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Showing posts with label rapamycin. Show all posts
Showing posts with label rapamycin. Show all posts

Sunday, 26 August 2012

Wednesday, 15 August 2012

Emma Rourke reviews Horizon: Eat, Fast, and Live Longer

reposted from: http://blogs.bmj.com/bmj/2012/08/14/emma-rourke-reviews-horizon-eat-fast-and-live-longer/
crabsallover highlightskey pointscomments / links.


14 Aug, 12 | by BMJ Group

There’s a new intervention being trialled. It will help you lose weight, it will delay the potential onset of dementia, and best of all it will enable you to live in the fullest of health for longer. Perhaps the main virtues of this intervention centre on its sheer simplicity: it doesn’t involve putting any chemicals into your body, it doesn’t involve surgery, and it doesn’t cost anything—it may even save you money. All you have to do is deprive yourself of one of life’s great pleasures—food.
The BBC aired Horizon: Eat, Fast and Live Longer earlier this week. During this one hour programme, Michael Mosley visits a number of institutions seeking to understand the ageing process. He meets a variety of experts, all of whom extol the virtues of caloric restriction (CR), and tries methods they advise in attempts to improve his performance on physiological testing. The most extreme of these methods involved 3 days and 4 nights of fasting, wherein Mosley consumed only water, black tea, and a single sachet of powdered soup.  Subsequently, he tried alternate day fasting, where consumption is limited to around 500 calories on one “fast” day and completely unlimited the following “feed” day. He finally settled for a 5 day “feed” period followed by a 2 day 500 calorie fast period.
For a supposedly scientific programme, however, the science was rather scant. The focus was strongly on the insulin-like growth factor 1 (IGF-1) as mediator of the benefits of CR. This signalling pathway has been widely studied and is known to stimulate growth and inhibit apoptosis of cells. Perhaps unsurprisingly given this role, it has been implicated in the pathogenesis of cancer [1]. It has several key functions in the body, including growth and maintenance of the skeletal system [2]. Interestingly, in vivo deficiency of IGF-1 in combination with testosterone correlates with reduced survival [3].
CR (without malnutrition) has been shown to increase lifespan in laboratory animals. In rodents, for example, CR postpones onset of age-related pathology and prolongs lifespan [4]. Is this explained solely by IGF-1 levels? Studies have sought to test the popular oxidative stress theory of ageing, and indeed noted reduced markers of oxidative damage in calorie restricted rodents [4]. This alternative mechanism by which CR may affect ageing is not even touched upon by the programme. As with much human science, it is more complicated than it seems and there is still no consensus on the role of antioxidant levels in CR—there’s something else at play [4]. That something may involve the nutrient-sensing pathways of target of rapamycin (TOR), it may involve the forkhead transcription factor (FOXO), and it may involve sirtuins [5]. In fact, the one thing we can be sure about is that the molecular determinants of lifespan are incredibly complex, and far from fully understood [6].
The programme furthermore neglected many social factors complicit in the ageing process. Humans are not laboratory animals and their environment cannot be so strictly controlled. Nevertheless, somewhat controversial experimentation in humans is ongoing. Accordingly, some may question whether it is responsible for a qualified doctor to so emphatically endorse such an approach in a prime time television slot? “This could radically transform the nation’s health,” he says.
The programme was littered with health warnings—“don’t do this without supervision” and “for some fasting can be dangerous”—but within hours online weight loss forums were overflowing with posts from people saying they’d give it a go. Mosley’s wife, a GP, appears to support his desire to pursue a 5 days feeding 2 days fasting regime, thus reinforcing to the public that this is a safe and worthwhile method.
Perhaps the diet Mosley ultimately adopts is not that radical, and perhaps it doesn’t even represent CR (the level at which CR is defined varies from 10-25% reduction in overall calorie intake in humans). Any attempt to encourage reduced calorie intake in a nation with such high rates of obesity as our own may be commendable, but critics will likely find little new in the advice Mosley dishes out: reduce your calorie intake, reduce your weight, reduce your cardiovascular risk factors. Perhaps that’s the message to hope people take forward from this.
References:

Sunday, 20 November 2011

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)

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Sunday, 21 November 2010

Live decades longer with a pill?

