A plaque on Easter Island commemorates the discovery of rapamycin
You don’t have to go far to find supposed ways of delaying the ageing process, from oddball diets to special supplements. But these fountains of youth are all hype and no substance. For now, there are only a few methods that have consistently extended the lives of mammals. Eating less – formally known as “caloric restriction” – is one of these. Rapamycin, a drug originally found in Easter Island bacteria, is another. It can lengthen the lives of old mice by 9 to 14 per cent, and it boosts longevity in flies and yeast too.
But rapamycin has its downsides. For a start, it strongly suppresses the immune system. That is why it is currently given to people who receive new organs, to stop them from rejecting their transplants. Rapamycin can also increase the risk of diabetes. In mice, rats and humans, the drug weakens the ability to stabilise levels of sugar in the blood. Individuals who take it for a long time become resistant to insulin, and intolerant to sugar.
You’d expect the opposite. Longer-lived animals ought to be better at dealing with sugar, and less likely to suffer from insulin resistance. Indeed, that’s what you see in individuals that cut down on calories. So why does rapamycin behave so paradoxically?
As we get older, many of the cells in our bodies go into retirement. Throughout our lives, they divided time and again, all in the face of radiation bombardments and chemical attacks. Slowly but surely, their DNA builds up damage to that threatens to turn them into tumours. Some repair the damage; others give up the ghost. But some cells opt for a third strategy – they shut down. No longer growing or dividing, they enter a state called senescence.
But they aren’t idle. Senescent cells still secrete chemicals into the body, and some scientists have suggested that they’re responsible for many of the health problems that accompany old age. And the strongest evidence for this claim comes from a new study by Darren Baker from the Mayo Clinic College of Medicine.
Baker has developed a way of killing all of a mouse’s senescent cells by feeding them with a specific drug. When he did that in middle age, he gave the mice many more healthy years. He delayed the arrival of cataracts in their eyes, put off the weakening of their muscles, and held back the loss of their body fat. He even managed to reverse some of these problems by removing senescent cells from mice that had already grown old. There is a lot of work to do before these results could be applied to humans, but for now, Baker has shown that senescent cells are important players in the ageing process.
As we get older, our memories start to fail us. The symptoms of this decline are clear, from losing track of house keys to getting easily muddled and confused. Many of these problems stem from a failure of working memory – the ability to hold pieces of information in mind, block out distractions and stay focused on our goals. Now, a team of American scientists has discovered one of the reasons behind this decline, and a way of potentially reversing it.
Our working memory depends on an area known as the prefrontal cortex or PFC, right at the front of the brain. The PFC contains a network of nerve cells called pyramidal neurons that are all connected to one another and constantly keep each other buzzing and excited – like a neural version of Twitter. This mutual stimulation is the key to our working memory. As we age, the buzz of the pyramidal neurons gets weaker, and information falls more readily from our mental grasp.
But this decline isn’t the fault of the neurons themselves. By studying monkeys, Min Wang from the Yale University School of Medicine has found that the environment around the neurons also changes with age. And by restoring that environment to a more youthful state, he managed to ease some of the age-related decline in working memory.
In the caves of Slovenia and Croatia lives an animal that’s a cross between Peter Pan and Gollum. It’s the olm, a blind, cave-dwelling salamander, also called the proteus and the “human fish”, for its pale, pinkish skin. It has spent so long adapting to life in caves that it’s mostly blind, hunting instead with various supersenses including the ability to sense electricity. It never grows up, retaining the red, feathery gills of its larval form even when it becomes sexually mature at sweet sixteen. It stays this way for the rest of its remarkably long life, and it can live past 100.
The olm was once described as a baby dragon on account of its small, snake-like body. It’s fully aquatic, swimming with a serpentine wriggle, while foraging for insects, snails and crabs. It can’t see its prey for as it grows up, its eyes stop developing and are eventually covered by layers of skin. It’s essentially blind although its hidden eyes and even parts of its skin can still detect the presence of light. It also has an array of supersenses, including heightened smell and hearing and possibly even the ability to sense electric and magnetic fields.
Warning: Since writing this article, it has become clear that the research in question has some serious flaws that came to light after it was published and widely reported. The conclusions here should be treated with caution. UPDATE: The paper has since been retracted.
