There may be ways to stay vibrant for much longer than we do today
On the inevitability scale, death and taxes are at the top. Aging is close behind.
It’s unlikely that scientists will ever find a way to avoid death. And taxes are completely out of their hands. But aging, recent research suggests, is a problem that science just might be able to fix.
As biological scientists see it, aging isn’t just accumulating more candles on your birthday cake. It’s the gradual deterioration of proteins and cells over time until they no longer function and can’t replenish themselves. In humans, aging manifests itself outwardly as gray hair, wrinkles and frail, stooped bodies. Inside, the breakdown can lead to diabetes, heart disease, cancer, Alzheimer’s disease and a host of other problems.
This story is part of a special report on aging. Read more:
Scientists have long passionately debated why cells don’t stay vigorous forever. Research in mice, fruit flies, worms and other lab organisms has turned up many potential causes of aging. Some experts blame aging on the corrosive capability of chemically reactive oxygen molecules or “oxidants” churned out by mitochondria inside cells. DNA damage, including the shortening of chromosome endcaps (called telomeres) is also a prime suspect. Chronic, low-grade inflammation, which tends to get worse the older people get, wreaks so much havoc on tissues that some researchers believe it is aging’s prime cause, referring to aging as “inflammaging.” All these things and more have been proposed to be at the root of aging.
Some researchers, like UCLA’s Steve Horvath, view aging as a biological program written on our DNA. He has seen evidence of a biological clock that marks milestones along life’s path. Some people reach those milestones more quickly than others, making them older biologically than the calendar suggests. Others take a more leisurely stroll, becoming biological youngsters compared with their chronological ages.
Many others, including Richard Miller, a geroscientist at the University of Michigan, deny that aging is programmed. Granted, a biological clock may measure the days of our lives, but it’s not a ticking time bomb set to go off on a particular date. After all, humans aren’t like salmon, which spawn, age and die on a schedule.
Instead, aging is a “by-product of running the engine of life,” says biodemographer Jay Olshansky of the University of Illinois at Chicago. Eventually bodies just wear out. That breakdown may be predictable, but it’s not premeditated.
Despite all the disputes about what aging is or isn’t, scientists have reached one radical consensus: You can do something about it. Aging can be slowed (maybe even stopped or reversed). But exactly how to accomplish such a counterattack is itself hotly debated. Biotechnology and drug companies are developing several different potential remedies. Academic scientists are investigating many antiaging strategies in animal experiments. (Most of the research is still being done on mice and other organisms because human tests will take decades to complete.)
Even researchers who think they have finally come up with real antiaging elixirs say they don’t have the recipe for immortality, though. Life span and health span, new research suggests, are two entirely separate things. Most researchers who work on aging aren’t bothered by that revelation. Their goal is not necessarily extending life span, but prolonging health span — the length of time people live without frailty and major diseases.
Aging as disease
Many health problems are so commonly associated with aging that some researchers take the highly controversial stance that aging itself is a disease, says Saul Villeda of the University of California, San Francisco.
If aging is a disease, in Villeda’s lab it’s almost a contagious one: He can artificially spread aging from old lab mice to young ones. One mode of aging transmission is to give genetically identical mice transfusions of young or old blood. In another approach, researchers sew together pairs of mice so that their blood vessels will join up and link their circulatory systems.
This artificial joining of two separate animals, known as parabiosis, was a staple of physiology experiments for over a century before Irina Conboy got the idea to pair an old mouse with a young one. Conboy, a stem cell researcher at the University of California, Berkeley, made headlines with her experiments.
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Scientists sewed together mice so that the rodents shared blood supplies. Young mice paired with old mice (left chart, two-toned) made fewer new cells in the brain’s hippocampus than when paired with another young mouse (yellow). Old mice made hundreds more new brain cells when paired with a young mouse (right chart, two-toned) than when paired with an old mouse (teal).
Source: S. Villeda et al/Nature 2011
Those headlines focused on the good news: Young blood rejuvenated old mice. In further studies by other researchers, infusions of young blood made broken bones in old mice heal better (SN Online: 5/19/15), gave their muscles extra spring and improved their memories (SN: 5/31/14, p. 8). Apparently some substances in the blood triggered the rejuvenation. Some candidates for those rejuvenation factors have been identified, although none are universally agreed on.
But news accounts mostly ignored the flip side of the experiment: Being tethered to an old mouse made young mice age faster. One substance in the blood of old mice, a protein called Beta‑2‑microglobulin, or B2M, seemed to prematurely age the young ones, Villeda and colleagues reported last year in Nature Medicine (SN: 8/8/15, p. 10). Parabiosis experiments don’t last very long, so no one knows whether youth or decrepitude will win in the end — or if the two mice would have settled into middle age together.
