News this Week

Science  04 Dec 2015:
Vol. 350, Issue 6265, pp. 1136

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  1. News at a glance

    BioArt finds beauty in spreading cells, Ebola, roundworms


    The above image isn't of a glass coffee table sculpture; it shows how fluorescent labeling can be used to track the spread of cells from different tumors in mice with pancreatic cancer. From these multicolored cells to roundworms congregating to feed on bacteria to structural proteins of the Ebola virus, the 2015 winners of the Federation of American Societies for Experimental Biology's (FASEB) BioArt competition reveal the artistic—even disconcertingly attractive—side of some of the less attractive subjects in the biomedical and life sciences. In all, the winners of the fourth annual competition, unveiled last week on FASEB's website (, include 11 images and two videos.

    Fish show signs of sentience in ‘emotional fever’ test

    A study of zebrafish upends a key argument against awareness in fish.


    Scientists have long believed that fish aren't capable of the same awareness as humans because they fail the “emotional fever” test. Birds, mammals (including humans), and at least one species of lizard experience a slight rise in body temperature—about 1°C to 2°C—when exposed to new environments; the fever is linked to emotions because it's triggered by an outside stimulus, yet produces behavioral and physiological changes. Previous tests suggested that toads and fish don't react this way, but a new experiment reported last week in the Proceedings of the Royal Society B suggests fish can indeed get stressed. Researchers confined some zebrafish to a chamber in a tank containing water at about 27°C (zebrafish prefer water of about 28°C), and allowed others to swim freely around five other chambers in the tank, each heated to a temperature between 17.92°C and 35°C. After about 15 minutes, the team set the confined fish free to roam through the chambers. The stressed fish spent more time in warmer waters than did the control fish, thus raising their body temperatures by about 2°C to 4°C—the fish equivalent of an emotional fever, the scientists say.

    $165,000,000—Global investment in Ebola research in 2014 in response to the West African epidemic, according to G-FINDER, an annual report on R&D on neglected diseases. Before 2014, G-FINDER didn't keep track because of Ebola's very low disease burden.

    Around the world

    Geneva, Switzerland

    U.N. notes AIDS progress, gaps

    Of the estimated 36.9 million people in the world infected with HIV, 70% of them live in sub-Saharan Africa. Of these, 49% do not know their HIV status, according to a report released last week by the Joint United Nations Programme on HIV/AIDS, and about 57% are not receiving antiretroviral drugs. The document, published on the eve of World AIDS Day, 1 December, celebrates the progress that has been made in reversing the spread of HIV/AIDS by getting antiretrovirals to 15.8 million people by June of 2015. But it also notes that many countries are still far from meeting World Health Organization guidelines issued in September, which recommend early antiretroviral treatment for every infected person. Recent evidence shows that fully suppressing infection by initiating treatment early benefits an individual's health and sharply decreases transmission rate. But in sub-Saharan Africa, the report notes, an estimated 68% of infected people remain untreated.


    French call for terror studies

    Memorials commemorate victims of the Paris attacks.


    Many French researchers have welcomed a call by the National Center for Scientific Research (CNRS) for study proposals to help understand and prevent terrorism in the wake of the 13 November attacks that killed 130 and profoundly shocked the country. The call came in a 18 November letter from CNRS president Alain Fuchs, who described it as “a rare opportunity for researchers to express a form of solidarity with all those who, directly or indirectly, have been affected” by the attacks. The letter doesn't specify topics of interest or a budget, but CNRS promises “a rigorous, simple and rapid procedure” for applicants that will allow the first research results to emerge next year.


    Spain to create funding agency

    The Spanish government finally made good on its promise to create a national science funding agency on 27 November when it announced the launch of the State Research Agency. The government says the new body, which was promised in a science law passed in 2011, will create a more stable funding stream and “more agile, flexible, and autonomous” management procedures. Although Spain's scientific community had long pleaded for a granting agency, some have doubts about the plan. Few operational details have been revealed, and there are questions about the scientific independence of the agency's management. Some researchers also wonder about the agency's future if the ruling People's Party loses Spain's parliamentary elections, slated for 20 December.


