IIS) pathway (Kimura et al. 1997; Lin et al. 1997; Ogg et al. 1997). 

These findings came as a considerable surprise, because a signalling pathway previously associated with control of growth and metabolism in mammals now turned out to play a role in determination of lifespan in a distantly related invertebrate.

Mutations with similar effects on lifespan were soon discovered in other model organisms. For instance, a similar screening effort in yeast led to the discovery that over-expression of a protein deacetylase, SIR2, extended replicative lifespan (Sinclair & Guarente 1997; Kaeberlein et al. 1999), while mutations in methuselah in Drosophila increased fly lifespan (Lin Seroude & Benzer 1998). Likewise, in the mouse, mutations in genes encoding transcription factors involved in the development of the pituitary gland resulted in long-lived dwarf mice (Brown-Borg et al. 1996). 

By the late 1990s, it was firmly established that lifespan of these model organisms could indeed be extended by mutations in single genes.

It had also been known since the 1930s that an environmental intervention, dietary restriction (DR), could produce substantial increases in lifespan in laboratory rodents (McCay et al. 1935). Although the exact mechanisms at work still await full elucidation, detailed study of DR rodents has demonstrated a broad-spectrum improvement in health and a delay in or amelioration of the impact of a wide range of ageing-related diseases (Masoro 2005, 2006). For instance, the animals are protected against cancer, cataract, diabetes, motor decline, osteoporosis and nephropathy (Weindruch & Walford 1988). These findings suggested that, in principle, multiple aspects of the ageing phenotype could be simultaneously ameliorated by a single intervention, albeit, in the case of DR, a complex one.

Previous SectionNext Section

3. Evolutionary conservation

The ultimate aim of biomedical research into ageing with animals is to improve the health of the older section of human populations. Laboratory model organisms have been key to understanding many other aspects of human biology. Embryonic development, the cell cycle, the functioning of the nervous system, cellular metabolism and many other processes have often been investigated by proceeding from simpler organisms to more complex ones. This process works because of evolutionary conservation of genes and their functions over the large evolutionary distances involved. Indeed, it is often possible to introduce a human gene into yeast or Drosophila and find that it functions quite normally there. However, because ageing is not an adaptive trait and because different kinds of organisms are exposed to different kinds of stress and damage, there has been a good reason to doubt that this kind of evolutionary conservation will apply to the ageing process.

DR extends lifespan not only in rodents but also in a wide range of distantly related organisms, including yeast (Jiang et al. 2000; Lin et al. 2000), C. elegans (Klass 1977; Lakowski & Hekimi 1998; Greer et al. 2007; Kennedy et al. 2007; Smith et al. 2008a) and Drosophila (Chippindale et al. 1993;Chapman & Partridge 1996).

Indeed recent work has demonstrated that DR increases lifespan in rhesus monkeys (Holloszy & Fontana 2007; Mattison et al. 2007; Colman et al. 2009) and short-term DR can produce improvements in function in humans (e.g. Holloszy & Fontana 2007). Because the details of the mechanisms by which DR extends lifespan are not fully elucidated for any organism, it is not clear whether this is a case of evolutionary conservation or whether instead there has been evolutionary convergence (Mair & Dillin 2008).

It was originally suspected that extension of lifespan by reduced IIS might turn out to be a worm peculiarity. This was because mutations in genes in the IIS pathway can also cause the worms to enter a type of developmental arrest (dauer), normally seen only in response to low food or crowding (Riddle & Albert 1997). Dauer larvae are long lived, and the long life of IIS mutant adult worms could therefore have been a result of re-expression in the adult of the genes that make the dauer larva long lived (Kenyon et al. 1993), a speculation confirmed by studies of gene expression (McElwee et al. 2003, 2004). Most organisms do not undergo this type of developmental arrest and might therefore lack the mechanisms for long life seen in dauer larvae. However, an important recent discovery has been that the IIS pathway has an evolutionarily conserved role in determining longevity; mechanisms of ageing therefore are, at least to some extent, ‘public’ or shared (Partridge & Gems 2002b). Remarkably, mutations in the singleDrosophila insulin receptor (Tatar et al. 2001) and insulin receptor substrate (Clancy et al. 2001) proved to extend lifespan in the fly. Furthermore, mutations in the genes encoding both the insulin (Bluher et al. 2003) and Igf-1 receptor (Holzenberger et al. 2003) extended lifespan in the mouse. Subsequent work with all three organisms has amply confirmed the evolutionarily conserved role of this signalling pathway (Russell & Kahn 2007; Piper et al. 2008; Taguchi & White 2008). Early evidence from population–genetic association studies has also started to implicate the pathway in determination of human lifespan (Mooijaart et al. 2005; Kuningaset al. 2007; Willcox et al. 2008).

