By addressing the root causes of ageing, American geroscientists are in search of a particular holy grail – hoping to stave off the disability and diseases that can make old age so miserable, and help people feel healthy, for longer.
In California, as a participant in a clinical trial at the nearby Buck Institute for Research on Ageing, every morning Scott Broadbent drinks 75ml of milky liquid.
The bottle might contain ketone ester, a supplement meant to help the body burn fat instead of carbohydrates, and which researchers are now testing to see whether it might also slow the ageing process.
Or, reports Science News, Broadbent might instead be getting a placebo, as part of the institute’s trial to assess the supplement’s safety and side effects in older adults.
Broadbent (70) is in excellent health, but he worries about the future. He’s not afraid of dying, but doesn’t want to be sick and in pain as he grows older. His dad had Parkinson’s disease.
Some scientists think there’s a better way. These researchers – part of a burgeoning field called “geroscience” – aren’t seeking immortality. The focus is more pragmatic. By addressing the root causes of ageing, they hope to stave off the disability and diseases that can make old age so miserable.
They want to help people feel healthy for longer, compressing the years of illness that often accompany old age into a much shorter time frame.
“Let’s build a medicine that would be safe enough for someone in midlife to take almost like a supplement, like a daily vitamin, but with more profound biological effects,” says James Peyer, CEO of Cambrian Bio in New York City.
Just don’t call these potential medicines anti-ageing therapies. “That term is associated with an industry that’s trying to sell products … to separate people from their money,” says Jay Olshansky, a demographer and geroscientist at the University of Illinois Chicago.
Instead, geroscientists are doing legitimate research at respected institutions to find medicines that can slow the ageing process. Many of the compounds under study show promise in mice and even humans; some are in clinical trials.
Better health in old age is not just about individual benefits. By 2030, 73m baby boomers in the United States will be 65 or older. By the same year, experts project, there will be a billion people 65 and older globally.
And though people are living longer, they are not necessarily living healthier than previous generations.
“There’s this fear of what this will do to our healthcare system,” says Laura Niedernhofer, a geneticist and researcher studying ageing at the University of Minnesota. “And it goes well beyond just healthcare. We don’t have the nursing homes, or the personal care staff to deal with this.”
Drugs to help keep older adults healthy, active and independent would be a societal boon.
But whether developing such drugs is even possible remains to be seen. Getting the medicines to market means securing more funding, overcoming stumbling blocks related to study design and combating near constant hype.
How did geroscience begin?
The advent of modern medicine and public health has more than doubled the average human life span, from about 30 in the early 1800s to more than 70 today. “This is perhaps one of the biggest things that has happened to humankind, period,” says Jamie Justice, a geroscientist who heads the health domain at the XPRIZE Foundation, which holds competitions to spur technological developments and which in November, announced a new prize related to ageing.
“We are a lot less dead than we used to be because of where public health and modern medicine have brought us.”
There’s a downside. We’re living long enough to see the frailty and illness accompanying old age. Cells stop dividing, DNA degrades, the immune system falters. We become increasingly vulnerable to disease.
Many of us spend our last decades beset by medical maladies – broken bones, weakness, dementia, cancer, heart disease and more.
For decades, scientists thought the gradual decline that comes with old age was unavoidable. But experiments in the 1980s and 90s suggested the process might not be so fixed.
One notable experiment, led by Cynthia Kenyon, a molecular biologist at the University of California, found that mutations in a single gene in the roundworm C. elegans could double its life span. Typical 13-day-old worms barely moved.
“The animal is clearly in the nursing home,” Kenyon said back then. The mutant worms moved as if they were much younger, and they lived longer too.
For researchers interested in human health, this and similar findings from other teams led to a profound realisation: perhaps the ageing process is malleable. If so, scientists might be able to develop therapies to attack the root of ageing rather than simply combating the pile-up of diseases.
By the late 2000s, “the whole perspective of the scientific community changed”, says Felipe Sierra, who was then a programme officer at the National Institute on Ageing in Bethesda.
Ageing biology moved from a phase of description into a phase of molecular investigation. Sierra wanted a name to bring the field together. He chose geroscience, a word he had first seen in a grant proposal by another researcher studying ageing, Gordon Lithgow, now chief scientific officer at Hevolution Foundation, a non-profit that funds geroscience research.
What compounds might fight ageing?
Though there are no proven therapies for people yet, geroscientists are eyeing several compounds that can slow the ageing process, at least in worms, fruit flies and mice. Some have already been tested in humans, and many more clinical trials are under way.
Perhaps the best studied is rapamycin, first discovered in a soil sample collected in 1964 from Rapa Nui, or Easter Island. Today, people who receive organ transplants take the drug to help keep their immune systems from rejecting the foreign tissue.
But rapamycin also prolongs life in yeast, flies and mice. And it’s being tested in people in clinical trials. How it counters ageing isn’t entirely clear. The drug inhibits a protein complex called mechanistic target of rapamycin, mTOR for short, which plays a role in cell growth and protein synthesis.