UCLA’s Horvath has evidence that the mice may never totally sync. He monitors aging by examining molecular tags called methyl groups, which attach to various locations on DNA in a process called methylation. Methylation is an epigenetic modification of DNA. Such modifications work something like flagging passages in a book with sticky notes. Attaching a tag doesn’t change the information in the book — it just draws attention to some passages and signals that others should be ignored.
Horvath measures DNA methylation changes at 353 different spots in the human genetic instruction book, or genome. As people age, 193 locations accumulate tags, like playbills plastered on urban buildings. At 160 others, methylation is gradually stripped away with age. Knowing how much methylation is normally found at each spot at a given chronological age allows Horvath to calculate biological age.
Taking their time
Semi-supercentenarians (people who live to be 105 to 109, yellow) tend to be biologically younger than their chronological age. So do their children (teal) compared with other people (gray). The rate of aging of the semi-supercentenarians and their children (teal line) is slower than normal (black line).
Source: S. Horvath et al/Aging 2015
Some people age at different rates than others, he discovered. For instance, semi-supercentenarians — people who live to be 105 to 109 — are about 8.6 years younger epigenetically than their chronological age. Their children are slow to age, too, though not as slow as their parents. Epigenetic clocks indicate that the offspring are about five years younger biologically than other people of the same chronological age.
People often joke about certain abilities, such as eyesight, memory or hearing being “the first to go.” Some of Horvath’s work suggests that the notion isn’t entirely far-fetched. He calculated the epigenetic age of specific organs and discovered that body parts can age at different rates. The cerebellum, the part of the brain that sits at the top of the brain stem and helps coordinate movement, speech and other activities, ages the slowest of the brain regions that Horvath analyzed. While there are natural differences in organ aging, some conditions, such as HIV infection and obesity, can prematurely age certain organs, Horvath and colleagues have found.
These experiments demonstrate that aging and its effects are malleable. “Aging is really plastic — it’s not set in stone,” says Conboy. Consequently, she and other researchers agree, something can be done to slow aging, or perhaps turn it around entirely. But exactly what can be done is vigorously disputed.
Interpret with caution
Most scientists working on aging urge caution in extrapolating promising results in animal studies to humans. For instance, one of the most promising early candidates for a rejuvenation factor from young blood was a protein called GDF11. Reports in 2013 and 2014 concluded that GDF11 levels in blood decline with age; restoring the protein in old animals could reverse some heart problems, improve muscle strength and spur nerve cell growth in the brain. Since those reports, other researchers have disputed the protein’s revitalizing powers. In a recent study, researchers measured GDF11 levels in 140 people aged 21 to 93. Levels of the protein didn’t decline with age, Mayo Clinic researchers reported in the June 14 Cell Metabolism. Previous researchers may have gotten GDF11 mixed up with a similar protein called myostatin, which does dip as people get older. Not only does GDF11 not decline with age, having too much of it could be bad, the Mayo team found. People with higher blood levels of the protein were more likely to be frail, have diabetes and heart problems, and have a more difficult time recovering from surgery than people with lower levels of the protein.
Beyond the blood experiments, scientists have examined various ideas about what goes wrong in aging and have devised strategies to counteract it. For instance, some evidence suggests that stem cells run out of steam as they get older. Restoring old stem cells to youthful vigor may enable them to repair or replace damaged tissues and turn back the biological clock. Keeping stem cells youthful may involve sheltering them from inflammation or things that could damage their DNA.
One way to keep stem cells and other cells working is to avoid the loss of telomeres capping the ends of chromosomes. As cells divide, their telomeres grow shorter until they are so short that chromosomes can no longer safely replicate. That may be a signal for the cell to shut down or die. So some researchers think that lengthening telomeres could give cells the protection needed to survive longer.
One biotechnology company executive flew from the United States to Colombia to try out her company’s gene therapy for lengthening telomeres. That decision bypassed U.S. government and other safety measures designed to protect human study participants. And no one knows whether it will work or doom her to cancer, which often relies on long telomeres to keep growing.
Other researchers are exploring more measured approaches to antiaging therapies. One study in dogs is testing rapamycin, the first drug shown to lengthen mouse life spans. Rapamycin is an immune suppressant that also has anticancer effects. The rationale for using it came from research on caloric restriction, the world-champion method for making animals live longer. Animals on calorie-restricted diets typically eat at least 25 percent fewer calories than normal. Such low-cal treatment has increased life spans in mice, dogs, fruit flies, yeast, worms and other lab organisms. Results from primate studies have been mixed (SN: 8/1/09, p. 9; SN: 10/6/12, p. 8). Some people have put themselves on caloric-restriction regimes (SN: 10/25/08, p. 17). A handful of studies suggest that those people have better health, but it’s too soon to know whether they will outlive their peers.