Evidence for evolutionary conservation of genetic determinants of lifespan is at present strongest for the IIS pathway, but others are likely to lengthen the list. For instance, the effect of elevated expression of SIR2 in yeast appears to be conserved in C. elegans (Tissenbaum & Guarente 2001) andDrosophila (Rogina & Helfand 2004), and mutations in genes encoding components of the target of rapamycin (TOR) pathway also extend the lifespan in all four organisms (Jia et al. 2004; Kapahi et al. 2004; Kaeberleinet al. 2005; Hansen et al. 2007; Pan et al. 2007; Sheaffer et al. 2008; Smithet al. 2008b; Harrison et al. 2009). 

Sufficient single-gene mutations that extend lifespan in yeast and C. elegans have now been identified to allow a quantitative estimate of the degree of evolutionary conservation of genetic modifiers of ageing between these two organisms (Smith et al. 2008b). In C. elegans, loss of function of a set of approximately 276 genes, or altered function of their protein products, has proved to extend lifespan. A set of 103 yeast orthologues of 78 of these 276 worm genes could be identified on the basis of sequence similarity, and deletion of 76 of these resulted in viable yeast strains. Eleven of the 76 were long lived, a proportion 4.3 times higher than would be expected from deletion of the same number of randomly selected yeast genes. Many of the genes with a conserved role in ageing in these two organisms are involved in protein synthesis (Smith et al. 2008b), a process whose importance to ageing has recently been demonstrated by experimental studies in C. elegans (Hansen et al. 2007;Pan et al. 2007). This strong signal of evolutionary conservation between these two distantly related organisms suggests that future studies of the role of protein synthesis in ageing in the fruitfly and the mouse would pay dividends.

Although there is abundant evidence for an evolutionarily conserved role for IIS and other pathways in determination of lifespan, it remains to be seen how deep that conservation penetrates. Even at the level of signalling mechanisms, there may be considerable variation between different organisms as is implied, for instance, by the presence of much larger numbers of insulin ligands in the worm (38) and the fly (7) than in mammals. In addition, similar changes in signalling in different organisms may have very different outcomes because of differences in structure and physiology. Of particular importance for IIS, insulin resistance and failure in insulin production can result in diabetes in mammals, with its consequent vascular damage, while the invertebrates, with their open circulatory systems, can probably better tolerate elevated blood sugar. Only a narrow range of alterations in IIS may therefore increase mammalian lifespan. There is some evidence for evolutionary conservation of the biochemical mechanisms by which altered IIS extends lifespan in different organisms. For instance, profiling of gene expression in long-lived, IIS mutant worms, flies and mice showed increased expression of genes encoding components of phase 1 and 2 detoxification pathway, important in the elimination of lipophilic endobiotics, xenobiotics and drugs (McElwee et al. 2007; Sykiotis & Bohmann 2008; Tullet et al. 2008). Subsequent work with a key transcriptional regulator of the pathway has demonstrated experimentally that increasing its activity can increase lifespan in both C. elegans and Drosophila (McElwee et al. 2007; Sykiotis & Bohmann 2008; Tullet et al. 2008). Cellular detoxification may therefore be an important process for protection against the effects of ageing in all three organisms, although whether the toxins involved are the same or different remains to be determined.

So far we have only scratched the surface of the mechanisms at work in lifespan extension. Nonetheless, these new findings have opened up the promise of a major scientific opportunity, to use the invertebrates and the mouse to understand human ageing, exploiting the full range of analytical tools available in the model organisms.

Previous SectionNext Section

4. Risk and damage

Slowing down ageing is not the only means by which lifespan can be extended. The ageing process is characterized by a decline in function with advancing age during adulthood; the state of the organisms progressively worsens. One might therefore expect that an intervention that extended lifespan by amelioration of the ageing process would do so by slowing down the rate at which state worsens with age (Finch 1990). A simple and direct way of assessing the state of a population is to measure mortality rate, which is, to a first approximation, the proportion of individuals that enter each age class that die during it. Mortality rates generally show a roughly exponential increase with age in humans and the laboratory model organisms and can hence be described in terms of two important parameters: the initial, baseline mortality rate, which is age independent, and the rate at which mortality rate increases with age (Finch 1990;Pletcher et al. 2000). Interventions, genetic and environmental, that increase lifespan can do so by decreasing either or both of these parameters (Pletcher et al. 2000). A reduction in the slope of a mortality trajectory is what would be expected if lifespan were increased by a reduction in the rate of ageing itself (Finch 1990).

