What if you could live to 85, 90 or even 100 with your mental faculties intact, able to live independently without debilitating conditions until the last year of your life? What if just one medical treatment could stave off a handful of terrifying ailments like heart disease, cancer and Alzheimer’s?
The idea of a pill for aging sounds like science fiction or fantasy. But the hunt is increasingly real. At the cutting edge of research, scientists and doctors are already deep into the quest for a drug that could transform the experience of aging. The goal isn’t a pharmaceutical fountain of youth, exactly; nobody is promising to stretch human lifespans indefinitely. Instead, they’re looking for a way to ensure healthier aging—a drug that could make it more likely people reach their eighth or ninth decade of life with fewer of the ailments that make old age painful and disabling for millions, and cripplingly expensive for the health care system.
The leading approach even has a name: senolytic drugs. The science is still far from proven; it may turn out that like many new ideas, these drugs never show up in American medicine cabinets at all. But the prospect of a drug for healthier aging has already attracted significant investment from well-known drug companies, and the first human studies of anti-aging drugs are getting underway. If the results pan out, the first drugs could be available in as little as a decade.
As the research moves forward, however, it is raising a series of new questions that both medicine and regulators will need to confront. And the most complex questions arise around exactly the issue that makes the field so exciting: The notion of treating the aging process itself. There’s never been a drug for aging in part because “aging” isn’t considered a disease by the FDA. Should it be? What signs and symptoms of aging is it OK to medicalize? And if a drug were approved for aging – something that every human experiences — who would bear the costs for a pill that potentially could be prescribed for every person alive?
And those aren’t the only questions. It turns out that evaluating the science is also complex, partly because it’s hard to measure whether a drug is fundamentally changing the course of human aging. It’s also ethically fraught: Aging is a normal human process, so testing a drug for “aging” means that otherwise healthy people would be subjected to its inevitable side effects, for unproven benefit. How long a trial would even be needed? Regulators aren’t close to answering this kind of question.
So far scientists are tiptoeing around many of these complicated issues by testing these drugs only in very sick people, studying to see if they help treat deadly diseases with few other treatment options. The idea is to get a potential anti-aging drug approved first under more traditional protocols without having to tackle the thornier, longer-term questions raised by the idea of treating “aging.”
However, doctors are unlikely to wait for answers to the larger questions around these drugs before they begin to prescribe them to patients. As soon as a senolytic or other anti-aging drug is approved for any purpose, physicians are allowed to start prescribing them to their patients for any condition they want, and likely will. Which means that these ethical challenges need answers soon — sooner than many expect. “It would change all of life,” said Robert Temple, FDA’s deputy center director for clinical science. “If there was something that really slowed the aging process, wouldn’t everyone want to be on it? I think so.”
“Zombie” cells
Anti-aging science has long been viewed with skepticism, a “soft” science more often the province of quacks selling dubious potions like jellyfish extract than serious medical researchers. But senolytic drugs are changing that. The idea behind them is to attack senescent or “zombie” cells – cells that have stopped dividing, but aren’t dead. Senescent cells release toxic and inflammatory compounds that impair the function of healthy cells, and scientists believe they help drive the decline of important body tissue, like organs. Scientists have found that the number of senescent cells increases with aging in mice, monkeys and humans; they’re associated with chronic conditions like diabetes, heart disease, cancer, arthritis and overall frailty.
ln small mammals, scientists have found that killing senescent cells delays and prevents many age-related conditions and diseases. In animal testing, senolytic agents have also successfully treated conditions including heart dysfunction, lung diseases, diabetes, osteoporosis, and damage induced by radiation. Clearing senescent cells from adult mice has even been shown to increase median lifespan.
Ethicists are also more comfortable with senolytics than some other anti-aging ideas, because the drugs aren’t intended to extend how long we live, but improve how well we live. The goal is to achieve what McGill University bioethicist Jennifer Fishman describes as the “ideal form of aging”: to be healthy until right before you die. People would experience more years of healthy, active, dementia-free life and then a briefer, more merciful final illness. “It’s not this sort of post-human robot, [or] artificial intelligence freezing your brain,” she said. “It’s not any of these fantastical things. It is actually targeting something that has been a dream of mainstream medicine for quite a long time, too.”
