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No Pain, No Aging

Age brings pain: back pain, eye strain, sore joints, and the like. And pain, too, seems to accelerate aging. Several studies have reported that people with chronic pain have shorter lives than everybody else.

But is the link between pain and aging due to the co-occurance of sickness and decay, or rather to the perception — the feeling — of pain itself?

“If you burn your finger right now, is that going to affect the aging process?” asks Celine Riera, a postdoc in Andrew Dillin’s lab at the University of California, Berkeley. The answer is yes, according a mouse study by Riera appearing today in Cell.

Riera’s study focuses on mice genetically engineered to lack a pain receptor called TRPV1. This receptor binds to capsaicin, the molecule that gives chili peppers their tingly spice.

After eating a high-fat diet, mice lacking pain receptors (right) are thinner than normal mice (left). From Motter & Ahern, 2008.
After eating a high-fat diet, mice lacking pain receptors (right) are thinner than normal mice (left). From Motter & Ahern, 2008.

In 2008, researchers found that these mutants have a fiery metabolism: When fed a high-fat diet, they gain a lot less weight than normal mice. “We showed that these animals had a greater capacity for energy expenditure,” says Gerard Ahern, a physiologist at Georgetown University who led that study.

Given the robust ties between metabolism and aging, Riera and her colleagues decided to track the lifespan of these mutant mice. They found that the animals live, on average, 100 to 130 days longer than typical lab mice, an increase of 12 to 16 percent. What’s more, the mutant mice showed a “youthful” metabolic profile in old age, including an increased energy expenditure, oxygen consumption, and activity levels.

So how could a pain receptor influence metabolism? Turns out that (in normal animals) these receptors cluster around beta cells of the pancreas, which secrete insulin. When the TRPV1 receptors are stimulated by pain, they release a protein called calcitronin gene-related peptide, or CGRP. And CGRP, in turn, blocks the pancreas from releasing insulin and promotes inflammation. Aging mice “secrete too much of this CGRP,” Riera explains, which leads to a host of metabolic and immunological problems.

Mice that don’t have the pain receptors, the study showed, don’t have this excess CGRP activity, which seems to be why they’re in better metabolic health and live longer than normal.

CGRP is a fascinating protein. Naked mole rats, which outlive their rodent cousins by some 30 years, don’t have the CGRP protein in their sensory nerves. And researchers have reported elevated amounts of CGRP in people with migraine headaches and joint disorders.

Because of the link to migraine, several drugs are in development that target CGRP. The new study suggests that those substances may influence the aging process as well. “It seems like a pathway that’s easily modulated by pharmacological manipulation, and that’s really exciting,” Riera says. (Interestingly, though, targeting the TRPV1 receptor directly isn’t likely to work out. The protein has been the target of several experimental drugs for chronic pain. But in clinical trials patients lose not only their pain but their ability to regulate temperature. “They end up getting hyperthermia or burning themselves in the shower,” Ahern says. “The drugs work too well.”)

There is still much to be figured out about the TRPV1/CGRP pathway and how it influences metabolism. While this new study shows that getting rid of the pain receptor revs up metabolism, other studies have shown that stimulating the receptor — say, by eating capsaicin-rich foods — does the same thing. “So the data is a little bit discordant,” Ahern says, perhaps because these proteins play different roles in different tissues.

The new work is part of a flurry of recent studies to show connections between sensory systems and longevity, notes Joy Alcedo, a neurobiologist at Wayne State University who was not involved in the new study.

For example, in 2004 Alcedo reported that in worms, certain taste neurons promote longevity while others restrict it, probably by influencing insulin signaling. That study showed that odor-sensing neurons, too, influence lifespan by tweaking the worm’s reproductive system. Just this week, another study found that fruit flies that can’t taste water live 43 percent longer than normal flies.

Considering the wide variety of environmental factors that can influence an animal’s lifespan, Alcedo says, “I would not be surprised if many more types of sensory receptors will be found to affect longevity.”

This piece has been changed from the original: People taking TRPV1 drugs sometimes get hyperthermia, not hypothermia.

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An Old and Optimistic Take On Old Age

I’ve been reading and thinking a lot lately about the process of aging. Many scientists who study it argue — quite convincingly — that it’s the most important scientific topic of our time. In his 1997 bestseller Time of Our Lives, biological gerontologist Tom Kirkwood writes that the science of human aging is “one of the last great mysteries of the living world.”