    New signs of dinosaur proteins

    In a series of papers since 2007, researchers led by Mary Schweitzer, a paleontologist at North Carolina State University in Raleigh, have reported that they've isolated fragments of intact collagen—a protein found in connective tissue and bones—from dinosaurs as old as 80 million years. Critics have raised concerns that the protein fragments were contaminants from bacteria or other organisms, as proteins normally decay within a few hundred thousand years after an animal dies. Now, Schweitzer and a new set of colleagues report in the Journal of Proteome Research that they have extracted samples from what appear, under a microscope, to be blood vessels in bone. After analyzing these samples, the team says, they found signatures of vertebrate collagen and blood proteins.

    Gender overlaps in human brains

    Human brains do not fit neatly into “male” and “female” categories, scientists reported this week in the Proceedings of the National Academy of Sciences. The researchers used existing sets of MRI brain images to measure the volume of gray matter (the knobby tissue that contains the core of nerve cells) and white matter (the bundles of nerve fibers that transmit signals) in the brains of more than 1400 individuals. Based on a few structural differences found more often in men or women—for example, men generally had a larger left hippocampus, associated with memory—the team created a continuum of “femaleness” to “maleness” for the entire brain. But the majority of the studied brains, they found, were a mosaic of male and female structures; only 0% to 8% of the brains contained all-male or all-female structures.

  2. Aging

    Why we outlive our pets

    1. David Grimm

    Cats and dogs are revealing some surprising insights into how animals age.

    Lily, a long-haired dachshund, at 8 months, 2 years, 7 years, and 15 years.


    Jeanne Calment has nothing on Creme Puff, the cat. The oldest living human made it to the ripe age of 122—not bad for a species with an average life span of 71 years. But Creme Puff, a Texas feline that allegedly subsisted on bacon, broccoli, and heavy cream, more than doubled the longevity of her kind, surviving a reported 38 years. Bluey, an Australian cattle dog, was no slouch either. At age 29, he became the oldest canine on record, living more than twice as long as the average pooch.

    For centuries, scientists have tried to understand the human life span. What sets the limits? What can be done to slow down the clock? Now, they're beginning to ask the same questions of our pets. As in humans, the answers have been hard to come by. But some intriguing hypotheses are emerging—ideas that may help explain everything from why small dogs live longer than big ones to why cats tend to outlast our canine pals.

    Figuring out how animals age is a “fascinating problem,” says Daniel Promislow, an evolutionary geneticist at the University of Washington, Seattle, and co-leader of the Dog Aging Project, which aims to extend the canine life span. “It integrates behavior, reproduction, ecology, and evolution. If we can understand how to improve the quality and length of life, it's good for our pets and it's good for us. It's a win-win.”

    SCIENTISTS HAVE BEEN PONDERING the mysteries of aging for more than 2000 years. “The reasons for some animals being long-lived and others short-lived, and, in a word, causes of the length and brevity of life call for investigation,” wrote Aristotle in 350 B.C.E. The Greek philosopher suspected the answer had something to do with moisture: Elephants outlast mice, he reasoned, because they contain more liquid and thus take longer to dry up. The idea hasn't exactly held water, but Aristotle's observation that bigger animals tend to live longer has. Indeed, it's the only trend today's scientists agree on.

    “All of the other hypotheses have fallen apart,” says Steven Austad, a biogerontologist at the University of Alabama, Birmingham. One of the most popular ideas of the past 100 years has been that animals with higher metabolic rates live shorter lives because they run out their body clock faster. But “it hasn't held up,” Austad says. Parrot hearts can beat up to 600 times per minute, for example, but they outlive by decades many creatures with slower tickers. Other assumptions, for example that short-lived animals generate more tissue-damaging free radicals or have cells that stop dividing sooner, also lack strong evidence. “A lot of simple stories have vanished,” he says.