The Easter Island compound – called rapamycin after the island’s Polynesian name Rapa Nui
 – was found to extend expected lifespan by 38 per cent when tested on mice.

A fungus from Easter Island has been used to create a life-extending pill, according to news reports


A new pill could help you live longer
“A wonder pill could extend the lifespan of people by up to 23 years,” the Daily Express has reported on its front page. Most other newspapers have also featured stories on an ‘anti-ageing drug’, which contains a chemical made by insects in the soil on Easter Island. They say that it stops cells in mice from ageing by blocking the damaging proteins thought to be responsible for the ageing process.
The lifespan of mice (up to the point where 90% had died) was extended by up to 38% if measured from the time that they were given the drug. The newspapers say this raises the possibility that a similar drug might delay ageing in people by several years. However, it is based on several assumptions, such as equating 10 mouse days to one year of a human life. The research also raises the possibility that the survival rates might vary due to different diets given to mice before they were given the drug.
The drug rapamycin has already been used in humans to prevent rejection after transplants, but the researchers say it is not licensed for healthy people, and may increase risk of infections. The main appeal of this research is the benefit seen in mice that were given the drug later in life. It means that researchers now have a target for the development of new drugs aimed at treating age-related diseases and extending healthy life in humans.

Where did the story come from?

This research was carried out by Dr David E. Harrison from the Jackson Laboratory in Maine, US. Other colleagues from departments and institutes of ageing around the US co-authored the paper, which was supported by grants from the National Institutes of Ageing and the Department of Veterans Affairs in the US. The study was published in Nature, the peer-reviewed scientific journal.

What kind of scientific study was this?

This animal study testing how the drug rapamycin might affect lifespan in specially bred mice.
mTOR signaling pathway.
Rapamycin, which was discovered in the 1970s in the hunt for new antibiotics, is a drug that inhibits the ‘TOR signalling pathway’. The TOR (Target of Rapamycin) signalling pathway (wikipedia) has been studied in yeasts and invertebrates, and it controls cell growth by activating and inhibiting important cell processes. In the laboratory, parts of this pathway have been inhibited by several things, such as low nutrient levels, caffeine and rapamycin. New TOR inhibitor drugs might potentially have roles in several areas of disease, particularly in the fight against cancer.
Rapamycin is currently used to suppress immune systems of patients who have had transplant operations, to prevent their bodies rejecting organs. It is also used in heart operations, and is being tested for its anti-cancer properties. It is not licensed for use in healthy people.
The research was conducted at three test sites in the US: The Jackson Laboratory, the University of Michigan and the University of Texas Health Science Center. All the mice were supplied by the Jackson Laboratory, and had been bred to be genetically unique despite the fact that they were all siblings. The researchers say that a 600-day-old mouse is roughly equivalent to a 60-year-old human. The initial research, which began in 2005, looked at 1,960 mice.
The researchers weaned the mice on a standard, specially formulated diet (mouse chow) until they were 600 days old, and then added rapamycin to the feed of the “rapamycin-fed group”. The remainder, “the control group”, continued to be fed on their normal diet. Rapamycin was prepared in capsule form so that it could pass through to the intestine undigested.
After the mice had been divided into the two groups at 600 days, they were followed until they died naturally or were judged to be too sick and “euthanised”. The researchers measured the average (median) survival and the number alive up to the last tenth of expected lifespan for a mouse. This was calculated by recording the day on which 90% of the mice had died. This is a measure of the mouse maximum survival, but not the actual length of time that all the mice lived.

What were the results of the study?

