Scientists Just Started Testing a New Class of Drugs to Slow--and Even Reverse--Aging
Eliminating "zombie-like" cells, called senescent cells, may hold the key to slowing aging and its chronic diseases.
Imagine reversing the processes of aging. It's an age-old quest, and now a study from the Mayo Clinic may be the first ray of light in the dawn of that new era.
The immune system can handle a certain amount of senescence, but that capacity declines with age.
The small preliminary report, just nine patients, primarily looked at the safety and tolerability of the compounds used. But it also showed that a new class of small molecules called senolytics, which has proven to reverse markers of aging in animal studies, can work in humans.
Aging is a relentless assault of chronic diseases including Alzheimer's, cardiovascular disease, diabetes, and frailty. Developing one chronic condition strongly predicts the rapid onset of another. They pile on top of each other and impede the body's ability to respond to the next challenge.
"Potentially, by targeting fundamental aging processes, it may be possible to delay or prevent or alleviate multiple age-related conditions and many diseases as a group, instead of one at a time," says James Kirkland, the Mayo Clinic physician who led the study and is a top researcher in the growing field of geroscience, the biology of aging.
Getting Rid of "Zombie" Cells
One element common to many of the diseases is senescence, a kind of limbo or zombie-like state where cells no longer divide or perform many regular functions, but they don't die. Senescence is thought to be beneficial in that it inhibits the cancerous proliferation of cells. But in aging, the senescent cells still produce molecules that create inflammation both locally and throughout the body. It is a cycle that feeds upon itself, slowly ratcheting down normal body function and health.
Disease and harmful stimuli like radiation to treat cancer can also generate senescence, which is why young cancer patients seem to experience earlier and more rapid aging. The immune system can handle a certain amount of senescence, but that capacity declines with age. There also appears to be a threshold effect, a tipping point where senescence becomes a dominant factor in aging.
Kirkland's team used an artificial intelligence approach called machine learning to look for cell signaling networks that keep senescent cells from dying. To date, researchers have identified at least eight such signaling networks, some of which seem to be unique to a particular type of cell or tissue, but others are shared or overlap.
Then a computer search identified molecules known to disrupt these signaling pathways "and allow cells that are fully senescent to kill themselves," he explains. The process is a bit like looking for the right weapons in a video game to wipe out lingering zombie cells. But instead of swords, guns, and grenades, the list of biological tools so far includes experimental molecules, approved drugs, and natural supplements.
Treatment
"We found early on that targeting single components of those networks will only kill a very small minority of senescent cells or senescent cell types," says Kirkland. "So instead of going after one drug-one target-one disease, we're going after networks with combinations of drugs or drugs that have multiple targets. And we're going after every age-related disease."
The FDA is grappling with guidance for researchers wanting to conduct clinical trials on something as broad as aging rather than a single disease.
The large number of potential senolytic (i.e. zombie-neutralizing) compounds they identified allowed Kirkland to be choosy, "purposefully selecting drugs where the side effects profile was good...and with short elimination half-lives." The hit and run approach meant they didn't have to worry about maintaining a steady state of drugs in the body for an extended period of time. Some of the compounds they selected need only a half hour exposure to trigger the dying process in senescent cells, which can then take several days.
Work in mice has already shown impressive results in reversing diabetes, weight gain, Alzheimer's, cardiovascular disease and other conditions using senolytic agents.
That led to Kirkland's pilot study in humans with diabetes-related kidney disease using a three-day regimen of dasatinib, a kinase inhibitor first approved in 2006 to treat some forms of blood cancer, and quercetin, a flavonoid found in many plants and sold as a food supplement.
The combination was safe and well tolerated; it reduced the number of senescent cells in the belly fat of patients and restored their normal function, according to results published in September in the journal EBioMedicine. This preliminary paper was based on 9 patients in an ongoing study of 30 patients.
Kirkland cautions that these are initial and incomplete findings looking primarily at safety issues, not effectiveness. There is still much to be learned about the use of senolytics, starting with proof that they actually provide clinical benefit, and against what chronic conditions. The drug combinations, doses, duration, and frequency, not to mention potential risks all must be worked out. Additional studies of other diseases are being developed.
What's Next
Ron Kohanski, a senior administrator at the NIH National Institute on Aging (NIA), says the field of senolytics is so new that there isn't even a consensus on how to identify a senescent cell, and the FDA is grappling with guidance for researchers wanting to conduct clinical trials on something as broad as aging rather than a single disease.
Intellectual property concerns may temper the pharmaceutical industry's interest in developing senolytics to treat chronic diseases of aging. It looks like many mix-and-match combinations are possible, and many of the potential molecules identified so far are found in nature or are drugs whose patents have or will soon expire. So the ability to set high prices for such future drugs, and hence the willingness to spend money on expensive clinical trials, may be limited.
Still, Kohanski believes the field can move forward quickly because it often will include products that are already widely used and have a known safety profile. And approaches like Kirkland's hit and run strategy will minimize potential exposure and risk.