    Longevity favors the big guysCREDITS: (GRAPHIC) A. CUADRA/SCIENCE; (DATA) ANAGE

    Austad should know something about animals. He worked as a lion trainer in the early 1970s, until one of the big cats tore up his leg—an injury that persuaded him to study, rather than tame, the world's creatures. By the mid-1980s, he was observing opossum behavior in Venezuela as a postdoc when he began to notice how quickly the marsupials aged. “They'd go from being in great shape to having cataracts and muscle wasting in 3 months,” he says. Austad also noticed something even more intriguing: Opossums on a nearby island free from predators seemed to age slower—and live longer—than their mainland counterparts.

    The observation helped explain why Aristotle's key insight continues to hold true. Large animals tend to live longer, says Austad, because they face fewer dangers. It's not a simple question of survival, he says, but rather the result of millions of years of evolutionary pressure. Whales and elephants can afford to take their time growing because no one is going to attack them, he explains. And that means they can invest resources in robust bodies that will allow them to sire many rounds of offspring. Mice and other heavily preyed-on small animals, on the other hand, live life in fast-forward: They need to put their energy into growing and reproducing quickly, not into developing hardy immune systems, Austad says. “You wouldn't put a $1000 crystal on a $5 watch.”

    WHEN IT COMES TO OUR PETS, the bigger-is-better theory gets flipped on its ear. Cats live an average of 15 years, compared with about 12 years for dogs, despite generally being smaller. And small dogs can live twice as long as large ones.

    Yet the lesson of Austad's opossums may still apply. Gray wolves, the ancestors of dogs, live a maximum of 11 or 12 years in the wild, whereas wildcats can live up to 16 years. This suggests that the two species face different evolutionary pressures, Austad says. Wolves are more social than cats and thus more likely to spread infectious disease, he says; wildcats, on the other hand, keep to themselves, reducing the spread of disease, and are adept at defending against predators. “Cats are so incredibly well-armed, they're like porcupines”—an animal that notably also has a long life span for its size, more than 20 years. Indeed, two other small animals that are good at avoiding danger, naked mole rats and bats, can live 30 and 40 years, respectively. (Mole rats spend most of their time underground, whereas bats can simply fly away.) Mice, meanwhile, live just a couple of years—unless they're eaten first.

    Poppy, recognized as the world's oldest cat in 2014, lived to the ripe age of 24.


    When it comes to why small dogs tend to outlive big ones, the story gets a bit more complicated. Large dogs like the 70-kilogram Irish Wolfhound are lucky to make it to age 7, whereas tiny pooches like the 4-kilo Papillon can live 10 years longer. Most dog breeds are less than a couple of hundred years old, so evolutionary pressure clearly isn't at work. Instead, hormones like insulin-like growth factor 1, which swells dogs to big sizes, may play a role; researchers have linked the protein to shorter life spans in a variety of species, though the mechanism is unclear. Larger canines also tend to grow faster, notes the Dog Aging Project's Promislow, which could result in “jerry-built” bodies that are more susceptible to complications and disease. Big dogs do tend to have more health problems than small ones—German Shepherds are prone to hip dysplasia, for example, and Siberian Huskies are plagued by autoimmune disorders—though these could also be the result of inbreeding.

    Despite the differences between cats and dogs, both pets are living longer than ever before. Dog life expectancy has doubled in the past 4 decades, and housecats now live twice as long as their feral counterparts. The reasons can largely be chalked up to better health care and better diet. Americans will spend $60 billion on their pets this year, with a large chunk of that going to humanlike health care (think annual physicals and open-heart surgery) and premium food. “The same things that allow us to live longer also apply to our pets,” says João Pedro de Magalhães, a biogerontologist at the University of Liverpool in the United Kingdom who maintains AnAge, the world's largest database of animal life spans. The trend may not continue, though: More than half of U.S. pets are overweight or obese, and they are exposed to the same pollutants and carcinogens we are.