This inhibition appears to have wide-ranging effects, including reducing inflammation, clearing old and damaged cells, and altering cellular metabolism, some of the key processes that researchers think are to blame for the ageing process.
Rapamycin isn’t the only drug to impact mTOR. Researchers at the biotech company resTORbio tested other mTOR inhibitors in elderly adults to try to improve immune function. About 250 people participated in the clinical trial, which tested two mTOR inhibitors alone and in combination compared with a placebo.
In 2018, the team reported that those who received the drugs had fewer infections and mounted a better response to the flu vaccine.
The company tried one of those compounds in a subsequent study, though, and it failed to show an effect on self-reported respiratory illnesses. resTORbio no longer exists, but the company’s chief medical officer, Joan Mannick, hasn’t given up on mTOR inhibitors.
She co-founded a new company called Tornado Therapeutics, based in New York City, that is working to develop new rapamycin analogs, or “rapalogs”.
Another promising class of drugs targets cells that have stopped dividing but don’t die. These senescent cells release chemical signals that can trigger inflammation, disrupt tissue repair and harm neighbouring cells. In some cases, these signals even prod neighbours to become senescent too.
The drugs, called senolytics, aim to eliminate senescent cells by prompting them to commit suicide. After showing promising results in mice, senolytics are now being tested in humans. More than 25 clinical trials have either been completed or are under way.
One of the most commonly tested senolytic regimens is a combination of two compounds: the anti-cancer drug dasatinib and quercetin, an antioxidant occurring naturally in grapes, berries and other fruits and vegetables.
Other research efforts plan to compare fisetin, a compound found in strawberries and apples, with a placebo to see if it has an impact on frailty and markers of inflammation in the blood.
Unity Biotechnology, in San Francisco, focuses on senolytic therapies exclusively. The company’s most advanced compound, called UBX1325, targets a protein abundant in the blood vessels and retina that regulates cell death. Preliminary results from a trial in patients with diabetic macular oedema, a thickening of the retina related to diabetes, suggest the compound can improve eyesight.
Diet is also known to profoundly affect the ageing process. Studies have found that the low-carb ketogenic diet, for example, can help mice live longer. But restrictive diets can be hard to follow and have side effects.
Broadbent followed the ketogenic diet for a month or so, but his cholesterol levels skyrocketed. Ketone ester, the compound he might be downing daily for the Buck Institute’s clinical trial, may mimic the longevity benefits of such diets.
When the body runs out of glucose to use for energy, the liver creates another source – converting fat into molecules called ketone bodies. “If we don’t eat for a day or so, we’ll start to make ketone bodies,” says John Newman, a geriatrician at the Buck Institute who is leading the trial. “And we’ll make more and more the longer we starve in order to fuel our bodies.”
These compounds are more than just fuel. They help regulate inflammation and control other cellular processes, many involved in the ageing process. Drinking ketone esters, which quickly break down, is a way to deliver the ketone bodies without the diet.
Among the dozens of clinical trials testing potential gerotherapies, few are yet assessing their ability to prevent the onslaught of diseases accompanying ageing. Instead, the goal is establishing safety or seeing whether a compound can nudge some biomarker in the right direction.
And many of the potential treatments under study are natural compounds or existing drugs that are already off patent, which might leave drug companies hesitant to invest in future trials or seek approval from the US Food and Drug Administration or other agencies.
And, as James Kirkland, a geriatrician at the Mayo Clinic in Minnesota, commented, many of the clinical trials happening now will fail.
What are the barriers to progress?
One of the big challenges for geroscience is to figure out how to show that a compound prevents age-related diseases in people. Scientists would have to give the drug to healthy people and then track their health as they age, an expensive, time-consuming endeavour. “In mice, it takes us four years. In humans, it would take decades and tens of thousands of people,” Niedernhofer says.
An easier path would be to develop these therapies as a treatment for a single disease rather than a multi-disease preventive.
One group of researchers has developed a clever work-around. Rather than treating healthy people and waiting for them to age, the team has devised a study to recruit people with one age-related disease and assess whether a drug reduces the time it takes to develop another.
In this case, the researchers have chosen the diabetes drug metformin, which has a long safety record, and with studies suggesting it can have an impact on heart disease, cancer and cognitive decline.
The precise mechanisms underpinning these effects aren’t entirely clear.
The study, called Targeting Aging with Metformin, or TAME, will look at things like cardiovascular events, cancer, cognitive decline, dementia and death.
But nearly eight years after investigators first announced the 3 000-person trial, they’re still trying to find funding. Metformin is cheap and readily available, no longer protected by a patent, so drug companies have no incentive to develop it for ageing.
Science News article – Is ageing without illness possible? (Open access)
See more from MedicalBrief archives:
The man on a quest to live forever
Clinical trial with ‘young blood’ to slow ageing is labelled a ‘scam’
Dietary supplement does not slow ageing
Rooibos shows potential in fight against Alzheimer’s