Exactly why drastically reducing food intake can extend life isn’t known. But researchers have good evidence that a series of biochemical reactions known as the mTOR pathway is involved. The protein mTOR helps monitor nutrient levels in cells and regulates cell movement, protein production, and cell growth and survival. When starvation sets in, cells turn off mTOR’s activity, which allows a self-cannibalizing process called autophagy to scavenge nutrients by digesting some of the cell’s internal organs. This internal garbage disposal and recycling method also removes old, worn-out mitochondria and proteins that may otherwise keep cells from functioning efficiently. That process and other cellular activities governed by mTOR may be responsible for making cells, and organisms, live longer.
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Life extension elixir?
Male mice receiving the diabetes drug metformin (top, yellow) had median life spans (the age at which half the population has died) that were slightly longer (8 percent) than untreated male mice (top, gray). Metformin did not increase life spans of female mice. Combined with rapamycin, metformin (teal) boosted median life span in both sexes about 23 percent, but the result wasn’t statistically different from life span boosts in mice given rapamycin alone in previous studies.
Source: R. Strong et al/Aging Cell 2016
Rapamycin gave mTOR its name — mechanistic target of rapamycin. Giving the drug might do what caloric restriction does without requiring superstrict diets (SN: 6/4/11, p. 22). Matt Kaeberlein, a geroscientist at the University of Washington, and colleagues conducted a safety study of the drug last year in 24 dogs. The study was only 10 weeks long, so the researchers can’t yet draw any conclusions about long-term effects on aging. But the dogs had no major side effects from taking low doses of the drug, a worry because rapamycin impairs immune system function and could make animals (including people) who take it more vulnerable to infection or cancer.
Rapamycin’s drawbacks make it unattractive for human studies. The diabetes drug metformin may instead be the antiaging drug of choice for people, says gerontologist Nir Barzilai. In addition to mTOR, metformin targets an insulin-like growth protein known as IGF-1. That protein has been implicated in a variety of biological processes that promote aging.
Barzilai, of Albert Einstein College of Medicine in New York City, and researchers at more than a dozen centers around the country plan to test metformin for its ability to fight aging in people 65 to 79. Barzilai and colleagues laid out the case for using metformin in the June 14 Cell Metabolism. Metformin is generally safe, with few major side effects. It has been shown to improve a variety of health measures and to impair cancer development in people with type 2 diabetes (SN: 11/30/13, p. 18). Barzilai says the drug may help people who don’t have diabetes also live healthier when they are elderly. If it does, commercials touting metformin might have to add another disclaimer, he jokes. “The commercials will go on: ‘This will make you healthy, but we have to apologize because you might live longer.’ ”
But studies of mice suggest that disclaimer may not be necessary. Research by Miller and others suggests that metformin may not prolong life. They have been dosing mice with various chemicals, including metformin and rapamycin, looking for drugs that will make mice healthier and live longer. In a new study, published online June 16 in Aging Cell, Miller and colleagues fed mice metformin starting when the rodents were 9 months old — middle age for a mouse. Combining metformin and rapamycin didn’t make the mice live much longer than rapamycin alone did in previous trials.
Other researchers are hoping to stave off death by getting rid of the undead. Cellular zombies called senescent cells are stressed cells that have entered a type of stasis — they’re not dead, but they’re not functioning either. Stress for cells usually means severe DNA damage that could produce cancer, critically short telomeres or other molecular catastrophes that trigger shutdown mode.
Live longer, but frailer
Mutations in certain genes (daf-2, ife-2, eat-2 and clk-1) can make Caenorhabditis elegans worms live longer than normal worms without these mutations. But researchers examining health measures, such as the worms’ ability to move or to withstand heat or oxidative stress, found that long-lived mutant worms spend a smaller proportion of their lives as healthy animals (indicated in yellow).
Source: A. Bansal et al/PNAS 2015
That lockdown is for the greater good, says aging researcher Judith Campisi, who studies senescence at the Buck Institute for Research on Aging in Novato, Calif. “It’s protective,” she says. “You don’t want defective cells to propagate.” (When damaged cells continue to grow they may become cancerous.)