    All of this uniquely positions dogs and cats to solve the riddle of how we ourselves grow old. After all, we have more medical records on them than on any other animal, save humans, and we learn more about their biology and genomes every day. Perhaps they hold the clues to slowing down the body clock for all of us—and maybe even stopping it. “I don't think there's a set max. longevity for any species,” Magalhães says. “The real question is, ‘How far can we go?’ Maybe a thousand years from now you could have a dog that lives 300 years.”

    That's good news, especially if our life spans increase dramatically as well. After all, who wants to live forever if you can't live with your best friend?

  3. Aging

    Death–defying experiments

    1. Jon Cohen

    Pushing the limits of life span in animals could someday help lengthen our own.

    This 1463-day-old mouse is part of a long-lived cohort at The Jackson Laboratory.


    On 8 January 2003, a mouse made news because it died.

    Unlike other caged animals that gain notoriety, this dwarf mouse was not particularly cute or charismatic. He had not performed a silly pet trick or some astonishing intellectual feat. This laboratory mouse, a resident of Southern Illinois University in Carbondale, won notoriety because he lived 1819 days. “He missed his fifth birthday by a week, which is kind of unheard of in life span for a mouse,” says Andrzej Bartke, the zoologist who ran the lab that bred and studied the murine wonder unimaginatively dubbed GHR-KO 11C.

    Bartke is too modest: It was unheard of. Lab mice typically live half as long, and GHR-KO 11C had, by Bartke's calculations, lived beyond 180 human years. “As pleasant as it was for us to get this notice and publicity, it's an n of 1,” he stresses. “I didn't get too excited.” (Some colleagues suspect there was a lab mix-up and GHR-KO 11C did not live as long as reported, but—reluctant to be seen as competing for a ridiculous title—keep their doubts quiet.)

    Deliberately mutated to knock out a gene for a growth hormone receptor, GHR-KO 11C was a beneficiary of Bartke's effort to tease out the forces that drive aging. Other researchers have bred or engineered animals from mice down to flies, worms, and even yeast to vastly exceed their normal spans. The effort is yielding insights into aging, but researchers concede that there is also a Guinness World Records–ish fascination about it. “‘My animal lives longer than yours’ is highly clickable,” says Richard Miller, who studies the biology of aging at the University of Michigan, Ann Arbor.

    Miller's own elderly mice have enjoyed a few brief moments in the limelight. The first came 2 years before GHR-KO 11C squeaked to fame when Miller claimed the title of having “the world's oldest normal lab mouse.” Dubbed IdG1-030, the mouse lived 1449 days, and its death elicited an obituary in the ironically short-lived Science of Aging Knowledge Environment. “Born and raised in a small plastic cage in Ann Arbor, Michigan, IdG1-030 was one of a set of quintuplets born to a mated pair whose own parents had romped, poor but free, in the barnyards of Moscow, Idaho,” read the heart-wrenching obit. The goal was to compare wild mice with their laboratory cousins, which have been bred for short life spans to make it easier to complete experiments.

    As Miller stressed in IdG1-030's death notice, his lab had not restricted the caloric intake of the mouse, a tried-and-true way to extend the life span of many species, including mice. Miller wrote that his mouse “was clearly willing to accept an asterisk in the record books as the price for a life of ready access to all-you-can-eat meals.” Today, several lab mice have passed their fourth birthdays, including one in Miller's lab named Yoda, a nod to the oldest Jedi master in Star Wars. “We now have at least five genes, two diets, and five drugs that extend mouse life spans,” Miller says. “There's an enormous amount that's been learned.”

    Geneticist Gary Churchill at The Jackson Laboratory in Bar Harbor, Maine, currently has the oldest living mice, several of which are 4.5 years old. “They've been dropping off,” Churchill laments. “I'm not holding my breath, but we could still make it to 5 years.”