Over the past century, Kirkwood notes, developed countries have used preventative and offensive tactics to slash infant mortality, smoking, and accident rates, and to conquer most infections. In the 1880s, the top causes of death were respiratory diseases (like tuberculosis and influenza) and digestive diseases (like cholera and typhoid), and life expectancy was around 46 years. Today, we’re living three decades longer and dying of illnesses — such as cancer, stroke, and dementia — that most of our ancestors didn’t grow old enough to get.

Perhaps because people are living longer and longer, we tend to think about aging as a modern phenomenon. “Data from the Census Bureau tell us that there are currently around 39 million Americans age 65 and older, up from 25.5 million just 30 years ago,” notes the website of the National Institute on Aging. “This population explosion is unprecedented in history, and the resulting demographic shift is causing profound social and economic changes.”

Though it may be getting a surge of scientific and cultural attention, aging isn’t a new problem. Far from it: Philosophers have been fretting over old age for thousands of years, asking essentially the same thorny, metaphysical questions that get asked today. This became obvious to me this weekend while reading The Nature of Man, a fascinating and surprisingly eloquent book published in 1903 by Russian biologist Élie Metchnikoff.

The book’s basic premise — that science and reason can lead to optimism and happiness, despite religious arguments to the contrary — is interesting in its own right. And I’ll get into how it relates to aging. But Metchnikoff’s argument is even more interesting if you know a bit about his personal life.

When he was 18 years old, Metchnikoff married a woman with tuberculosis. She was sick enough on their wedding day to be carried to the church, and stayed sick for the next decade before dying in 1873. Devastated, Metchnikoff tried to kill himself with an opiate overdose. He married again in 1875, and five years after that his second wife caught typhoid fever. She almost died, and Metchnikoff again attempted suicide.

Metchnikoff’s depression lifted in 1883 with the discovery that would make him famous (and later earn him the Nobel Prize). He was the first to identify phagocytes, cells of the immune system that engulf and destroy invading microbes. He became friendly with Louis Pasteur, whose discoveries of microbes and vaccines had prevented all kinds of sickness and death. In 1888, Metchnikoff was given an appointment at Pasteur’s prestigious research institute, in Paris, where he worked until his death in 1916.

Given Metchnikoff’s life experiences, you can understand why he may have felt reverence and gratitude for science. This was the era, after all, when scientists like Metchnikoff and Pasteur and many others were figuring out how pathogens worked and, with that scientific understanding, developing methods to fight them off.

The premise of Metchnikoff’s The Nature of Man is underscored in its subtitle, “Studies in Optimistic Philosophy.” In it Metchnikoff explains his optimism not only about science’s ability to fight disease, but to ward off a much more menacing threat: aging.

The inevitable decline of aging, Metchnikoff notes, has long pushed people away from science and into the consoling hug of religion. He cites a 2,000-year-old sermon by the Buddha: “Behold, O monks, the holy truth as to suffering. Birth is suffering, old age is suffering, disease is suffering, and death is suffering.” And he notes the same fatalism in a slew of modern writings, from Ecclesiastes (“He that increaseth knowledge, increaseth sorrow”) to Shakespeare (“Conscience does make cowards of us all”), Jean-Jacques Rousseau (“Know O people that nature has desired to preserve you from science as a mother tries to snatch a dangerous weapon from the hands of a child”), and Ferdinand Brunetière (“Science is powerless to resolve the sole problems that are essential, that concern the origin of man, the rules for his conduct, and his future destiny”).

But Metchnikoff seems especially irked by fellow Russian Leo Tolstoy’s thoughts on the inadequacies of science — perhaps because Tolstoy also struggled with depression and suicidal thoughts. Here’s a long snippet from his A Confession, published in 1884, in which he describes how he was satisfied with science until he began feeling the decline of old age and the reality of his own death:

My question — that which at the age of fifty brought me to the verge of suicide — was the simplest of questions, lying in the soul of every man from the foolish child to the wisest elder: it was a question without an answer to which one cannot live, as I had found by experience. It was: “What will come of what I am doing today or shall do tomorrow? What will come of my whole life?”

