En español | Here it is, the elixir of life!” Joan Mannick says, jokingly, as she drops a shiny, salmon-pink pill into my palm. It’s RTB101, a drug developed by Mannick’s Boston-based biotech company that could change the future of aging forever.
I feel a crazy urge to pop it into my mouth. Similar drugs have extended the lives of countless worms, fruit flies and mice by slowing down an ancient aging process. But unlike most other promising substances that have come and gone, this one has been shown to work in another notable species: humans.
In studies of more than 900 people by Mannick and her team, RTB101 and drugs like it bolstered aging immune systems, cut risk for respiratory diseases and may have lowered the risk of urinary tract infections. A version of the RTB101 drug could win Food and Drug Administration (FDA) approval as early as 2021 for a single, age-related health threat: the winter colds, flu, pneumonia and other respiratory tract infections that send over 1 million older adults to the hospital every year and kill more than 75,000. Studies of the drug as a preventive for Parkinson's disease are set for later this year, with additional research looking into its effect in reducing heart failure being eyed for some time in the future.
In the suddenly hot world of aging science, RTB101 is an A-list celebrity. It's the biggest star in the current quest for a drug that extends the healthy lifespan, a quest aided by the National Institutes of Health's little-known, taxpayer-funded Interventions Testing Program (ITP). The ITP has been quietly experimenting with compounds thought to extend longevity in mice and worms at three major laboratories across the nation. One of the best-kept secrets in aging research, the $4.7 million-a-year ITP has also debunked some big antiaging crazes, including green tea, curcumin and resveratrol.
But RTB101 has shown real promise, as have other similar drugs. An unprecedented number of age-defying compounds from labs across the U.S. are now heading into human clinical trials for the first time.
"We've reached the perfect storm in aging science,” says physician Nir Barzilai, founding director of the Institute for Aging Research at Yeshiva University's Albert Einstein College of Medicine in the Bronx, New York. “Everything is happening. We have the foundation from decades of animal studies. We're ready to move on to people."
The ultimate goal: to put the brakes on aging itself — preventing the pileup of chronic health problems, dementia and frailty that slam most of us late in life. “I want 85 to be the new 65,” says Mannick, the chief medical officer and cofounder of resTORbio, the company developing RTB101.
Not longer life, but better life
The need is enormous. In a decade, nearly 1 in 5 Americans will be 65 or older. Three out of 4 will have two or more serious health conditions. At least 1 in 4 can expect memory lapses and fuzzy thinking, while 1 in 10 will develop dementia.
"Right now doctors play whack-a-mole with chronic diseases in older adults. You treat one, another pops up,” says Felipe Sierra, director of the National Institute on Aging's Division of Aging Biology. “The goal instead is to tackle aging itself, the major risk factor for almost every major disease."
While these drugs might also extend longevity, experts say that's a side effect, not the real goal. “People don't want to live longer,” notes S. Jay Olshansky, a professor of public health and a researcher on aging at the University of Chicago. “They want to stay out of the red zone — the years when health and quality of life decline drastically. A drug that slows the biological process of aging will be a medical revolution on par with the discovery of antibiotics. Whoever develops the first one will be very, very famous."
It's no wonder, then, that Mannick says, “I stayed up all night at my kitchen table, with a piece of paper, a pencil and the raw data” when she ran a 2012 study widely regarded as the first human aging trial. The results were thrilling. Older people who took RAD001, a similar drug to RTB101, had a stronger response to a flu vaccine. Their immune systems looked younger, with fewer exhausted T cells — a depressingly common feature of aging called immunosenescence. “This was the first evidence that if you target a pathway in humans, you may actually impact how we age."
Slender and dressed casually in a cotton skirt, tights and flats, Mannick tells me she's turning 60 soon. She views her own aging with cheery wonder. “I look in the mirror and think, Wow! My body is completely different now! It's kind of cool,” she says, chopping the air with her hands to emphasize her point.