    RESEARCHERS WHO STUDY Drosophila melanogaster, the fruit fly elevated to super star status in genetic studies by Nobel laureate Thomas Hunt Morgan, have never reported a Yoda, GHR-KO 11C, or IdG1-030. “There is no oldest fly,” says Marc Tatar, an evolutionary biologist at Brown University. “We don't really pay that much attention. People who work on Drosophila look at cohorts and populations.”

    Nobody even knows the average life span of Drosophila, Tatar says, because the flies are so sensitive to diet, temperature, access to mates, and other environmental forces. “In my lab, the average might be 40, 50 days, and long-lived ones might be 80 or 90.” That said, his lab and others have shown that they can produce long-lived fly populations by mutating genes—including the comically named Indy (I'm not dead yet)—that affect metabolic pathways.

    Evolutionary biologist Michael Rose, whom Malcolm Gladwell profiled in The New Yorker in 1996 for his creation of “Methuselah” flies, pushed their life spans to 4 months and more by selectively breeding them for longevity. Rose, who works at the University of California (UC), Irvine, insists that he no longer is interested in setting records. Just the same, he says, “Our Methuselah flies wipe the floor with everyone else's mutant Drosophila,” adding, “what most people work with in most labs is inbred garbage.” His lab now studies how aging can be stopped. “It renders the question of the longest lived organism meaningless,” he says.

    Getting more mileage from miceGRAPHIC: ADAPTED FROM BARTKE ET AL. NATURE 414 (22 NOVEMBER 2001) © 2001 MACMILLAN MAGAZINES LTD

    James Carey's landmark fly studies also challenge the notion of an upper age limit. Carey, an entomologist at UC Davis, and colleagues studied 1.2 million medflies at a factory in Mexico that bred sterile versions of these fruit-destroying pests as part of a biological control strategy. The work, reported in Science in 1992, helped overturn the theory that mortality risks increase with age. The percentage of medflies that die at a certain day, it turns out, decreases as they age. So if you have a population of medflies that reaches 100 days, you might see 10% of them die by 110 days, but between 110 and 120 days the mortality rate could drop to 9%. “It was a big surprise that there's a slowing of mortality,” Carey says. “You still have a high probability of dying, but it's just not as high.”

    The findings suggest that “there's not a wall of death,” he says. He points to Jeanne Calment, the longest-lived human on record, who died in France at age 122. “It's inconceivable to me that 122 will never ever be broken in the history of humankind,” he says.

    LONGEVITY RESEARCHERS have had the most success increasing the life span of Caenorhabditis elegans, the soil roundworm that Nobel laureate Sydney Brenner brought into the lab in 1963 to study neural development. “We have single gene mutations with the greatest percentage increase in any animal life span by far,” says molecular geneticist Robert Shmookler Reis of the University of Arkansas for Medical Sciences in Little Rock.

    In 2008, Reis and colleagues reported in Aging Cell that two strains of C. elegans with mutations in the same gene, age-1, had an average life span of 145 to 190 days—nearly 10 times longer than the wild-type worms living in the same environment. The oldest worm in their study lived 270 days. “We were astonished,” Reis says. “The first time we did it I said ‘No, no, they can't still be alive, you must be looking at descendants of the starting worms.’ Except these worms were absolutely sterile!” The researchers are still working to explain the extraordinarily long life spans, but have evidence that their longevity is tied to silencing of insulinlike signaling pathways and stress responses.

    The worms, bizarrely, had “near normal” motility and feeding rates—similar to wild-type worms at one-tenth their age—until they neared death. “The last few worms to die are always on their last legs,” says Reis, who quickly adds, “I know they don't have legs, but they don't look that great.”