Differently expressed, the question is: “Why should I live, why wish for anything, or do anything?” It can also be expressed thus: “Is there any meaning in my life that the inevitable death awaiting me does not destroy?”

… From early youth I had been interested in the abstract sciences, but later the mathematical and natural sciences attracted me, and until I put my question definitely to myself, until that question had itself grown up within me urgently demanding a decision, I contented myself with those counterfeit answers which science gives.

Now in the experimental sphere I said to myself: ‘Everything develops and differentiates itself, moving towards complexity and perfection, and there are laws directing this movement. You are a part of the whole. Having learnt as far as possible the whole, and having learnt the law of evolution, you will understand also your place in the whole and will know yourself.’ Ashamed as I am to confess it, there was a time when I seemed satisfied with that. It was just the time when I was myself becoming more complex and was developing. My muscles were growing and strengthening, my memory was being enriched, my capacity to think and understand was increasing, I was growing and developing; and feeling this growth in myself it was natural for me to think that such was the universal law in which I should find the solution of the question of my life.

But a time came when the growth within me ceased. I felt that I was not developing, but fading, my muscles were weakening, my teeth falling out, and I saw that the law not only did not explain anything to me, but that there never had been or could be such a law, and that I had taken for a law what I had found in myself at a certain period of my life. I regarded the definition of that law more strictly, and it became clear to me that there could be no law of endless development; it became clear that to say, ‘in infinite space and time everything develops, becomes more perfect and more complex, is differentiated’, is to say nothing at all. These are all words with no meaning, for in the infinite there is neither complex nor simple, neither forward nor backward, nor better or worse.

Science and rationality, Tolstoy continued, are what make life insufferable. The only way to survive is to give in to an irrational faith: “Whatever the faith may be, and whatever answers it may give, and to whomsoever it gives them, every such answer gives to the finite existence of man an infinite meaning, a meaning not destroyed by sufferings, deprivations, or death.”

Metchnikoff, an atheist, is unsurprisingly critical of this outlook. His book (spoiler alert) doesn’t give the answer to the inevitability of death, but it does offer some hope regarding life’s sufferings and deprivations. Just as science had begun to unravel the mechanisms of microbial disease, Metchnikoff argues, so could it find the biological underpinnings of aging. And if aging could be understood, then its painful manifestations could be slowed, or even stopped. Released of the pain of growing old, there’d be no reason for anyone to be fearful or pessimistic about life, no reason to want to leave this earth.

It turns out that Metchnikoff’s specific ideas about what causes aging didn’t pan out.* But his ultimate claim — that science can help more of us live longer, and with less pain — has proven true, as evidenced by the last century’s rise in life expectancy and the increasing numbers of very old people. Obviously, today’s scientists have not yet figured out how to dramatically slow or stop the aging process. But there’s no inherent reason to think they won’t get there eventually — just as Pasteur’s work on microbes paved the way for treatments for the tuberculosis and typhoid that struck Metchnikoff’s wives.

“Scientists are accustomed to exploring the unknown,” Kirkwood writes in Time of Our Lives. “It serves no useful purpose to pretend that the deep secrets of aging will come easily. But the more we learn, the more reliably we will be able to anticipate future discoveries.”

*Metchnikoff believed that aging was caused in part by the distribution of gut bacteria, which, he wrote, “contributes nothing to the well-being of man” and “is the source of many poisons harmful to the body.” He drank sour milk every day, claiming that the lactic acid it contained would kill harmful gut bacteria. Some thirty years later, inspired by Metchnikoff’s book, Japanese scientist Minoru Shirota created a drink, called Yakult, made of a cultured strain of lactic acid bacteria. It was the world’s first commercial probiotic.

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Why Do We Age? A 46-Species Comparison

Why we age is a tricky evolutionary question. A full set of DNA resides in each of our cells, after all, allowing most of them to replicate again and again and again. Why don’t all tissues regenerate forever? Wouldn’t that be evolutionarily advantageous?

Since the early 1950s, evolutionary biologists have come up with a few explanations, all of which boil down to this: As we get older, our fertility declines and our probability of dying — by bus collision, sword fight, disease, whatever — increases. That combination means that the genetic underpinnings of aging, whatever they are, don’t reveal themselves until after we reproduce. To use the lingo of evolutionary biology, they’re not subject to selective pressure. And that means that senescence, as W.D. Hamilton wrote in 1966, “is an inevitable outcome of evolution.”