One intervention that clearly can slow down the rate of ageing is lowered temperature for ectotherms. In Drosophila, lowered temperature increases lifespan entirely by lowering the slope of the mortality trajectory, with no effect on the initial mortality rate (Mair et al. 2003). These flies are too small to thermoregulate and are thus forced to adopt ambient temperature. Lowering of the slope of the mortality trajectory in cooler environments is consistent with the idea that lowered temperature decreases the rate of most or all molecular processes in the organism, including the rate of ageing. In support of this view, when flies are switched between temperatures, the subsequent slope of the mortality trajectory immediately changes to that characteristic of flies kept permanently in the new thermal regime (Mair et al. 2003). The flies therefore bear the permanent imprint of their thermal history, with warmer temperatures leading to the accumulation of a higher level of irreversible damage, and no acute effect of temperature on mortality rate. Lowered temperature thus decreases the rate of ageing in Drosophila and provides a useful benchmark for an intervention that does so.

Rather than decreasing the rate of ageing, the increase in lifespan in industrialized human societies has occurred by a reduction in baseline mortality rates, with no reduction in the slope of the mortality trajectory (Wilmoth 2000). This suggests that overall health, at all ages, has improved, but that the underlying process of accumulation of ageing-related damage has not been ameliorated. This finding leaves open the question of the time course of these effects. For instance, events early in life or even in utero could have a lifelong impact on health, and there could also be more acute effects of recent and current environments. To measure such timing effects, it is necessary to compare individuals with currently similar circumstances but different past environments, and vice versa.

Interestingly, DR can have a similar effect on mortality trajectories to that associated with the increase in human lifespan expectancy; DR extends life in Drosophila entirely by reducing the initial mortality rate with no lowering of its slope (Pletcher et al. 2000). Similar findings have been reported for DR in mice (Weindruch et al. 1986; Hursting et al. 1994), and for one form of DR in C. elegans (Smith et al. 2008a), suggesting that, in these three organisms at least, DR may not slow down the rate of ageing and may instead increase lifespan through a different mechanism. Indeed, experimental reversal of the nutritional status of flies has shown that the effect of DR on mortality rate is acute. Later onset DR leads, within 48 h, to a switch in subsequent mortality rates to those of permanently DR flies (Mair et al. 2003). Likewise, previously DR flies that are switched to full feeding at later ages show a rapid increase in mortality rates to those characteristic of flies that are permanently fully fed. DR and fully fed flies thus age at the same rate, and DR instead extends lifespan by reducing the acute risk of death.

There is little information on the timing of the effects of single-gene mutations on mortality rate. In C. elegans, switches in IIS status using double stranded RNA interference have shown that the pathway acts specifically during adulthood to determine adult survival (Dillin Crawford & Kenyon 2002), but more detailed timing information is not yet available. In Drosophila, an inducible system for gene expression was used to show that, at least up to a month of adult age, the IIS pathway acts acutely to determine mortality rate, similar to DR (Giannakou et al. 2007). It will be important to determine whether this kind of acute effect on mortality rate applies to other pathways that determine lifespan and, in particular, whether it extends to mammals. But it is already clear that, in principle, lifespan can be extended by making the animal less likely to die of the damage that it has accumulated, rather than by reducing the accumulation of damage.

Previous SectionNext Section

5. Ageing and ageing-related diseases

It has long been known that DR in rodents reduces the impact of a wide range of ageing-related diseases, and it has also been shown to reduce the impact of proteotoxicity in C. elegans (Steinkraus et al. 2008). Because the single-gene mutations that extend lifespan have only been discovered recently, less information is available, but already it seems that aspects of function and health during ageing are improved. For instance, associative learning is more strongly maintained at later ages in long-lived IIS mutants worms (Murakami et al. 2005), while locomotor function is better maintained during ageing in long-lived IIS mutant flies (Martin & Grotewiel 2006). Loss of the insulin receptor substrate 1 in the mouse also protects against loss of glucose homeostasis, immune and motor function and reduces the impact of osteoporosis, cataract and ulcerative dermatitis (Selman et al. 2008). As well as maintaining function and health during ageing, lifespan-extending mutations can protect against the pathology associated with specific genetic models of ageing-related disease. For instance, recent work with C. eleganshas revealed that mutations in IIS that increase lifespan can reduce the pathology associated with genetic models of cancer (Pinkston et al. 2006;Pinkston-Gosse & Kenyon 2007) and of proteotoxicity-induced neurodegeneration (Cohen et al. 2006; Pinkston et al. 2006; Steinkraus et al. 2008). Furthermore, mutations in IIS in the mouse can protect against the pathology associated with specific genetic models of Alzheimer's disease (Freude et al. 2009; Killick et al. 2009). The indications are, therefore, that these interventions can produce an improvement in health and function in diverse tissue systems and reduce the impact of ageing-related diseases with diverse aetiology (Butler et al. 2008).