    THE SPECIES that still holds the lab longevity sweepstakes is Hydra vulgaris, a tiny relative of the jellyfish made up of three lineages of self-renewing stem cells that—unlike in other species—do not lose their capacity to replace themselves as they age. Evolutionary biologist Daniel Martínez of Pomona College in Claremont, California, in 1998 published a study in Experimental Gerontology describing how 145 Hydra had lived in his lab for 4 years without any signs of aging, leading to his claim that they “may be potentially immortal.” His work purported to end a century-old scientific debate about whether these creatures age.

    “After I published this initial paper I stopped,” Martínez says. “I couldn't figure out what to do. You can't study aging in something that doesn't age.” The Hydra had to be fed three times a week with live brine shrimp and were fussy about salinity (hate it), their own waste, temperature, and overfeeding. “I was just sick of them,” he said. “I put them in alcohol and killed them.”

    When researchers from a Max Planck institute in Germany convinced Martínez that there was more to learn from these apparently immortal animals, he restarted his experiments. Working together, the two groups now have Hydra that are 10 years old. “There's no evidence of aging, no decay in reproduction, and no sign of mortality,” he says. The team also has shown that FoxO, a gene that increases tolerance to oxidative stress—and is linked to longevity in Drosophila and C. elegans—may play a central role in Hydra's ability to maintain its stem cells.

    In contrast to H. vulgaris, its cousin, H. oligactis, will senesce if confronted by lowering water temperatures. Basically, the cooler water prompts the Hydra to switch from its usual, asexual mode of reproduction to sexual reproduction. “They switch from being stem cells into differentiated cells,” Martínez notes. Now, he's comparing the two Hydra species to learn what controls the change.

    Last year Martínez's collaborators claimed in Nature that 5% of adults cared for in a lab would still be alive after 1400 years; the others would have died of accidents and disease, but not old age. “I'm reluctant to say that what we're going to learn in Hydra will make us immortal,” Martínez says. “But you never know when you're going to learn something that will apply to humans.”

  4. Aging

    The final countdown

    1. Emily Underwood

    In the race to find a biological clock, there are plenty of contenders.


    A few years ago, molecular bio logist John Sedivy took an online quiz billed as a test of his true, “biological” age. Among questions about how often he smoked and exercised was an odd one: what kind of car he drove. Sedivy first checked the box for a small sedan. Then, out of curiosity, he switched his answer to a large SUV.

    Opting for the bigger vehicle subtracted 3 years from his age. Later, at an aging conference in Europe, the Brown University researcher joked that Americans had figured out the secret to longevity: “Drive big honking cars.”

    More-scientific efforts to determine biological age—how rapidly a person's body is aging, regardless of their chronological age—are equally fraught, Sedivy says. After decades of failed efforts to identify “biomarkers” in blood and different tissues that correspond to the aging process, scientists still don't agree on whether “biological age” can be measured, or even what it means. Indeed, despite some companies' claims, “there's no way that you can take a sample of someone's skin or blood and tell them what their true ‘biological’ age is,” he says.

    Yet the allure of an objective test for aging is powerful. Such a test could, for example, aid the search for antiaging drugs and help doctors plan treatments for older patients. Recent advances in the molecular biology of aging have yielded a host of candidates. All rely on molecular changes linked to aging, but all are confounded by individual variation or by other processes, such as disease, that may speed or slow aging. As aging pioneer Carol Greider of Johns Hopkins University in Baltimore, Maryland, puts it, “My guess is that there is going to be a huge amount of heterogeneity in any marker.”


    TELOMERE LENGTH. In the 1980s, a trio of biologists—Grieder; Elizabeth Blackburn, then at the University of California (UC), Berkeley; and Jack Szostak, then at Harvard Medical School in Boston—wowed the scientific world with the discovery that protective caps on the ends of chromosomes, called telomeres, must maintain a certain length for cells to continue dividing. They also found a mechanism for repairing and lengthening damaged telomeres: an enzyme called telomerase.