Except when it’s not.

Today in Nature, evolutionary biologist Owen Jones and his colleagues have published a first-of-its-kind comparison of the aging patterns of humans and 45 other species. For folks (myself included) who tend to have a people-centric view of biology, the paper is a crazy, fun ride. Sure, some species are like us, with fertility waning and mortality skyrocketing over time. But lots of species show different patterns — bizarrely different. Some organisms are the opposite of humans, becoming more likely to reproduce and less likely to die with each passing year. Others show a spike in both fertility and mortality in old age. Still others show no change in fertility or mortality over their entire lifespan.

That diversity will be surprising to most people who work on human demography. “We’re a bit myopic. We think everything must behave in the same way that we do,” says Jones, an assistant professor of biology at the University of Southern Denmark. “But if you go and speak to someone who works on fish or crocodiles, you’d find that they probably wouldn’t be that surprised.”

What’s most interesting to Jones is not only the great diversity across the tree of life, but the patterns hidden within it. His study found, for example, that most vertebrates show similar patterns, whereas plants are far more variable. “You have to then begin to ask yourself, why are these patterns like they are?” he says. “This article is probably asking more questions than it’s answering.”

This sweeping comparison didn’t require particularly high-tech equipment; it could probably have been done a decade ago, if not before. But nobody had done it. One challenge is that it required a deep dive into the published literature to a) find the raw data on all of these species, and to b) get in touch with the researchers who conducted the field work to see if they’d be willing to share it.

After rounding up all of that data there was then the problem of standardizing it. Mortality and fertility rates of various organisms can differ by orders of magnitude. What’s more, for some species — like the white mangrove, red-legged frog, and hermit crab — this data comes from defined stages of development rather than across the entire lifespan. Jones got around these obstacles by defining “relative mortality” and “relative fertility” numbers for each species, calculated by dividing fertility or mortality rate at a particular age by the average rate across the organism’s entire lifespan. This allows for easy comparison across species, just by looking at the shapes of the curves.

“That’s what’s so disarming about it,” says David Reznick, a distinguished professor of biology at the University of California, Riverside, who was not involved in the new study. “They’ve come up with a way of putting everything on the same scale, so you can perceive patterns that have never been looked at before.”

The study shows, for example, that most mammals and, importantly, the species that scientists tend to use in the laboratory, such as C. elegans and Drosophila, have shapes like ours. But others are weird, at least from a human-centric view. Here’s a sampling:

Red lines show relative mortality and blue lines show relative fertility. Shaded areas show the proportion of individuals still alive at a given age. The box colors indicate the type of species: orange is invertebrates; brown is non-mammalian vertebrates; green is plants. From Jones et al., Nature 2013
Jones et al., Nature 2013

“Some patterns have emerged in this paper that none of us knew were there,” says Reznick, who has studied aging patterns among different populations of guppies. “It’s crazy to think that we’ve been working on aging for so long and something as fundamental as this hasn’t been seen before.”

What the new study didn’t find, notably, is an association between lifespan and aging. It turns out that some species with pronounced aging (meaning those with mortality rates that increase sharply over time) live a long time, whereas others don’t. Same goes for the species that don’t age at all. Oarweed, for example, has a near-constant level of mortality over its life and lives about eight years. In contrast, Hydra, a microscopic freshwater animal, has constant mortality and lives a whopping 1,400 years.

This is a problem for the classical theories of aging that assume that mortality increases with age, notes Alan Cohen, an evolutionary biologist at the University of Sherbrooke in Quebec.

“The traditional idea is that this is what most things do, and that there were a few weird creatures out there that were exceptions,” he says. “But there are actually a lot of exceptions.”

The question that the classical theories try to answer — How could aging evolve? — is no longer the most interesting question, Cohen adds. “What we really need to explain is why some things age and some don’t.”

Cohen is currently collaborating with Jones’s team to formulate a new theory that answers that question. (Stay tuned for more on this! I’ll be digging into all of the various theories over the next couple of months, as I work on a feature story for Mosaic, a new digital publication.)