An infectious disease specialist with a Harvard Medical School degree, she walks fast on a treadmill every day and generally follows a healthy diet — a habit fostered by her nutrition-conscious mom. Indeed, her personal passion for the science of aging grew as she watched her parents age. “They were raised in similar kinds of families in the Midwest and West. Both were college athletes, both went to Harvard Medical School and lived in the same environment for the decades of their marriage,” she says.
"But they have aged completely differently. Both are 90. My dad is robust and energetic. My mother is frail and has dementia. Our society, our drug companies and medical profession aren't addressing all this suffering that happens as people grow old. But the older people in my life are beloved to me. If we can do something about aging, we shouldn't ignore it."
In the winter of 2015, Ken Butterfield, 67, took a small pill every morning as part of a clinical trial run by resTORbio. The study tested the effects of several doses of RTB101, some mixed with a second drug, on respiratory infections in 652 adults 65 and older.
"I don't like getting sick,” says this retired mental health caseworker and commercial refrigeration installer from upstate New York. “The possibility of fewer winter colds was a selling point for me.” Swallowing an experimental drug didn't worry him. “I've been in clinical trials before, so I felt safe,” he adds. “My first was a smallpox vaccine booster study right after 9/11. There was a smallpox scare. I was too old to fight in the military and wanted to help people."
Butterfield and resTORbio don't know whether he took RTB101 or a placebo; the results are “blinded,” to curb bias. Statistically, though, those who took 10 milligrams of RTB101 daily had 31 percent fewer respiratory infections — including colds, flu, bronchitis and pneumonia. There were 52 percent fewer severe infections, too. Those with asthma fared even better, with 68 percent fewer infections. “Their antiviral defenses were turned up,” Mannick says.
The results were particularly strong for people 85 and older; they had 67 percent fewer infections. That's good news, because — in part due to an age-related weakening of the immune system — respiratory infections are the fourth-leading reason older U.S. adults wind up in the hospital and their eighth-leading cause of death. “The results show that RTB101 translates to fewer infections,” Mannick notes.
Firsthand experience with the woes of winter colds and flu may be why volunteers signed up for the respiratory infection study in record time. “When I told my mom about the study, she said she'd give anything not to get a cold every winter,” says physician Kerry Russell, vice president of clinical development at resTORbio.
Some volunteers went overboard. In New Zealand, where part of one study took place, men from a recreational rugby club signed up together. That study, which measured the effect of a drug like RAD001 on the immune system, also kept tabs on other signs of health and fitness, such as changes in walking speed. “They'd have their checkups together and then go out for a pint,” Mannick says. “But they turned the walking-speed check into a competition, which totally threw off those results. We learned to stop giving people those numbers."
Other checks included electrocardiograms before and after, and tests of hand strength. “We're looking for signals that may be worth studying in the future, such as heart function and muscle strength,” Mannick explains. (ResTORbio is still reviewing the data.) Meanwhile, the company recently launched a phase 3 study of RTB101 for immunity and prevention of respiratory infections in hundreds of older adults, designed in consultation with the FDA. If the drug is successful, it could be approved for those uses as early as 2021.
A separate clinical trial in people with and without GBA-associated Parkinson's disease (which results from a mutation of the GBA1 gene) is set to begin this year as well, according to Russell. “At first we'll look at safety and whether the drug crosses the blood-brain barrier,” she says. “If that's successful, later studies will look at whether RTB101 has an effect on Parkinson's symptoms and on the progression of the disease in the brain."
Common side effects so far are diarrhea and headache. But in the respiratory tract infections study, more people in the placebo group had side effects than did those who took the drug.
A drug such as RTB101 could start out as a boutique antidote aimed at a couple of age-related problems, not all of aging. “That could happen if the same dose helps several conditions, but you'd need individual studies, which could take months or years, first,” say Mannick.