As it happens, the drug first in line for possible anti-aging approval is not new, and not a senolytic agent – it’s an old, off-patent diabetes treatment that has been used in other parts of the world for more than 50 years. The drug, called metformin, has been shown to delay aging and extend health span in animals. Observational studies in humans have linked metformin to decreased incidence of cancer, improved cardiovascular function and reduced risk of cognitive impairment.
Scientists believe that if regulators approve metformin as an anti-aging drug, it could pave the way for other, newer agents. They have pitched a large, long-term randomized controlled trial of metformin called TAME: Targeting Aging with Metformin. It would be a test case to convince FDA it is possible to devise trials that can show a drug helps prevent or delay multiple age-related diseases – what the FDA calls “indications.” That’s needed so the agency could eventually sign off on marketing language that would let companies sell products with anti-aging claims,
including senolytic medicines.
Right now, “aging is not an indication, it’s not a disease, so health care providers won’t pay,” said Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York and the leader of the TAME study. “If health care providers will not pay, then pharmaceuticals [companies] won’t jump in to develop more drugs, better drugs, combination drugs.”
Metformin may not be the strongest potential drug in the anti-aging arsenal, but Barzilai and fellow aging researchers see it as a good stepping stone. It’s cheap, available and has been used by humans for decades with a reasonably clean safety record. All that should make it easier for the FDA to say yes to approval as an anti-aging treatment. The TAME trial has received preliminary approval from FDA, but Barzilai and other researchers are still trying to line up the funding needed to launch it.
Even if they find the money, there are still plenty of unanswered questions. Because the nature of anti-aging drugs is fundamentally different than drugs designed to treat a specific disease, the kinds of clinical trials they need will also be different. “The traditional approach is one drug, one target, one disease… ” said James Kirkland, a researcher at the Mayo Clinic who helped develop the idea that removing senescent cells may ease the disabilities of old age. “This is not in that realm at all.”
The TAME study would evaluate metformin versus placebo in 3,000 American patients – ages 65 to 79 – measuring the time to a new occurrence of diseases including cardiovascular disease, cancer, dementia, or time to death. But to get FDA to sign off on an anti-aging claim, scientists will likely need to go further. So the six-year trial would also look at the drug’s effect on other conditions of old age, like walking speed and injuries from falls. It would also assess how well study participants perform what the medical field calls “activities of daily living” — the basic skills people need to take care of themselves and live independently as they age, like preparing meals or using the restroom.
Interpreting results of such anti-aging studies won’t be easy. If, for instance, the TAME study shows metformin decreases chances of a heart attack, we won’t necessarily know whether that’s because the drug prevented heart attacks or because it slowed aging overall, said FDA’s Temple. “All chronic disease always gets worse over time,” Temple said. “Is that because having the disease for longer makes it worse? Or does it have something to do with the age of the patient?”
To prove that a drug prevents aging, companies will ultimately have to find changes in people that aren’t known to be affected by disease. For example, skin gets lined and wrinkled and loses elasticity over the years – but that doesn’t cause illness. Muscle mass also decreases with age. If a company could show that the drug alters these changes, “that’s a pretty good argument that you are affecting aging,” Temple said.
But the potential for approving anti-aging drugs on the basis of these signposts is already triggering the alarm bells of bioethicists. They fear companies’ pressure to approve these medicines quickly could lead to patients being exposed to medicines that offer only superficial benefits – and possibly hidden harm. For McGill’s Fishman, this harkens back to mistakes made when hormonal treatments for post-menopausal women were approved. Those studies, she said, were too short to pick up on significant adverse effects that occurred in women taking the drug for a long time. And while the drugs were approved specifically to treat symptoms of menopause, in practice they were often prescribed for a general anti-aging benefit.
This concern over “indication creep,” as Fishman calls it—the tendency for drugs to be prescribed for problems they weren’t approved to treat—is another trigger for ethicists. Many of the companies testing the first senolytic drugs aren’t trying to get them approved for aging but instead are targeting diseases where they believe senescent cells play a role. For example, Unity Biotechnology plans to start its first clinical trials with a senolytic for osteoarthritis of the knee in 2018.