Given my obsession with people, I asked some of these researchers what the new findings might mean for our understanding of human aging, which most of us would like to avoid. Will studying species that age like we do — or those that live 1,400 years, for that matter — help us defy age-related decline? Would these studies lead to treatments that might, say, double our lifespan?

Cohen politely reminded me that we have already figured out how to extend our lives. The new study, in addition to comparing 46 species, compared trajectories of three groups of humans: hunter-gatherers, those who were born in Sweden in 1881, and modern Japanese women. The differences are stark:

Red lines show relative mortality and blue lines show relative fertility. From Jones et al., Nature 2013

“In industrial societies, we continue on average to add about a year of lifespan every five years,” Cohen says, thanks to advances in public health, nutrition, and medical care. That’s pretty impressive, and likely to continue if we all eat well, exercise, and avoid stress and smoking, he says. “That’s not going to get us living to 200, but it might eventually get us to 110.”

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Scent of Opposite Sex Shortens Lives of Flies and Worms

Smells change us. Inhale the vapours of an apple pie or a bacon sandwich, and your body immediately starts getting ready for an incoming meal. You salivate. You start to produce more digestive enzymes. Your bloodstream courses with insulin, preparing your organs to absorb the nutrients that you’re about to consume.

But smells can have even more profound effects. Two teams of scientists have found that in worms and flies, the scent of pheromones from the opposite sex can speed up an individual’s ageing process and shorten its life. This happens even if no one has any sex.

Just by being around, one worm or fly can control the ageing process in another, at a distance.

While studying the nematode worm Caenorhabditis elegans, Anne Brunet’s team from Stanford University noticed that males seemed to shorten the lives of the opposite sex (hermaphrodites, whose bodies are female but who make both eggs and sperm).

Other scientists had noticed the same effect 17 years earlier, but they assumed that it was due to the “stress of copulation”. But Brunet’s postdoc Travis Maures found that sterile hermaphrodites still suffered in the presence of males… and even in their absence! When he added hermaphrodites to containers that had previously housed males, they still aged more quickly. Their movements slowed, their bodies deteriorated, and their lifespans shortened by some 20 percent.

The males must be secreting some type of pheromone that stays in their environment and curtails the lives of the opposite sex. The team proved this by showing that mutant males which don’t produce pheromones don’t kill their mates early, while mutant hermaphrodites that can’t sense pheromones are immune to the males’ life-shortening powers.

Meanwhile, Scott Pletcher from the University of Michigan found similar patterns in fruit flies. In 2007, his team showed that the mere smell of food can influence the lifespan of flies. Now they’ve found that sex pheromones can do the same.

The problem with fruit flies is that their sperm is toxic and every sexual encounter shortens the lives of females. To work out what the pheromones are doing, the team needed to somehow expose the flies to these smells without actually allowing them to mate. They did it through a clever genetic trick. A single gene called tra determines whether a fly produces male or female pheromones. By switching it on or off, postdocs Christi Gendron and Tsung-Han Kuo engineered male flies that smell like females, and vice versa.

Using these smell-swapped flies, they found that male flies store less fat, become easier to starve, age faster, and die quicker after detecting the scent of female. (The same thing happens to females that smell male pheromones, but to a less dramatic extent.)

“Initially, we thought that the males were just courting a lot or becoming more active, which wouldn’t be that interesting,” says Pletcher. But after carefully watching the flies, his team discounted these explanations. Instead, they showed that the ageing effect is driven by a few taste-sensitive neurons in the flies’ first pair of legs. When they disabled these neurons or just amputated the legs, the males became immune to the female pheromones.

The team also found a way of reversing this life-shortening effect—conjugal visits. If the males were actually allowed to have sex, their lifespans bounced back. That surprised Pletcher, who notes that people have long viewed reproduction and ageing as opposites. “The more energy you put towards reproduction, the less you have remaining to support your health,” he says. “But in this context, reproduction was actually beneficial.”

Why do these pheromones speed up the ageing process? Neither team knows, but both have some ideas. Pletcher speculates that it may be due to the trade-off between sex and longevity. Insulin, for example, is a hormone that’s best known for its role in controlling sugar levels in our blood, but it’s also involved in ageing. “If you reduce insulin signalling, organisms are long-lived but turn off reproduction,” says Pletcher. Pheromones may boost levels of insulin to get flies ready for sex, “and that might lead to enhanced ageing for reasons we don’t understand yet”.