What Speeds Aging Up
As we age, Mother Nature tosses all sorts of monkey wrenches into the cellular machinery that once kept us healthy. Here are six of the ways our bodies age on a cellular level.
A natural defense against infection, it can get stuck in high gear as we age, boosting our risk for diabetes, cancer and more.
A protein called mTOR senses nutrients and determines when to grow new cells. It can misfire and speed up with age.
This refers to damage caused by free radicals, mischief-making compounds that cause aging throughout our bodies by messing up our DNA.
Our body's ability to heal itself — our internal “quality control” — is reduced as we age, resulting in undead “zombie cells."
These become new cells for rebuilding body components. With age, this process slows; the body gets less able to activate stem cells.
Physical and emotional stress take a greater physical toll as we age. Especially harmful are big short-term stresses (such as losing a spouse) and chronic low-level stress (caregiving, financial problems and the like).
Keeping cells young
How does RTB101 circumvent aging? We've arrived at the part of the story that reads like a scientific detective novel — a tale with some remarkable thrills and chills.
Drugs like RTB101 work by inhibiting an enzyme in the mTOR pathway, a basic process that regulates growth and metabolism in cells. As we get older, part of this pathway, TORC1, seems to rev up a bit. That's bad. “More TORC1 activity seems to be associated with age-related health problems,” Mannick says. The drugs throttle it back. “It works the same way calorie restriction and intermittent fasting work. In aging studies in animals, cutting back on calories increases life span. But that's difficult for people to do for decades. Inhibiting TORC1 this way seems to do the same thing, without the dieting."
Scientists discovered mTOR while studying rapamycin, a drug that is used today to prevent rejection in some organ transplants and cancer. In fact, mTOR is short for “mammalian target of rapamycin.” But rapamycin almost landed in a pharmaceutical-company trash can in the 1980s.
First discovered seeping from bacteria scraped up on Easter Island, it showed promise as a remedy for yeast infections. When a Canadian drug company halted its development (because it negatively affected immunity), an enterprising scientist stashed the last research vials at home in his freezer, beside the ice cream. His devotion paid off. A few years later, rapamycin was brought back into research and became the antirejection drug sirolimus and the cancer drug everolimus.
Along the way, scientists realized rapamycin “didn't really look like any other drug,” one researcher recalled. “Its pattern of activity was unique.” One weird trick: This Easter Island ooze made fruit flies, worms and yeast cells live longer.
Could it help humans? The Interventions Testing Program looked for clues in a mammal surprisingly like us: the mouse. Testing the drug for this new usage was a big step. The ITP is high powered, rigorous and brutally honest. Launched in 2003, it tests potential age-defying compounds in extremely strict mouse studies at the University of Michigan; the Jackson Laboratory in Bar Harbor, Maine; and the University of Texas Health Science Center in San Antonio. Richard Miller, professor of pathology and director of the Glenn Center for Aging Research at the University of Michigan Medical School, runs one of the labs.
"We are rigorous about making sure the conditions are exactly the same at all three labs: the same food, the same water, the same lab temperatures, the same training for lab technicians,” Miller says. “The doors are kept locked; only people working on the study can enter. The goal is to be sure mouse longevity-study results are reproducible. So often in the past, an exciting study in one lab could never be repeated anywhere else. We're also notable because we publish all of our results, whether a compound extends longevity or not.” So far, only a few compounds have shown promise — with rapamycin the strongest.
In 2007, the ITP tested rapamycin in hundreds of mice. The results: Old mice (equivalent to 60-year-old people) who got rapamycin lived longer (28 percent for males and 38 percent for females), according to a 2009 study in the journal Nature. “It's one of the most exciting interventions we have,” says David Harrison of the Jackson Laboratory, which participates in the ITP. “It works at any age in mice, and that makes it interesting.” In other studies, mice on rapamycin were healthier, leaner and stronger into their rodent golden years.
Mannick read all this research and more. And the pattern was clear. In mice, yeast, worms and flies, you could extend life span and improve health by inhibiting the mTOR pathway. “That made me think, Someone has to test this in humans,” she says.