The implication of these findings is that protection against the ageing process results in protection against diverse, ageing-related diseases. The ageing process itself is acting as the major risk factor for these conditions. This realization leads in turn to the conclusion that there is an underlying commonality in the aetiology of these ageing-related diseases, despite their diverse manifestations. It is early days yet, and a great deal more work needs to be done to understand exactly how the ageing process increases vulnerability to these diseases. We need also to understand how transition into loss of function and disease occurs, and how a single environmental intervention or gene mutation can have such broad-spectrum effects. A key challenge in the biology of ageing, and one that is increasingly being recognized, is to understand how events at different levels of organization contribute to loss of function during organismal ageing and to eventual death (Kirkwood 2008; Murphy & Partridge 2008). Presumably, in a complex chain of events, damage to macromolecules and organelles causes decline in cellular function and cell loss, which in turn compromise the function of tissues. Dysfunctional tissues could in turn act systemically to cause stress and eventual damage to other tissues, which could to some extend cause a correlation in the rate of ageing of different parts of the body within an individual. Many of these key changes may be susceptible to acute intervention, similar to the effects of DR in the invertebrate model organisms. At some point, irreversibility must enter the system, because of the emergence of lethal, ageing-related disease that cannot be rescued by the intervention (Partridge Pletcher & Mair 2005b). Identifying, experimentally investigating and modelling these temporal changes and their dynamics will require considerable effort, and in the near future much more experimental work will be needed to bring understanding of these systems to a level of maturity where productive modelling will be possible.

Previous SectionNext Section

6. Will lifespan extension in laboratory model organisms be relevant to human ageing?

The findings from the model organisms have a clear, potential message for the medical treatment of ageing-related diseases (Butler et al. 2008). At present, these diseases are treated piecemeal by different medical specialists, because they are regarded as separate medical problems. Patients themselves generally visit a clinician because they have a specific medical problem, not because they are old.

However, if in humans, also, protection against the effect of ageing can delay or ameliorate diverse ageing-related diseases, then a quite different approach to the health of older people would pay dividends. A broad-spectrum, preventative approach would be required, with individuals who reached a certain age being treated even in the absence of any ageing-related disease. 

Furthermore, if the effects of a beneficial intervention were acute, as has occurred in some of the animal models, then it would need to be applied for the rest of life. Clinical trials would also need to be conducted for a protracted period. All of these features would pose significant obstacles to translating the findings from basic science into drug development and clinical practice. However, if the findings from the animal models turn out to apply to humans, then a major opportunity could be missed. What, then, is the likelihood that evolutionary conservation of the mechanisms will extend to our own species?

There are some obvious questions about lifespan extension in animal models that have a bearing on likely relevance to humans. If these single gene mutations can produce such broad-spectrum benefits to health, then why is the mutant not the wild-type? These mutants must have side effects that mean that they are not the fittest genotype in the wild. Some mutants that extend lifespan clearly delay or reduce fecundity, as does DR (Partridgeet al. 2005a). However, it is also clear that, at least in the laboratory, impaired fecundity is not necessary for extension of lifespan by some single-gene mutations (Partridge et al. 2005a), although some claims that this is the case may have been based on failing to measure all aspects of fecundity or doing so in benign circumstances (Rogina et al. 2000; Walker et al. 2000;Marden et al. 2003; Jenkins et al. 2004). Nature is in general a more exacting place than the laboratory, where the animals are kept largely free of pathogens, have an abundant and highly accessible food supply and are kept largely free of competition with conspecifics. However, many of these considerations apply also to humans in developed countries. It will be important to evaluate what are the negative effects of single-gene mutations that make them disadvantageous under natural circumstances, to understand how important these might be for humans.

It should also be borne in mind that medical interventions into ageing are likely to be applied only later in the lifespan, when some of the negative side effects may no longer be relevant, and it has already been demonstrated that administration of a TOR inhibitor, rapamycin, later in life in mice can extend the lifespan (Harrison et al. 2009). The prospects that the findings from the laboratory will prove to be of medical relevance to humans therefore look promising.

Humans are, obviously, much longer lived than any of the laboratory model organisms. This could have a bearing on the extent to which interventions could ameliorate the effects of ageing, or not. It is notable that many of the genes that have so far come to light as affecting longevity in the laboratory are involved in nutrient sensing pathways, which contribute to matching the growth and reproductive rate of the animals to their nutritional status. Human growth and reproduction respond to nutrients, but not to such an extent as do those of the laboratory model organisms, which are all subject to boom and bust conditions in nature.

However, even if human lifespan is not as plastic as that of laboratory animals, the same may not be true for ageing-related disease. The aim of this research is to improve human health during ageing, not to extend lifespan per se, and it remains to be seen to what extent this is going to be possible.