He also suspects that the clash between expectations and experience is important. If we smell food and can’t eat any, the build-up of digestive enzymes can actually cause us harm. Likewise, male flies that smell females but can’t actually mate may suffer the consequences for their unfulfilled expectations. “They make this bet that they’re going to be reproducing soon, and they engage some physiological changes, like producing hormones.” If there’s no sex, these changes are harmful.

Brunet has a different hypothesis. “This is wild speculation,” she says, “but it may be due to sexual conflict.” By shortening the lives of their partners, males could ensure that their offspring aren’t facing competition from their mothers, while also reducing the mating opportunities available to other males. “That’s something we hadn’t considered,” says Pletcher. “It doesn’t entirely fit with our data because when males mate, some of those negative consequences go away, but maybe that means they are battling back?”

These quirky effects are fascinating in their own right, but it’s unclear if they have any relevance to us or to other mammals. “The jury’s out,” says Pletcher, “but I’m as optimistic as I’ve ever been that this would apply to mice, or even humans.” He’s particularly encouraged that both his team and Brunet’s have found similar phenomena in worms and flies—species that have been separated by over 900 million years of evolution. “Historically, genes and pathways of ageing that have been identified in worms and flies have also been relevant to mice.”

Brunet is more circumspect. “We joke that we should open a fragrance company, with fine-print warning labels that say, Caution: this might cause the premature demise of your mate,” she says. More seriously, she notes that it’s not clear what part pheromones play in sexual communication in humans. Mice clearly do use pheromones for this purpose, so the next step would be to see if mice can influence the pace of ageing in the opposite sex, without ever actually mating. “The experiments could be done, but they’re tricky,” she says.

Reference: Gendron, Kuo, Harvanek, Chung, Yew, Dierick & Pletcher. 2013. Drosophila Life Span and Physiology Are Modulated by Sexual Perception and Reward. Science http://dx.doi.org/10.1126/science.1243339

Maures, Booth, Benayoun, Izrayelit, Schroeder & Brunet. 2013. Males Shorten the Life Span of C. elegans Hermaphrodites via Secreted Compounds. Science http://dx.doi.org/10.1126/science.1244160

More on ageing:

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Almond-Sized Brain Region is Control Centre for Ageing

In a New York laboratory, a special group of mice is destined to outlive their cage-mates. Their muscles will stay strong for longer. Their brains will stay sharp for longer. When they eventually die, they will have seen more months than their peers.

The secret to their longevity isn’t a drug or a special diet. Instead, Dongsheng Cai from the Albert Einstein College of Medicine simply reduced the levels of a single protein called NF-kB in part of the brain called the hypothalamus. That was enough to extend their lives.

The hypothalamus is an almond-sized structure on the floor of the brain. It’s a control centre for many aspects of our lives that we don’t actively think about. The nervous system feeds it with information about the state of our body and the world around us, and it uses these to coordinate the release of hormones that influence our hunger, thirst, temperature, sleep cycles, and more.

Now, Cai has discovered yet another vital duty on the hypothalamus’ already impressive CV—it’s a command centre that coordinates the ageing process across the entire body. By manipulating proteins within it, Cai managed to speed up or slow down the pace of ageing in mice.

Headlines will inevitably talk about scientists discovering fountains of youth, but that would be hype. As Cai emphasises, “We can’t prevent ageing.” Although his experiments point to ways of extending life or avoiding the health problems that accompany old age, there’s a long history of supposed breakthroughs in ageing research that have led down false turns and dead ends. Other scientists need to repeat these experiments to show that the result aren’t one-offs and that they apply to humans as well as mice.

As we get older, our organs start to deteriorate across the board. It’s possible that this all happens independently and randomly. But studies of worms and flies suggest that parts of the brain might help to coordinate this body-wide decline. Cai suspected that the hypothalamus might play this role in the brains of mammals.