Because of the enthusiasm around the drugs, researchers are already concerned about anecdotal stories of people wanting to use the medicines to treat aging before they’re ready for prime time. Paul Robbins of the Scripps Institute said some senolytics are natural products you can buy from Walgreens or Amazon — compounds like quercetin, which gives many fruits and vegetables their color. Others are older drugs like dasatinib, a blood cancer chemotherapy drug. He’s heard of clinics already being set up overseas to provide drugs like these as anti-aging treatments, even without evidence they work, or data on the right dosage.
The hype is dangerous, warns Kirkland, whose employer, the Mayo Clinic, is investing in senolytics through Unity and other companies. Lots of drugs look promising when they are used in mice or rats or monkeys – but fail in humans. “Anything can go wrong along the way,” Kirkland said. “If you could caution your readers, tell them absolutely not to take these drugs until trials are done, because this is a new way of doing things. We don’t know if they are going to work and we don’t know what the side effects are.”
‘Crazy lucrative’
The potential benefits of drugs that extend the healthy period of human life are huge. But so are the potential costs.
The United States’ population aged 65 and older is expected to double by 2050; the population over age 80 will triple. After age 65, the incidence of chronic degenerative diseases increases exponentially. More than 75 percent of people over age 65 have two chronic diseases, and the older people get the more health spending they require.
“If you demonstrate that these drugs work, probably everybody is going to want to take the drugs. So then the question becomes a question of cost,” said Steven Austad, scientific director of the American Federation for Aging Research, which is sponsoring the TAME study.
While metformin is relatively cheap, the drugs that follow could be much more expensive. Senolytics “could be crazy lucrative for a pharmaceutical [company] in a way that we might find problematic,” Fishman said. It’s also likely that there won’t be one silver bullet anti-aging drug, meaning different people may require different treatments or combinations of anti-aging treatments, adding to the costs.
A high-priced drug taken by everyone could place a burden on an already strained health care system, including Medicare, which presumably would have to pay for everyone to take the drug for many decades. And the longer people live, the longer they will draw from Social Security and other government benefit programs. “Politically, this is a hot topic,” said Laura Niedernhofer of the Scripps Research Institute. “Someone who does not dig in deeply thinks immediately, ‘Oh my God, lifespan is going to extend and Social Security is already in bad shape, and so how are we going to handle this’?”
Niedernhofer is an optimist, however, arguing that the costs of anti-aging therapies will more than pay for themselves, their costs offset by the fact that healthier people will require less medical care in the final years of their lives. The drugs may even allow people to work longer, contributing more to the economy and to Social Security and freeing up family members to stay in the workforce instead of taking care of elderly relatives.
Another concern, said University of Minnesota bioethicist Leigh Turner, is pushing resources toward an unproven idea, instead of toward tried-and-true public health programs that have already been proven to extend lives and improve health, like providing clean drinking water or better waste management. Even in the United States, these social determinants of health — unequal access to good education, economic opportunities and even health insurance coverage and health care — often contributes to poor health outcomes, particularly for minorities and those with fewer financial resources.
But “nothing in our world is equitably distributed — not money, not food, not water,” counters S. Jay Olshansky, who studies aging at the University of Illinois at Chicago School of Public Health. These inequities aren’t an excuse to stop pursuing an idea that could improve health for everyone. And the potential high cost shouldn’t stop the research, he says: Richer countries have pursued a lot of expensive health interventions that were at first not affordable, or are still not affordable to parts of the developing world, he said.
Finally, there’s the question of what ethicists call “moral hazard” — whether availability of an anti-aging medicine might backfire, by encouraging people to skimp on healthy habits like eating right or exercising. Why work up a sweat earlier in life when there’s a pill you can take later? This risk isn’t purely hypothetical; a 2014 study in the Journal of the American Medical Association found people taking the cholesterol-lowering drugs increased their intake of fat and calories more than people not on the medicines. So, after spending millions of dollars and years of research on anti-aging drugs, could the net effect be … zero?
In the end, the bottom line for many senolytic advocates is that despite the ethical quandaries, the reality is that hundreds of thousands of people suffer tremendously in the last years of their life. And relieving that suffering is a worthy goal. Just talk to people who treat geriatric patients, said Niedernhofer, watching them live longer but not healthier. “First, you are going to hand them a cane and then a walker and then a diaper and then [they] are completely dependent on help,” she said. “Anything is going to be an improvement.”
Sarah Karlin-Smith is a health care reporter, specializing in covering the policy and politics that affect the drug industry.
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