    The work later won the Nobel Prize, in part because it promised profound insights into aging. Because telomeres get shorter every time a cell divides, many researchers viewed them as a clocklike molecular aging signature. Despite intriguing population-wide correlations between telomere length, disease, and mortality, however, subsequent efforts to use telomeres as the long-sought aging biomarker have sputtered, Greider says. Among the confounding variables is the diversity of telomere lengths among people of the same age, she notes. Recently, scientists have also discovered an apparent tradeoff between the age-buffering effects of long telomeres and a greater risk of some cancers, she adds.

    Such caveats have not prevented a number of companies and researchers, including Greider's former mentor Blackburn, from developing commercial telomere-based tests. In 2010, Blackburn co-founded the Menlo Park, California–based company Telome Health, now Telomere Diagnostics, which provides analyses of telomere length in cells from a person's saliva to their doctors. Although the tests are not meant to predict how long an individual will live, Blackburn emphasizes, they may help physicians evaluate a patient's risk for a variety of age-related diseases and early mortality. Blackburn has recently distanced herself from the company—a year ago she donated all her shares to a nonprofit organization.

    Grieder served on the advisory board of a Menlo Park–based biotechnology company called Geron in the 1990s, but left because she felt the company was overstating the tests' clinical benefits. She still doubts that such tests hold much value for consumers at present. Only extremely short telomeres, resulting from genetic disorders known as telomere syndromes, are known to cause disease, she says.

    Others share her skepticism. The value of such tests for individuals lies mostly in their “cocktail party” appeal, says Jerry Shay, a biologist at the Texas Southwestern Medical Center in Dallas. Still, Shay serves as consultant to the Madrid-based company Life Length, which claims to be able to calculate a person's biological age by the median length of their telomeres for roughly $395 a pop. He's convinced that the tests do more good than harm—if one's telomere age were higher than expected, “that might be tap on the shoulder, letting you know that you're doing something wrong” in terms of lifestyle or diet, he says.

    GENES AND DNA. In 2013, bioinformaticist and geneticist Steve Horvath at UC Los Angeles, proposed a new aging clock based on epigenetics, DNA alterations due to the addition and removal of chemical tags called methyl groups. Methylation can alter gene expression, and its pattern across the genome is known to evolve over the course of a lifetime.


    Horvath has discovered what he believes to be a molecular aging signature in that pattern. By analyzing methylation levels at 353 sites on the genome from more than 13,000 human tissue samples, he developed an algorithm that can predict an individual's chronological age with more than 90% accuracy. Then he zeroed in on specific organs and tissues to measure his algorithm's performance. Would it show that tissues that are more prone to disease age faster than the body's average?

    He found provocative patterns: cancerprone breast tissue, for example, was several years older than the body as a whole, according to his epigenetic clock. Samples of cerebellum taken from deceased centenarians, in contrast, showed a comparatively youthful pattern of DNA methylation.

    Horvath isn't yet sure what causes these differences, but he hopes they point to fundamental aging mechanisms that might be delayed or interrupted with drugs or other interventions. Although a number of independent labs have replicated his findings, scientists need a better understanding of what drives the epigenetic clock before the approach can be used in the clinic, says Horvath, who has no plans to commercialize his clock right now.

    Other groups are attempting to use different genetic indicators to distinguish patterns of healthy aging from those of disease. This month, researchers described an approach based on certain mutations that accrue steadily over time in human tissue. Unlike the bursts of mutations triggered by exposure to environmental factors such as UV light or tobacco smoke, these mutational “signatures” show a strong, linear correlation with a person's chronological age, says Ludmil Alexandrov, a theoretical biologist at the Los Alamos National Laboratory in New Mexico and co-author of the new study, published in Nature Genetics. People who accumulate these mutations faster than others may age faster and be at higher risk of cancer, he adds.


    All such markers need to be independently replicated and better understood before the community will embrace them, Sedivy says. Prospective, longitudinal studies testing whether people with specific patterns of methylation or gene expression are actually at higher risk of disease or death are also badly needed, Greider says.