Doctors can't yet prescribe a life-extending pill. They can offer an Rx for a life-extending way of living.
There are more than 20,000 different phytonutrients in fruits and vegetables, and each has a unique role in fighting age-related damage to our bodies.
Studies have shown that people hold on to muscle better if they eat enough protein — at least 25 to 30 grams per meal.
This can help improve metabolism and mobility, by maintaining muscle.
Walk, run, bike — move for a minimum of 30 minutes, five times a week.
They help reduce the sun exposure that activates free radicals and damages DNA.
Losing extra pounds, especially around the midsection, can help reduce inflammation.
Offset chronic stress, which speeds aging by producing inflammation. For acute stress, such as grief, counseling may help.
Attacking the “zombie cells"
Alas, there's more going wrong in older cells than on-the-fritz mTOR. “We've identified several major pillars of aging,” says Sierra, of the National Institute on Aging. The list reads like the plagues of the Old Testament. Among them: inflammation; out-of-whack metabolism; inactive stem cells that can't repair body tissues; damage from stress, environmental toxins and free radicals; reduced “quality control,” which can't eliminate rogue cells. These glitches boost the risk for everything from heart disease and stroke to diabetes, osteoarthritis, Alzheimer's disease, Parkinson's and cancer.
This is an important point. If these and other cellular issues are the underlying causes of so many diseases, preventing cells from succumbing to them as they age is a key to preventing disease. That's why resTORbio, other biotech start-ups and university aging labs across the U.S. are launching an unprecedented number of human clinical trials with experimental compounds aimed at these pillars.
"It's a cautious period,” says physician James Kirkland, director of the Mayo Clinic's Kogod Center on Aging in Rochester, Minnesota. “Exciting findings in mice often don't turn out so well in people. It's impossible to predict what the human trials will show."
One big target: “zombie cells” — aging, or “senescent,” cells that refuse to die, instead glomming up in joints and other body tissues. They pump out dozens of inflammatory compounds and other chemicals that contribute to osteoarthritis, Alzheimer's, glaucoma, high blood pressure, type 2 diabetes, disk degeneration in the spine, lung problems and more. In a raft of mouse studies, clearing out these senescent cells boosted health — easing arthritis pain, improving kidney and lung function, increasing fitness, extending life and even making fur thicker.
In January, the first-ever human study of a treatment to kill senescent cells in the lungs was published, in the journal EBioMedicine. Fourteen people with the fatal lung disease idiopathic pulmonary fibrosis took a mix of the drugs dasatinib and quercetin for three weeks. The verdict: The drug combo was safe, triggered just one serious side effect (pneumonia), and seemed to improve study volunteers’ basic ability to stand up and walk. There were also hints it may have reduced senescent-cell activity, but the researchers say bigger, longer studies are needed.
In the meantime, Kirkland says, human trials of other zombie slayers are underway in “a number of groups around the world, including several at the Mayo Clinic.” In June 2018, Unity Biotechnology of San Francisco began its first human trial injecting UBX101, a senolytic (that is, a drug that kills senescent cells), into the achy knees of 40 people, ages 40 to 85, with moderate to severe osteoarthritis.
Kirkland and others at the Mayo Clinic are also paying attention to potential senolytics such as fisetin, which is found in fruits and vegetables. In a planned study, researchers will give fisetin to 40 women ages 70 to 90 to see if it helps them walk faster and become more active. Plus, researchers will look at the effects on bone density, inflammation, blood sugar processing and frailty. “I don't want to say a lot about these studies now,” Kirkland adds. “Some are in compounds that people can buy as supplements, and I'm very worried about people self-medicating. To get to the amounts in our study, you'd have to eat 15 pounds of strawberries in two minutes. Taking unproven supplements just isn't safe."