Unfortunately, says Campisi, the senescent cells don’t die. Instead they send out messages to neighboring cells: “Hey, there’s a problem. Be prepared. What happened to me could happen to you.” Such messages are probably intended as public service announcements, but they could trigger mass panic and inflammation. Like zombies putting the bite on the living, senescent cells damage surrounding cells and accelerate aging.
Researchers have worked out methods for hitting the zombie cells with genetic shots to the head, effectively destroying the cells and removing them from the body. Mice from which senescent cells have been removed had increased median life span and improved health, researchers reported in Nature in February (SN: 3/5/16, p. 8).
Campisi and other researchers are working on ways to clear senescent cells from humans, too. But no antiaging treatment makes mice or any other animal live forever. Researchers have yet to increase a mouse’s life span (which rarely goes above two years) to five years, although one mouse fell just short of that mark.
Much research suggests that things that extend life span, such as rapamycin, might not stretch health spans. Mutations that make millimeter-long transparent worms known as Caenorhabditis elegans live longer also extend the proportion of their lives the worms spend being frail, Heidi Tissenbaum of the University of Massachusetts Medical School in Worcester and colleagues reported last year in the Proceedings of the National Academy of Sciences.
But living healthy doesn’t guarantee longevity either, a new study of sea urchins suggests. Red sea urchins (Mesocentrotus franciscanus) live well past 100 years old in the wild, while purple sea urchins (Strongylocentrotus purpuratus) make it to 50. But variegated (also called “green”) sea urchins (Lytechinus variegatus) normally die after four years.
Ways to be wellderly
A similar paradox is also seen in “wellderly” people that geneticist Ali Torkamani has been studying at the Scripps Research Institute in La Jolla, Calif. About eight years ago, Torkamani started bringing in people over 80 who had made it to an advanced age without any sign of chronic disease. The idea was to study their DNA and learn the secrets of healthy aging.
Despite living healthy, the wellderly didn’t carry genetic variants connected with extremely long lives, Torkamani and colleagues discovered. The wellderly also had no genetic advantage when it comes to cancer, stroke or diabetes. What they did have was a lower risk of getting Alzheimer’s and heart disease. Each of the wellderly seemed to have their own genetic recipe for success, suggesting there are lots of ways to stay healthy into old age. The researchers didn’t rule out that diet and lifestyle also help. “There’s hope for everybody,” Torkamani declares.
But his cloud of optimism may have a tarnished lining. His findings, along with the sea urchin and worm results, suggest that aging and longevity aren’t the same things. If that’s the case, it would mean that stopping aging would not extend human life span by much. The oldest (verified) person to have ever lived was Jeanne Louise Calment, a French woman who died at age 122 in 1997. People might top out at 130 if aging is controlled (and most people still would not make it that long because they just don’t have the necessary makeup). As a species, humans probably can’t go further without changing whatever controls longevity too, some researchers think.
Exactly how long people can live won’t be answered until proven antiaging therapies are developed. If aging and longevity are linked, then treating aging could very well make people live longer, healthier lives. If they are separate phenomena, then people could forgo the cancer, heart disease and other ailments of aging, but they would still have limited life spans. In that case Star Trek’s Mr. Spock might need to revise his usual parting words. When talking to humans, he should wish that they will live long or prosper. We may not get both.
A rushed, maybe risky, telomere test
Elizabeth Parrish was growing old before her time. The 45-year-old chief executive of BioViva USA Inc. had the telomeres of a 65-year-old.
Telomeres are long stretches of repetitive DNA at the ends of chromosomes. They work like plastic aglets on shoelaces, preventing chromosomes from fraying and getting chewed up. When telomeres get too short, the risk of dying increases (SN: 12/15/12, p. 13). Mice in which telomeres have been lengthened by gene therapy tended to live longer in some studies than mice that didn’t get the treatment.
Parrish and researchers at her company decided it was time to see if stretching telomeres in people could also lengthen life. Too impatient to wait for Food and Drug Administration approval for clinical trials in people, Parrish went to Colombia to test her company’s antiaging gene therapy on herself.
An intravenous infusion delivered viruses carrying a gene for a telomere-lengthening enzyme into her bloodstream. The gene therapy was also designed to inhibit action of the myostatin gene, which stops muscle cells from growing. Inhibiting that gene may allow muscles to better repair themselves. Parrish said she had “myriad injections we didn’t even count — we would have lost count if we had” — into her muscles and other parts of her body. Her aim was to demonstrate that the therapy is safe. “I felt like we really had to take the first risk,” she says.