The developed world is an ageing one. In 2008, the number of pensioners in the UK exceeded the number of minors for the first time in history. Centenarians – those who’ve lived for a century or more – are our fastest-growing demographic. By 2030, ageing baby-boomers will swell the ranks of centenarians to around a million worldwide. That will have important implications, not just socially and economically, but scientifically too. The genomes of these ‘oldest old’ provide a window into the biology of ageing and the secrets to a longer (and healthier) life. It’s a window that Paola Sebastieni from Boston University School of Public Health has just peered through. By studying the genomes of over a thousand centenarians, she has developed a model that can predict a person’s odds of living into their late 90s and beyond with an accuracy of 77%. On the surface, this might seem like a very complicated piece of fortune-telling, but getting accurate predictions isn’t an end unto itself. The point of the exercise is to better understand the full complement of genetic variants that can affect our risk of living to an older age and doing so healthily.
An assortment of tree-living mammals
In The Descent of Man, Darwin talked about the benefits of life among the treetops, citing the “power of quickly climbing trees, so as to escape from enemies”. Around 140 years later, these benefits have been confirmed by Milena Shattuck and Scott Williams from the University of Illinois.
By looking at 776 species of mammals, they have found that on average, tree-dwellers live longer than their similarly sized land-lubbing counterparts. Animals that spend only part of their time in trees have lifespans that either lie somewhere between the two extremes or cluster at one end. The pattern holds even when you focus on one group of mammals – the squirrels. At a given body size, squirrels that scamper across branches, like the familiar greys, tend to live longer than those that burrow underground, like prairie dogs.
These results are a good fit for what we already know about the lives of fliers and gliders. If living in the trees delays the arrival of death, taking to the air should really allow lifespans to really take flight. And so it does. Flight gives bats and birds an effective way of escaping danger, and they have notably longer lives than other warm-blooded animals of the same size. Even gliding mammals too tend to live longer than their grounded peers.
If I say the phrases ‘anti-ageing’ and ‘nutritional balance’ to you, you’d probably think of the pages of quack websites selling untested supplements than the pages of Nature. And yet this week’s issue has a study that actually looks at these issues with scientific rigour. It shows that, at least for fruit flies, eating a diet with just the right balance of nutrients can lengthen life without the pesky drawback of producing fewer offspring.
Despite the claims of the cosmetic and nutritional industries, chemicals or techniques that slow the ageing process are few and far between. We’re a long way from any fountains of youth, but there is at least one conclusive way of extending an animal’s life – restricting the calories it eats. It works in yeast, flies, worms, fish, mice, dogs and possibly even primates, but it comes at a cost. The dieting organisms had lower reproductive rates (technically, they had lower ‘fecundity’).
Scientists suspected that eating fewer calories mimicked the effects of famine and food shortages. In such conditions, parents who breed put their health at risk and their offspring’s odds of survival are slim anyway. So animals divert their resources to maintaining their health at the cost of their fecundity. This explanation suggests that survival and reproductive success are at odds with one another – fewer offspring is simply the price of a longer existence.
But Richard Grandison and Matthew Piper have found that this isn’t true. Working with Linda Partridge at University College London, they have shown that you can improve both the fecundity and lifespan of a fruitfly by supplementing its restricted diet with the amino acid methionine. The trick won’t work in exactly the same way for other animals so don’t go bulk-ordering methionine yet. However, the results do prove the point that flies can have their cake (or lack thereof) and eat it, provided the cake has just the right balance of nutrients.
Grandison and Piper fed Drosophila flies with diluted stocks of yeast, so they are the same amount that they would normally do, but had fewer calories to show for it. As usual, their lives increased and their reproductive rates fell. The duo tweaked the diet until it gave the flies the maximum possible lifespan and then systematically added back nutrients until they hit on some that would restore their fecundity while retaining their extra years.
Vitamins didn’t do it; nor did fats or carbohydrates. Extra doses of essential amino acids improved fecundity but it brought lifespan down too, as if the flies had eaten a full meal in the first place. This shows that calorie-restricted diets do their thing because they change the levels and ratios of amino acids in a fly’s food.
Grandison and Piper discovered that one particular amino acid, methionine, was crucially important. Methionine is a boon to reproduction, but it conspires with other amino acids to shorten lifespan. Without methionine, the flies lived to a ripe, old age but their fecundity faltered. The best combo was methionine on its own, without the other amino acids – that boosted fecundity and maintained the flies’ extended lifespans.