    LONG-LIVED PROTEINS. Although gene expression and methylation clearly change with time, neither is a direct measure of the damage that time inflicts on the body's cells as they age, says Martin Hetzer, a molecular biologist and co-director of the Glenn Center for Aging Research at the Salk Institute in San Diego, California. Hetzer recently introduced another, speculative aging clock, based on the changes that accumulate in the body's oldest proteins.

    Unlike cells in the liver or intestines, which regularly regenerate, nerve cells in the brain and some cells in the heart never divide. “They are literally as old as you are,” Hetzer says. Scientists have long assumed that even if the cells do not regenerate, the proteins within them must be replaced on a regular basis. Recently, however, Hetzer and colleagues made what he describes as a “shocking” discovery in mice: Rather than constantly being replaced, some proteins actually persist throughout an animal's entire life span.


    Because long-lived proteins are more likely to accumulate damage and lose function, they might be a way to track the aging process, Hetzer and his team believe. In a September study in Cell Systems, they extracted tens of thousands of proteins from the livers and brains of 6-month-old mice—the equivalent of young human adults—and compared them with proteins from the same tissues in geriatric, 24-month-old mice. They found 468 changes in protein abundance between the young and old animals—some proteins increased with age, whereas others declined—as well as 130 proteins that changed location over time.

    Most of the age-related changes in the rats occurred in the brain and involved proteins key to functions such as neuronal plasticity, cell organization, and memory formation. This is “super interesting,” Hetzer says, because aging-related neurodegenerative diseases often involve damaged or misfolded proteins, such as the amyloid protein that builds up in the brains of patients with Alzheimer's disease. Amyloid doesn't normally last long in the brain, but might do so under diseased conditions, or when it gloms together in the telltale plaques of the disease, Hetzer speculates.

    The team is now searching for a way to track chemical changes and damage in long-lived proteins, and explore their effect on cellular function and aging, he says. Even if they do discover an aging clock based on proteins, he adds, it could be hard to turn into a practical aging test because invasive biopsies or postmortem samples are needed to extract the telltale proteins.

    METABOLITES IN BLOOD. A practical aging biomarker should be cheap, and easy to detect in blood samples, says Eline Slagboom, a molecular epidemiologist at Leiden University Medical Center in the Netherlands. Her group is running a multigenerational study of 3500 people ages 40 to 110, looking at metabolites in blood serum and plasma that correspond to cardiovascular health, depression, dementia, diabetes, and mortality. One candidate is a substance called α1-acid-glycoprotein, which has been shown to increase with age and be associated with higher mortality risk. Slagboom's group is also exploring the relation between metabolic health and aging in a joint study with 20 other Dutch cohorts, including 25,000 people between the ages of 15 and 110.

    In a smaller study, Slagboom and her colleagues are sizing up the entire field of aging clocks by pitting them head-to-head. They are collecting data on telomere length, methylation, metabolites, and gene expression in 6000 people ages 20 to 90, to determine which, if any, marker best predicts mortality and disease.

    The stakes are high, says Luigi Fontana, a systems biologist at Washington University in St. Louis in Missouri. Meaningful biomarkers are “really, really important” to move aging research forward, because they could enable short-term clinical trials of promising antiaging drugs such as rapamycin, he says. They could also help tease out which elderly people are healthy enough to benefit from a hip replacement or new medication, who needs extra support, training, or nutrition before such an intervention, or who shouldn't be treated at all, Slagboom says.

    In the end, no single marker is likely to give a definitive reading of a person's true age, Sedivy says—it will take multiple markers to paint a true picture. Nor will tests focused on any single organ or tissue reveal how much of a person's allotted time remains. Aging researchers, he says, should take their cue from the way a mechanic would size up a used car: as a collection of parts, aging at different rates, some more critical than others. After all, “if you blow a tire, it's not so serious,” Sedivy says. But, “blow a transmission, and you're dead.”