In April, BioViva reported in a news release that telomeres in Parrish’s white blood cells were longer, now consistent with those of a 45-year-old instead of those of a retiree. No one knows how the treatment will affect Parrish’s health or life span. Some scientists say her risk of cancer may increase, a concern the company dismisses.
“It’s absolutely premature” to conduct telomere therapy in people, says Matt Kaeberlein, a geroscientist at the University of Washington. “We don’t have the technology to do this in a safe way. We don’t even understand the biology that well,” he says. “It’s absurd for somebody to be doing this, and trying to get other people to participate is dangerous, in my view.” — Tina Hesman Saey
This article appears in the July 23, 2016, Science News with the headline, "Slowing Time."
A. Roy. First gene therapy successful against human aging. BioViva USA Inc. press release. April 21, 2016.
D. E. Harrison et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. Vol. 460, July 16, 2009, p. 392. doi:10.1038/nature08221.
F. Neff et al. Rapamycin extends murine lifespan but has limited effects on aging. Journal of Clinical Investigation. Vol. 123, August 1, 2013, p. 3272, Published online July 25, 2013. doi:10.1172/JCI67674
A. G. Bodnar and J. A. Coffman. Maintenance of somatic tissue regeneration with age in short- and long-lived species of sea urchins. Aging Cell. Published online April 20, 2016. doi: 10.1111/acel.12487.
A. C. Hinken et al. Lack of evidence for GDF11 as a rejuvenator of aged skeletal muscle satellite cells. Aging Cell. Vol. 15, June 2016, p. 582, published online March 28, 2016. doi: 10.1111/acel.12475.
A. Bansal. Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proceedings of the National Academy of Sciences. Vol. 112, January 20, 2015, p. E277. doi: 10.1073/pnas.1412192112.
S. Horvath. DNA methylation age of human tissues and cell types. Genome Biology. Vol. 14, October 21, 2013, p. R115. doi:10.1186/gb-2013-14-10-r115.
S. Horvath et al. Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging. Vol. 7, December 15, 2015, p. 1159. PMCID: PMC4712339.
S. Horvath et al. The cerebellum ages slowly according to the epigenetic clock. Aging. Vol. 7, May 11, 2015, p. 294. PMCID: PMC4468311
S. Horvath and A. J. Levine. HIV-1 infection accelerates age according to the epigenetic clock. Journal of Infectious Diseases. Vol. 212, May 12, 2015, p. 1563. doi: 10.1093/infdis/jiv277
S. Horvath et al. Obesity accelerates epigenetic aging of human liver. Proceedings of the National Academy of Sciences. Vol. 111, October 28, 2014, p. 15538. doi: 10.1073/pnas.1412759111
C. E. Brun and M. A. Rudnick. GDF11 and the mythical fountain of youth. Cell Metabolism. Vol. 22, July 7, 2015, p. 54. doi: 10.1016/j.cmet.2015.05.009
M. J. Schafer et al. Quantification of GDF11 and myostatin in human aging and cardiovascular disease.Cell Metabolism. Vol. 23, June 14, 2016, p. 1207.
N. Barzilai et al. Metformin as a tool to target aging. Cell Metabolism. Vol. 23, June 14, 2016, p. 1060. doi: 10.1016/j.cmet.2016.05.011
R. Strong et al. Longer lifespan in male mice treated with a weakly-estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. Published online June 16, 2016. DOI: 10.1111/acel.12496
G. A. Erikson et al. Whole-genome sequencing of a healthy aging cohort. Cell. Vol. 165, May 5, 2016, p. 1002. doi: 10.1016/j.cell.2016.03.022
T. H. Saey. Age isn’t just a number. Science News. Vol. 188, August 8, 2015, p. 10.
M. Rosen. Broken bones heal with young blood, how remains a mystery. Science News Online. May 19, 2015.
L. Sanders. Young blood proven good for old brain. Science News. Vol. 185, May 31, 2014, p. 8.
T. H. Saey. Telomere length linked to risk of dying. Science News. Vol. 182, December 15, 2012, p. 13.
T. H. Saey. Dining In. Science News. Vol. 179, March 26, 2011, p. 18.
N. Seppa. Low-cal longevity questioned.Science News. Vol. 182, October 6, 2012, p. 8.
T. H. Saey. Caloric restriction extends life in monkeys, study finds. Science News. Vol. 176, August 1, 2009, p. 9.
T. H. Saey. Don’t forget diet composition. Science News. Vol. 174, October 25, 2008, p. 17.
L. Beil. Healthy Aging in a Pill. Science News. Vol. 179, June 4, 2011, p. 22.
N. Seppa. Old drug, new tricks. Science News. Vol. 184, November 30, 2013, p. 18.