His team showed that as mice get older, the NF-kB protein becomes more active throughout their brains, but especially in the hypothalamus. Next, the team delivered genes into their mice that reduced the levels of NF-kB in their hypothalamus. Even if the animals were already well into middle-age, the loss of the protein still extended their lives by around 10 percent. And if they had less NF-kB from birth, they lived 20 percent longer—a gain of around 7 months.

Better still, those extra months were healthier ones. The mice performed better in maze tests that tested their learning and memory, their muscles and tendons were stronger, their bones were heavier and their skins were thicker. And when Cai’s team delivered genes that increased levels of NF-kB, they saw the opposite effects. The rodents’ bodies declined more quickly, and they died after an average of 30 months.

“This is a brilliant study,” says Caleb Finch from the University of Southern California, who studies ageing. In the 1970s, he suggested that the hypothalamus might contain pacemakers of ageing, and these experiments support his ideas.

Changing an animal’s lifespan is cool enough, but the results are also important because they support a close connection between ageing and the immune system. NF-kB is a key part of the immune system and plays the role of ‘first responder’. It’s activated by everything from radiation to infectious microbes to stress, and coordinates the immune system’s response to these potential threats. This includes setting up a state of inflammation, where teams of cells can destroy invaders and repair damage. In the short term, this saves our lives, but in the long term, chronic inflammation can contribute to many diseases of old age, such as cancer and heart disease. Could it also age the entire body?

Cai’s team found that the ageing hypothalamus builds up more microglia—a dedicated brand of inflammatory immune cells in the brain, which destroy infectious microbes and vacuum up debris. They also produce NF-kB, which tells neighbouring neurons to do the same. This flood of NF-kB switches off the gene for a hormone called GnRH.

That’s a surprise—GnRH is best known as a reproductive hormone. It controls the development of our sexual organs and the making of eggs and sperm. Why does it affect ageing?

To find out, Cai’s team injected GnRH into the hypothalamus of old mice. They found that the hormone triggers the birth of new neurons (neurogenesis), not just in the hypothalamus but also in other areas like the hippocampus, involved in memory. As mice get older, this production line grinds to a halt, but GnRH can rev it back into action. The team even managed to increase the lifespan of mice, and delay the decline of their muscles, brains and bones, by injecting them with GnRH.

Howard Chang from Stanford University says, “If reproduced by others, this work provides further evidence that aging is a regulated rather than a [random] process.” As mice age, microglia build up in their hypothalamus and raise local levels of NF-kB. This reduces the levels of GnRH, and stops the creation of new neurons. What happens next is unclear. It’s possible that the newborn neurons affect many different organs, and their loss leads to the widespread decline that we experience as we age. The next step is to work out exactly what these new neurons do and the connections they form.

But let’s recap what we already know, just to appreciate how bizarre this chain of results is. You have a life-support centre in the brain, a protein that coordinates the immune system, and a hormone that controls our sex organs, all working together to influence… the pace of ageing?

At first, Cai’s discovery feels like a unifying or simplifying one—just one small part of the brain can influence ageing in a broad range of organs. In fact, it just makes things even more complicated than they were before.

Reference: Zhang, Li, Purkayastha, Tang, Zhang, Yin, Bo, Liu & Cai. 2013. Hypothalamic programming of systemic ageing involving IKK-b,NF-kB and GnRH. http://dx.doi.org/10.1038/nature12143

Update: The original version of this post implied that increasing levels of NF-kB led to longer lifespan, and reducing those levels led to shorter lifespan. In fact, it’s the opposite. Obviously. Sorry. Sometimes, I suck. Regret the error, etc. Thanks to Emily Willingham for pointing out the flaw.

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Neurons Could Outlive the Bodies That Contain Them

Most of your body is younger than you are. The cells on the topmost layer of your skin are around two weeks old, and soon to die. Your oldest red blood cells are around four months old. Your liver’s cells will live for around 10 to 17 months old before being replaced. All across your organs, cells are being produced and destroyed. They have an expiry date.

In your brain, it’s a different story. New neurons are made in just two parts of the brain—the hippocampus, involved in memory and navigation, and the olfactory bulb, involved in smell (and even then only until 18 months of age). Aside from that, your neurons are as old as you are and will last you for the rest of your life. They don’t divide, and there’s no turnover.