These results clearly show that survival and reproduction aren’t opposed – you just have to get the right balance of nutrients. Getting that balance could be the key to achieving the same winning combo of longer life and better reproductive success without actually cutting down on the calories.
But clearly, there’s a massive word of warning to all of this: methionine happens to be the magic ingredient for flies fed on yeast. Going out and buying methionine supplements is not going to turn you into an immortal Casanova. In this study, methionine only worked in a restricted diet where other amino acids are scarce. Likewise, in previous studies, mice and rats live longer if they cut down on methionine.
The main message from this study is that lifespan and fecundity don’t always trade-off against one another – getting the ideal balance of nutrients unlocks the best of both worlds. It’s likely that the same principle applies to other animals, because the biology of ageing is remarkably consistent across species, but we still don’t know where the point of balance rests. Look on the shelves of a health store and you might think that we’ve got questions like this cracked. We don’t – ageing research is in its infancy and there’s a lot of work left to be done.
Reference: Nature doi:10.1038/nature08619
More on ageing:
I was browsing a copy of New Scientist in the supermarket today and realised that I actually have a feature in it, having completely forgotten that it was coming out this week!
This one’s on the fate of the oldest old – people aged 100 or over. This is one of the fastest rising demographics in the world and their numbers will surely swell even further with ageing populations and advances in modern medicine. The feature looks at what happens when people reach these extreme ages and what happens to them when they do.
It ended up being surprisingly optimistic. Far from being a helpless drain on society, there’s growing evidence tha ta substantial proportion of centenarians lead fulfilling and independent lives. Indeed, I’ve previously written about a study involving everyone in Denmark born in 1905, which found that the loss of independence that comes with age is balanced out by the fact that the sickest people die earlier. The upshot is that the proportion of people who can take care of themselves remains steady and extreme longevity doesn’t lead to extreme disability.
The piece looks at what happens to the two sexes in extreme old age and why women are more likely to get there but why the men who do tend to be fitter. I consider the diseases that affect the oldest old – cancer, chronic diseases and Alzheimer’s are rare, but other forms of dementia and arthritis are common. And I look at our growing knowledge of the “centenarian genome” and what it tells us about the ageing process.
Hope you enjoy it.
It’s 1964, and a group of Canadian scientists had sailed across the Pacific to Easter Island in order to study the health of the isolated local population. Working below the gaze of the island’s famous statues, they collected a variety of soil samples and other biological material, unaware that one of these would yield an unexpected treasure. It contained a bacterium that secreted a new antibiotic, one that proved to be a potent anti-fungal chemical. The compound was named rapamycin after the traditional name of its island source – Rapa Nui.
Skip forward 35 years and rapamycin has made a stunning journey from the soil of a Pacific island to the besides of the world’s hospitals. Its ability to suppress the immune system means that it’s given to transplant patients to stop them from rejecting their organs and its ability to stop cells from dividing has formed the basis of potential anti-cancer drugs. But the chemical has an even more interesting ability and one that has only just been discovered – it can extend lifespan, at least in mice.
David Harrison, Randy Strong and Richard Miller, leading a team of 13 American scientists, have found that capsules of rapamycin can extend the lifespans of mice that eat them by 9-14%. That’s especially amazing given that the mice were already 20-months-old at the time of feeding, the equivalent in mouse years of a 60-year-old human.
There will undoubtedly be headlines that proclaim the discovery of the fountain of youth or some such, but it is absolutely critical to say up front that this is not a drug that people should be taking to extend their lives. Rapamycin has a host of side effects including, as previously mentioned, the ability to suppress the immune system. Harrison says, “It may do more harm than good, as we know neither optimal doses nor schedules of when to start for anti-ageing effects.” So the new discovery doesn’t put an anti-ageing pill within our grasp. It’s far better to see it as a gateway for understanding more about the basic biology of ageing, and for designing other chemicals that can provide the same benefits without the unwanted risky side effects.
Nonetheless, it’s still very exciting, especially since the nutrition market is already awash with supplements that claim to slow the ageing process but which have little evidence to back their claims. Likewise, scientists have tested a number of different chemicals but the few positive effects have typically been small or restricted to a specific strain of mouse. Rapamycin is different – as Harrison himself explains, “no other intervention has been this effective when starting so late in life on such a diverse population.”