The researchers say that rapamycin extended the median and maximal lifespans of both male and female mice when fed the drug from 600 days of age. Combining results from the three test sites showed that rapamycin led to an increased survival time of 14% for females and 9% for males when measured from the start of the study to the point where 90% of the mice had died. The control female mice lived 1,094 days, which increased to 1,245 days in the treated females. The respective lifespan for males was 1,078 days, which increased to 1,179 days with treatment.
Patterns of disease did not differ between control mice and normal mice.

What interpretations did the researchers draw from these results?

The researchers say that “these are the first results to demonstrate a role for the mTOR signalling in the regulation of mammalian lifespan” and the “pharmacological extension of lifespan in both genders”.
They suggest that their findings have implications for the further development of interventions which target the mTOR pathway for the treatment and prevention of age-related diseases. They also suggest that rapamycin may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or through a combination of the two.

What does the NHS Knowledge Service make of this study?

This study has several interesting features and will provide an added impetus to research in this area. However, there are important points to consider when interpreting this study.
Across the groups mice actually had about the same lifespan, about 1,250 days, and the survival improvements reported are due to the measures used in this study, and the fact that fewer mice in the treated group died in the first 90% of their lifespan, and instead died in the last 10%. This difference is apparent from an examination of the survival curves reported in the study. Survival curves simply report the proportion of mice surviving at all time points throughout the study.
Looking at these curves, it is apparent that in two of the laboratories the survival curves begin to separate before the 600-day point. This suggests that there was a difference in the number of mice surviving in the control and treated groups, even before they were given the active drug.
This is a puzzling finding, which indicates that a factor other than the drug had affected their rates of survival. The researchers say that this difference was partly due to the control mice in the two labs receiving a different formula of mouse feed.
On this basis, the researchers say they cannot rule out the possibility that improved survival among these two groups of males might reflect differences in nutritional or health status between control and rapamycin groups before 600 days, rather than solely the effects of rapamycin.
Finally, it should be noted that this was an experiment in mice, therefore the benefit of longer lifespan found in this study may not translate directly into humans. On this basis, rapamycin should not yet be considered to ‘extend life by 20 years’. A further consideration of potentially extending lifespans must also be the quality of life experienced during any extra years gained.

Links to the headlines

Tests raise life extension hopes. BBC News, July 09 2009
Secret to a longer life lies on Easter IslandThe Independent, July 9 2009
New pill can add 20 years to lifeDaily Express, July 9 2009
Dirty secret to staying youngDaily Star, July 9 2009

Links to the science

Harrison DE, Strong R, Sharp ZD, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous miceNature [advance online publication] 8 July 2009

Further reading

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.

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.

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 2000Oeppen & 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. 2004Baudisch 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 19461952). 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 1952Williams 1957Hamilton 1966Hughes & Reynolds 2005Partridge & Gems 2006Moorad & 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).

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. 1997Lin et al. 1997Ogg 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 1997Kaeberlein 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 20052006). 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.

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. 2000Lin et al. 2000), C. elegans (Klass 1977Lakowski & Hekimi 1998Greer et al. 2007Kennedy et al. 2007Smith 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 2007Mattison et al. 2007Colman 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. 20032004). 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 2007Piper et al. 2008Taguchi & White 2008). Early evidence from population–genetic association studies has also started to implicate the pathway in determination of human lifespan (Mooijaart et al. 2005Kuningaset al. 2007Willcox 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. 2004Kapahi et al. 2004Kaeberleinet al. 2005Hansen et al. 2007Pan et al. 2007Sheaffer et al. 2008Smithet al. 2008bHarrison 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. 2007Sykiotis & Bohmann 2008Tullet 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. 2007Sykiotis & Bohmann 2008Tullet 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.

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. 1986Hursting 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.

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. 2006Pinkston et al. 2006Steinkraus 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. 2009Killick 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 2008Murphy & 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.

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. 2000Walker et al. 2000;Marden et al. 2003Jenkins 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.