At 67 years old, Dr. Nir Barzilai looks about the same as, if not younger than, he did 10 years ago. It’s apparent in side-by-side photographs, and it’s what most people who know him say. Barzilai lives a healthy lifestyle. He exercises every day, eats right, and practices intermittent fasting.
He’s also been taking the diabetes drug metformin off label for 10 years. He has never been diagnosed with diabetes or prediabetes—the conditions for which the drug is approved and prescribed—but takes it for a different off-label reason.
“We know that it targets aging,” said Barzilai, who is a professor of medicine and genetics at Albert Einstein College of Medicine and director of the American Federation for Aging Research.
“People on metformin have 30% lower rates of almost every kind of cancer. It delays cognitive decline. Even people with diabetes who are obese and have more disease to start with but are on metformin have lower mortality rates than people without diabetes who aren’t on the drug.”
What he says is born out in numerous studies. Overall, this safe, super-cheap, decades-old drug not only treats diabetes, but it also seems to delay and compress the years of chronic illness associated with the final stage of life and extend what geroscientists call the “healthspan.”
Metformin is just one of many medications, including other old ones and some brand new inventions, that academic researchers and biotech startups are exploring to slow, stop, or perhaps even reverse aging.
What is aging
All sorts of processes are happening in our bodies as we age. Some of which make us more vulnerable to the diseases most linked to old age: cancer, dementia, heart disease, stroke, macular degeneration and so forth.
Doctors and scientists in the longevity field are trying to determine which of those processes is the strongest hallmark of overall aging and declining health and how to target that process with a drug in the same way that current drugs target specific diseases.
“We can target aging,” Barzilai said. “We can delay it. And in several instances, we can stop and reverse it. At one point we had hope. Then we moved to promise. Now, we need to move to realize that promise. That’s where we are.”
Courtesy of Nir Barzilai
Targeting undead cells
Dozens of biotechs want to be the first to realize that promise through drugs called senolytics. In certain diseases, these pharmaceuticals can clear out toxic, old, dysfunctional cells and leave only young, healthy, well functioning ones behind. Senolytic Dasatinib (Sprycel) is FDA-approved for certain types of chronic myelogenous leukemia.
Here’s why researchers think senolytics could do more than treat one specific disease.
Your cells constantly reproduce and divide throughout their lifespan to create new, healthy cells. When they stop doing this, they die. But with some cells, even though they’ve stopped reproducing, they don’t die off like they should. These undead cells, called senescent cells, stick around and give off toxic substances that can harm the healthy cells around them—like the one bad apple that spoils the whole bunch.
As you get older, your aging body becomes less efficient at clearing out senescent cells, so they accumulate, especially around the sites where chronic diseases develop, like macular degeneration.
Unity Biotechnology has a senolytic, dubbed UBX1325, in phase 2 clinical trials for diabetic macular edema (DME) and age-related macular degeneration (AMD). In both conditions, damage to the retina can lead to vision loss.
Preliminary findings in DME patients in the trial suggest that the drug clears out problem-causing senescent cells in the eye and allows the remaining healthy cells to repair and regenerate the retina and bring lost vision back.
“It takes about 8 weeks to kick in, and at 24 weeks, you can see that the tissue has dramatically remodeled,” said Anirvan Ghosh, PhD, Unity CEO. “We had patients who had big gains in vision and big improvements in retinal structure.”
As incredible as these results are, vision restoration isn’t the endgame for Unity or most any company invested in senolytics development. The idea is to develop another drug that will have this same effect on another progressive disease and another and another until, ideally, researchers can figure out how to make a drug that would clear out all senescent cells, not just the one type behind a certain disease.
“In different tissues, it’s not always the same cell type that becomes senescent. I think next we will have tissue-specific senolytics for a specific disease or if you’re high-risk for that disease.” But to target aging, rather than just individual diseases, he says, “We’d have to have something that clears these cells from multiple tissue types.” That’s the long-term goal. And it may still be a long road to get there.
Understanding biological age
While zombie cells build up in the aging body, wreaking havoc as their numbers grow, critical changes are taking place on the surface of DNA, too. That is, in the epigenome, a landscape of proteins and chemicals that sits atop your genetic material.
These changes over time are the result of your environment, behaviors and exposures throughout your lifetime. Think: pollution, trauma, diet, exercise, and secondhand smoke. They don’t change your DNA, but they change the way your DNA acts. Genes that once functioned perfectly may at some point in life slow down, speed up, shut off, or just go generally haywire. Any dysregulation can cause disease or the signs and symptoms of old age.
Epigenetic changes are like scratches on a record: You can still hear the music, but it’s not what it used to be.
Led by Harvard Medical School professor and molecular geneticist David Sinclair, PhD, Tally Health is already bringing epigenetic approaches to aging directly to consumers. The company offers a cheek swab test that estimates customers’ biological age—how old they seem based on their epigenetics rather than their birth year.
“Biological age is a much better representation of health status than birthday candles,” Sinclair says. “Birthday candles don’t tell you how well you’ve been living and they certainly don’t tell you how many years you’ve got left.”
Tally Health creates personalized recommendations based on customers’ biological age for how they might reduce that age because, as Sinclair points out, “Your biological clock is not unidirectional.”