He says the NIA is going to support a number of clinical trials using these new approaches. Pharmaceutical companies may feel that they can develop a unique part of a senolytic combination regimen that will justify their investment. And if they don't, countries with socialized medicine may take the lead in supporting such research with the goal of reducing the costs of treating aging patients.
Chicken that is grown entirely in a laboratory, without harming a single bird, could be sold in supermarkets in the coming months. But critics say the doubts about lab-grown meat have not been appropriately explored.
Last November, when the U.S. Food and Drug Administration disclosed that chicken from a California firm called UPSIDE Foods did not raise safety concerns, it drily upended how humans have obtained animal protein for thousands of generations.
“The FDA is ready to work with additional firms developing cultured animal cell food and production processes to ensure their food is safe and lawful,” the agency said in a statement at the time.
Assuming UPSIDE obtains clearances from the U.S. Department of Agriculture, its chicken – grown entirely in a laboratory without harming a single bird – could be sold in supermarkets in the coming months.
“Ultimately, we want our products to be available everywhere meat is sold, including retail and food service channels,” a company spokesperson said. The upscale French restaurant Atelier Crenn in San Francisco will have UPSIDE chicken on its menu once it is approved, she added.
Known as lab-grown or cultured meat, a product such as UPSIDE’s is created using stem cells and other tissue obtained from a chicken, cow or other livestock. Those cells are then multiplied in a nutrient-dense environment, usually in conjunction with a “scaffold” of plant-based materials or gelatin to give them a familiar form, such as a chicken breast or a ribeye steak. A Dutch company called Mosa Meat claims it can produce 80,000 hamburgers derived from a cluster of tissue the size of a sesame seed.
Critics say the doubts about lab-grown meat and the possibility it could merge “Brave New World” with “The Jungle” and “Soylent Green” have not been appropriately explored.
That’s a far cry from when it took months of work to create the first lab-grown hamburger a decade ago. That minuscule patty – which did not contain any fat and was literally plucked from a Petri dish to go into a frying pan – cost about $325,000 to produce.
Just a decade later, an Israeli company called Future Meat said it can produce lab-grown meat for about $1.70 per pound. It plans to open a production facility in the U.S. sometime in 2023 and distribute its products under the brand name “Believer.”
Costs for production have sunk so low that researchers at Carnegie Mellon University in Pittsburgh expect sometime in early 2024 to produce lab-grown Wagyu steak to showcase the viability of growing high-end cuts of beef cheaply. The Carnegie Mellon team is producing its Wagyu using a consumer 3-D printer bought secondhand on eBay and modified to print the highly marbled flesh using a method developed by the university. The device costs $200 – about the same as a pound of Wagyu in the U.S. The initiative’s modest five-figure budget was successfully crowdfunded last year.
“The big cost is going to be the cells (which are being extracted by a cow somewhere in Pennsylvania), but otherwise printing doesn’t add much to the process,” said Rosalyn Abbott, a Carnegie Mellon assistant professor of bioengineering who is co-leader on the project. “But it adds value, unlike doing this with ground meat.”
Lab-Grown Meat’s Promise
Proponents of lab-grown meat say it will cut down on traditional agriculture, which has been a leading contributor to deforestation, water shortages and contaminated waterways from animal waste, as well as climate change.
An Oxford University study from 2011 concludes lab-grown meat could have greenhouse emissions 96 percent lower compared to traditionally raised livestock. Moreover, proponents of lab-grown meat claim that the suffering of animals would decline dramatically, as they would no longer need to be warehoused and slaughtered. A recently opened 26-story high-rise in China dedicated to the raising and slaughtering of pigs illustrates the current plight of livestock in stark terms.
Scientists may even learn how to tweak lab-grown meat to make it more nutritious. Natural red meat is high in saturated fat and, if it’s eaten too often, can lead to chronic diseases. In lab versions, the saturated fat could be swapped for healthier, omega-3 fatty acids.
But critics say the doubts about lab-grown meat and the possibility it could merge “Brave New World” with “The Jungle” and “Soylent Green” have not been appropriately explored.
A Slippery Slope?
Some academics who have studied the moral and ethical issues surrounding lab-grown meat believe it will have a tough path ahead gaining acceptance by consumers. Should it actually succeed in gaining acceptance, many ethical questions must be answered.
“People might be interested” in lab-grown meat, perhaps as a curiosity, said Carlos Alvaro, an associate professor of philosophy at the New York City College of Technology, part of the City University of New York. But the allure of traditionally sourced meat has been baked – or perhaps grilled – into people’s minds for so long that they may not want to make the switch. Plant-based meat provides a recent example of the uphill battle involved in changing old food habits, with Beyond Meat’s stock prices dipping nearly 80 percent in 2022.
"There are many studies showing that people don’t really care about the environment (to that extent)," Alvaro said. "So I don’t know how you would convince people to do this because of the environment.”