But do neurons have a maximum lifespan, just like skin, blood or liver cells? Yes, obviously, they die when you die, but what if you kept on living? That’s not a far-fetched question at a time when medical and technological advances promise to prolong our lives well past their usual boundaries. Would we reach a point when our neurons give up before our bodies do?

Lorenzo Magrassi, a neurosurgeon at the University of Pavia, thinks not. He recently transplanted neuron-making cells from mouse embryos into the developing brains of longer-lived rats. These cells matured into neurons that looked like mouse neurons… but with rat lifespans. They survived for up to 36 months, around twice as long as they normally do in their native mouse brains.

“Neurons do not have a fixed lifespan,” says Magrassi. “They may survive forever. It’s the body that contains them that die. If you put them in a longer-living body, they survive as long as the new body allows them to. It increases our hope that extending lifespan will not necessarily result in brain depleted of neurons.”

Magrassi worked with genetically modified mouse embryos whose cells all produce a glowing green protein, and could be easily tracked. From these embryos, he removed the precursors of brain cells, and transplanted them into rat embryos. In their new hosts, the green glow of these foreign cells gave away their presence, and that of any of their descendants.

The transplanted cells survived in around a third of the rats. They produced many types of mature brain cells, including several classes of neurons and supportive cells called glia. The neurons hooked up with their rat counterparts while staying true to their mouse origins in terms of size and shape.

Their lifespans, however, shot up. Magrassi focused on Purkinje cells—a class of large, bushy, many-branching neurons that are involved in controlling movements. These cells spontaneously die during ageing, in both humans and rodents. But while their donor mice live for around 18 months, and 26 at the most, the transplanted Purkinje cells lived for as long as their new rat hosts did—around 30 months, and 36 at the most. Their maximum lifespan went up by 38 percent. Their branches thinned with time, but they didn’t die.

For perspective, while some exceptional mice lead very long lives, there is no artificial way of extending an entire mouse’s life by 38 percent—not through good diets, drug treatments, or genetic engineering.

Diana Woodruff-Pak, a neuroscientist from Temple University, is certainly impressed. “Purkinje neurons are the most vulnerable of neurons and one of the few kinds lost in normal ageing,” she says. “To extend the life of mouse Purkinje neurons is remarkable.”

But Judith Campisi, who studies ageing at the Buck Institute in California, is not surprised by the study’s results. “The idea that an organism dies when its cells die is not mainline thought in ageing research,” she says. “If you take a neuron from a mouse and put it in an elephant, would you really expect that neuron to live for2.5 years?” She thinks not. “Most people die with most of their neurons intact. If you live to 123, you’ll die with much of the cells you were born with.”

But Magrassi says that the idea that extending lifespan would lead to a neuronally impoverished brain was a “generalised belief until quite recently”. And the evidence to the contrary—like the fact that very old people still have most of their neurons—has been indirect. His experiments provide more direct confirmation that neurons don’t have some fixed lifespan, set by their genes. Instead, it’s their environment that determines when they die.

Magrassi doesn’t think that the rat brain provides anything special that the mouse brain lacks. It’s the same proteins at work in both rodents, but presumably deployed to different rhythms. (And Woodruff-Pak suspects that the rats’ own glia are working to support the mouse Purkinje neurons and extend their lives.)

The team are now dissecting the transplanted cells to understand why they live longer in rats. “If we discover what factor or factors are responsible, we may hope to use them in those diseases when neurons start to die much earlier,” says Magrassi. “Of course, there is still a long way to go.”

Reference: Magrassi, Leto & Rossi. 2013. Lifespan of neurons is uncoupled from organismal lifespan. PNAS http://dx.doi.org/10.1073/pnas.1217505110

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The two faces of rapamycin – why a life-extending drug also increases risk of diabetes

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?


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Extending healthy life by getting rid of retired cells

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.


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Memory improves when neurons fire in youthful surroundings

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.


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The olm: the blind cave salamander that lives to 100

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.


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[RETRACTED] Genetic signatures for extreme old age accurately predict odds of living past 100 [RETRACTED]


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.


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A life in the trees is a longer one

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.


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Balancing amino acids for a longer life

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

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Secrets of the supercentenarians: Life begins at 100

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.

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Rapamycin – the Easter Island drug that extends lifespan of old mice

Blogging on Peer-Reviewed ResearchIt’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.”