For now, the means to turn back the clock are mostly lifestyle changes. But Sinclair, who has founded several biotechs, and others are researching and developing drugs that might slow or restart the clock so genes will act like they are young again.
Sinclair and his collaborators have shown that this is possible in the eyes of blind mice. In newborn mice, if the optic nerve – the nerve that carries messages from the retina to the brain—is damaged, it will recover. But in old mice, it can no longer heal.
In Sinclair’s lab, they crushed the optic nerves of mice to blind them. The serious injury to the eye caused epigenetic changes that resemble those that happen in old age. They then injected the nerves with genes that contained factors they expected would reprogram the genes to behave like they were young again.
The treatment reversed the age-related epigenetic changes in the eyes, rescued retinal cells, and led to regeneration of neurons. Since then, Sinclair and his colleagues have corrected similar age-related epigenetic changes in muscle and kidney tissue. Other researchers have successfully used the technique to extend the overall lifespan of mice. Sinclair expects to release results of his study which tests this concept in primates in a few months.
The holy grail, of course, is to erase the scratches that time puts on our own epigenetic records. Sinclair says that’s coming.
“Resetting the whole human body in this way is a different matter,” he says. “Are we one day going to be able to turn ourselves back 20 years? I don’t see any reason why that won’t be possible. It’s just a question of when.”
Drugs that treat aging
But some drugs that could lower risk for multiple age-related diseases at once and, perhaps, treat aging as a whole, might already be on the shelves of the pharmacy.
Rapamycin, an mTOR inhibitor, got FDA approval in 1991 as an immune suppressor that prevents organ recipients from rejecting a new organ. But shutting off the mTOR protein, it prevents immune system cells from proliferating to attack the donated organ.
“But in every species that’s been studied to date – yeast, worms, flies, mice – when they are given rapamycin, healthspan and lifespan are extended. No other therapeutic has that degree of validation,” says Joan Mannick, MD, CEO of Tornado Therapeutics.
Mannick and other mTOR researchers believe that, among the other deleterious processes of aging, mTOR proteins might start to malfunction, too. In a healthy, young person, mTOR, which supports cell growth, is active when we eat. That’s critical for growth, development and reproduction. When we fast, like during the night, mTOR is inactive, which allows for cell repair.
This, by the way, is probably one of the reasons intermittent fasting has so many health benefits, Mannick says, because it blocks mTOR and allows for more cell repair.
As we get older, mTOR may stay active all the time—opening the door to out-of-control cell growth that can lead to cancer and closing the door on cell repair. In older adults, low doses of rapamycin, an mTOR inhibitor, seem to set mTOR activity back to its youthful state: on when you need it, off when you don’t.
“When they get rapamycin, their immune systems, which have already been damaged by old age, start to function better,” Mannick says. “There’s research to suggest that when you rejuvenate the immune system, you make a lot of other organ systems function better. But well-powered, placebo-controlled clinical trials to find out the dose, what conditions it improves, and who responds best.”
To carry out that research, Tornado Therapeutics has acquired a portfolio of rapamycin derivatives, or “rapalogs,” from Novartis, which they are studying as treatments for aging. If it can increase the lifespan of every plant and animal that’s been exposed to it, Mannick and the company’s investors, such as Cambrian Bio, bet it might increase the human lifespan, too.
“I think in the next 5 to 10 years, FDA will have approved the first drug to target aging biology,” Mannick says. “It very well could be a new rapalog that is going to have benefits for an aging-related condition as our first step to a much broader aging medicine advance.”
Type 2 diabetes is an age-related condition. Numerous studies show that metformin, a drug that’s FDA-approved to treat it, may also lower risk for cancer, heart disease, stroke, dementia, or death for any other reason, including COVID-19.
The benefits, researchers suspect, are a result of metformin’s ability to control blood sugar, blunt the effects of a lifetime of oxidative stress on the body, and protect cardiovascular function. That is, it may meet a host of needs that grow greater as we age.
Of course, the overwhelming majority of data on metformin’s benefits comes from people with diabetes. Numerous clinical trials currently underway are looking at its effects on specific diseases in people who don’t have diabetes. But longevity researchers, like Barzilai, want to prove to the FDA that it doesn’t have to be taken for a specific disease. Older adults should simply take it for aging.
Barzilai’s TAME (Targeting Aging with Metformin) trial, which will last six years, aims to prove that anyone between the ages of 65 and 79 can extend their healthspan with metformin.
“We’re using metformin as a tool,” he says, “to show the FDA that aging itself can be targeted.”
Targeting the healthspan
No matter which approach becomes the first prescription drug for aging, researchers in the area tend to agree it’s coming soon. It would be expected to improve and extend life not only for average older adults, but also for those who currently tend to get chronic diseases and die sooner: childhood cancer survivors, people living with HIV, people living in poverty.
Researchers predict the implications will be huge when the healthy years of life last longer for everyone. Economist Andrew Scott calculated that a slowdown in aging that increases life expectancy by just one year would be worth $38 trillion. A ten-year increase would be worth $367 trillion.
“That’s because with this kind of increase in life expectancy, we are not spending that time in the hospital, we are not sick,” Barzilai says. “We’re shopping, we’re traveling, we are participating in society. We are living life. And that’s what we want.”