“From my research, I understand that the taste (of lab-grown meat) is not quite there,” Alvaro said, noting that the amino acids, sugars and other nutrients required to grow cultivated meat do not mimic what livestock are fed. He also observed that the multiplication of cells as part of the process “really mimic cancer cells” in the way they grow, another off-putting thought for would-be consumers of the product.
Alvaro is also convinced the public will not buy into any argument that lab-grown meat is more environmentally friendly.
“If people care about the environment, they either try and consume considerably less meat and other animal products, or they go vegan or vegetarian,” he said. “But there are many studies showing that people don’t really care about the environment (to that extent). So I don’t know how you would convince people to do this because of the environment.”
Ben Bramble, a professor at Australian National University who previously held posts at Princeton and Trinity College in Ireland, takes a slightly different tack. He noted that “if lab-grown meat becomes cheaper, healthier, or tastier than regular meat, there will be a large market for it. If it becomes all of these things, it will dominate the market.”
However, Bramble has misgivings about that occurring. He believes a smooth transition from traditionally sourced meat to a lab-grown version would allow humans to elide over the decades of animal cruelty perpetrated by large-scale agriculture, without fully reckoning with and learning from this injustice.
“My fear is that if we all switch over to lab-grown meat because it has become cheaper, healthier, or tastier than regular meat, we might never come to realize what we have done, and the terrible things we are capable of,” he said. “This would be a catastrophe.”
Bramble’s writings about cultured meat also raise some serious moral conundrums. If, for example, animal meat may be cultivated without killing animals, why not create products from human protein?
Actually, that’s already happened.
It occurred in 2019, when Orkan Telhan, a professor of fine arts at the University of Pennsylvania, collaborated with two scientists to create an art exhibit at the Philadelphia Museum of Art on the future of foodstuffs.
Although the exhibit included bioengineered bread and genetically modified salmon, it was an installation called “Ouroboros Steak” that drew the most attention. That was comprised of pieces of human flesh grown in a lab from cultivated cells and expired blood products obtained from online sources.
The exhibit was presented as four tiny morsels of red meat – shaped in patterns suggesting an ouroboros, a dragon eating its own tail. They were placed in tiny individual saucers atop a larger plate and placemat with a calico pattern, suggesting an item to order in a diner. The artwork drew international headlines – as well as condemnation for Telhan’s vision.
Telhan’s artwork is intended to critique the overarching assumption that lab-grown meat will eventually replace more traditional production methods, as well as the lack of transparency surrounding many processed foodstuffs. “They think that this problem (from industrial-scale agriculture) is going be solved by this new technology,” Telhan said. “I am critical (of) that perspective.”
Unlike Bramble, Telhan is not against lab-grown meat, so long as its producers are transparent about the sourcing of materials and its cultivation. But he believes that large-scale agricultural meat production – which dates back centuries – is not going to be replaced so quickly.
“We see this again and again with different industries, like algae-based fuels. A lot of companies were excited about this, and promoted it,” Telhan said. “And years later, we know these fuels work. But to be able to displace the oil industry means building the infrastructure to scale takes billions of dollars, and nobody has the patience or money to do it.”
Alvaro concurred on this point, which he believes is already weakened because a large swath of consumers aren’t concerned about environmental degradation.
“They’re going to have to sell this big, but in order to convince people to do so, they have to convince them to eat this product instead of regular meat,” Alvaro said.
Hidden Tweaks?
Moreover, if lab-based meat does obtain a significant market share, Telhan suggested companies may do things to the product – such as to genetically modify it to become more profitable – and never notify consumers. That is a particular concern in the U.S., where regulations regarding such modifications are vastly more relaxed than in the European Union.
“I think that they have really good objectives, and they aspire to good objectives,” Telhan said. “But the system itself doesn't really allow for that much transparency.”
No matter what the future holds, sometime next year Carnegie Mellon is expected to hold a press conference announcing it has produced a cut of the world’s most expensive beef with the help of a modified piece of consumer electronics. It will likely take place at around the same time UPSIDE chicken will be available for purchase in supermarkets and restaurants, pending the USDA’s approvals.
Abbott, the Carnegie Mellon professor, suggested the future event will be both informative and celebratory.
“I think Carnegie Mellon would have someone potentially cook it for us,” she said. “Like have a really good chef in New York City do it.”
In this week's Friday Five, breathing this way may cut down on anxiety, a fasting regimen that could make you sick, this type of job makes men more virile, 3D printed hearts could save your life, and the role of metformin in preventing dementia.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five, featuring interviews with Dr. David Spiegel, associate chair of psychiatry and behavioral sciences at Stanford, and Dr. Filip Swirski, professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai.
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Here are the promising studies covered in this week's Friday Five, featuring interviews with Dr. David Spiegel, associate chair of psychiatry and behavioral sciences at Stanford, and Dr. Filip Swirski, professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai.
- Breathing this way cuts down on anxiety*
- Could your fasting regimen make you sick?
- This type of job makes men more virile
- 3D printed hearts could save your life
- Yet another potential benefit of metformin
* This video with Dr. Andrew Huberman of Stanford shows exactly how to do the breathing practice.