On another front, a small human study recently tested the effects of NMN (nicotinamide mononucleotide), a chemical that in a 2013 Harvard study revitalized mitochondria — the power plants inside cells — in aging mice. In a 2018 lab study, it improved blood vessel growth and exercise endurance in mice, too. NMN raises levels of NAD, the compound that seems to help mitochondria work better. Lead researcher David Sinclair, a professor of genetics at Harvard Medical School and codirector of the school's Paul F. Glenn Center for the Biological Mechanisms of Aging, began studying NMN in people last year. “The approach stimulates blood vessel growth and boosts stamina and endurance in mice, and sets the stage for therapies in humans to address the spectrum of diseases that arise from vascular aging,” he says.
There are other promising aging-research fronts. For example, a six-year study of the generic diabetes drug metformin in 3,000 older nondiabetic adults will likely begin this year, notes Barzilai of the Institute for Aging Research. “We have already seen that people who take metformin for type 2 diabetes have less cardiovascular disease, less cancer, less cognitive decline and live longer than people without diabetes,” he points out. “Now we want to test it in people without diabetes."
Metformin may delay problems such as heart disease by two to three years. “It's a weak aging drug, but it will let us study aging itself instead of individual age-related diseases. That will be a first,” Barzilai says. “We've been talking with the FDA about it. Nobody wants to ever call aging itself a disease. We just want to keep people healthier."
Winning the life span lottery
Right now, simply staying healthy into our 80s, 90s and beyond is a lot like hitting the Powerball jackpot. In a survey of 55,000 Americans age 65-plus, just 48 percent rated their health as very good or excellent. No wonder drugstores, the internet and human history are littered with unproven rejuvenation come-ons such as the Fountain of Youth in the 1500s and goat-testicle implants (yikes!) in the Roaring ‘20s. Today's questionable offerings range from stem cells, growth hormones and transfusions of teenage plasma, to supplements and more. In 2017, Americans spent $194 billion on products and treatments like these. This is why serious aging-science researchers steer clear of the word “antiaging” when talking about their work. “ ‘Antiaging’ is my enemy,” Barzilai adds. “Some of those charlatans hurt our reputation."
Meanwhile, as researchers slowly test these more legitimate drugs, what can we do today if we wish to retain good health longer? That answer has been with us all along. “Not smoking, eating healthy, getting exercise, managing stress and sleep,” says physician Thomas Perls, founding director of the New England Centenarian Study. Those steps can keep you healthier into your 90s. You'll have to wait for an aging drug, or inherit lucky genes, to go further. “Centenarians seem to have groups of genes that delay age-related diseases."
More than offering longevity, age-defying drugs may help us escape the red zone — the time when physical health often crashes late in life. “We think future drugs that target aging will go beyond what a healthy lifestyle can do,” says Olshansky, of the University of Chicago. How much longer we can live is unknown. “The outside of normal human aging is about 115, while the average life span is about 80 or 85, so I think we have about 30 extra years to think about,” Barzilai says.
Just feeling 65 at 85 could be a seismic shift. “If I can live long enough to meet my great-grandchildren and great-great-grandchildren and be healthy, I'd love to do it,” Mannick says.
Daniel Callahan, of the Hastings Center for Bioethics in Garrison, New York, explains that it's a balance. “I've never been an enthusiast for longevity for longevity's sake,” he notes. “We would see a great imbalance between the young and the old. One of my main objections to radical life extension is that proponents haven't answered the question, ‘What would life be like?’ On the other hand, I am now 88. Improving aging really means finding ways to prevent cancer, heart disease, stroke. Health is what matters."
At 87, Doris Overton of Austin, Texas, agrees. A retired nurse with three children and five grandchildren, she participated in resTORbio's RTB101 respiratory-infection study several winters ago. “I get bronchitis every winter, and it takes so long to get better,” she says. “If a drug like that can help, it would be a really good thing."
Sari Harrar has authored or coauthored 15 health books and contributes frequently to AARP The Magazine.