Slowing Aging Could Transform Society As We Know It
A young woman portrayed next to her old counterpart.
People's lives have been getting longer for more than a century. In 1900, in even the wealthiest countries, life expectancy was under 50, according to the World Health Organization. By 2015, the worldwide average was 74, and a girl born in Japan that year could expect to live to 87. Most of that extra lifespan came from improvements in nutrition and sanitation, and the development of vaccines and antibiotics.
People's lives have been getting longer for more than a century. In 1900, in even the wealthiest countries, life expectancy was under 50, according to the World Health Organization. By 2015, the worldwide average was 74, and a girl born in Japan that year could expect to live to 87. Most of that extra lifespan came from improvements in nutrition and sanitation, and the development of vaccines and antibiotics.
The question is, how will slowing aging change society?
But now scientists are trying to move beyond just eliminating the diseases that kill us to actually slowing the aging process itself. By developing new drugs to tackle the underlying mechanisms that make our bodies grow old and frail, researchers hope to give people many more years of healthy life. The question is, how will that change society?
There are several biological mechanisms that affect aging. One involves how cells react when they're damaged. Some die, but others enter a state called senescence, in which they halt their normal growth and send out signals that something's gone wrong. That signaling causes inflammation at the sight of a wound, for instance, and triggers the body's repair processes. Once everything is back to normal, the senescent cells die off and the inflammation fades. But as we age, the machinery for clearing senescent cells becomes less efficient and they begin to pile up. Some researchers think that this accumulation of senescent cells is what causes chronic inflammation, which has been implicated in conditions such as heart disease and diabetes.
The first clinical trial in humans of senolytic drugs is happening now.
In 2015, researchers at the Mayo Clinic in Minnesota and the Scripps Research Institute in Florida tested the first so-called senolytic drugs, which cause senescent cells to die. After the scientists treated mice with a combination of an anti-cancer drug and a plant pigment that can act as an antioxidant, some of the senescent cells shrank away and caused the mouse's heart function to revert to that of a much younger mouse.
"That suggests that senescence isn't just a consequence of aging, it's actually a driver of aging," says Paul Robbins, a professor of molecular medicine at Scripps and one of the researchers involved. Other animal studies have found that reducing the number of senescent cells improves a variety of age-related conditions, such as frailty, diabetes, liver disease, pulmonary fibrosis, and osteoporosis.
Now the same researchers are moving those tests to humans in the first clinical trials of senolytic drugs. In July 2016, the Mayo Clinic launched what may be the first clinical trial of senolytic therapy, studying the effect of the two drugs, called dasatinib and quercetin, on people with chronic kidney disease, which they hope to complete in 2021. Meanwhile Mayo and Scripps researchers have identified six different biochemical pathways that give rise to senescence, along with several drug candidates that target those pathways. Robbins says it's likely that different drugs will work better for different cells in the body.
Would radical life extension lead to moral deterioration, risk aversion, and an abandonment of creativity?
In Robbins' work, treating mice with senolytic drugs has extended their median lifespan—the age at which half the animals in his experiment have died—by about 30 percent, but hasn't extended the maximum lifespan. In other words, the oldest mice treated with the drugs died at the same age as mice who hadn't been treated, but more of the mice who received senolytics lived to that ripe old age. The same may turn out to be true for humans, with more people living to the limits of the lifespan—estimated by some to be about 115—but no one living much longer. On the other hand, Robbins says, it's early days for these therapies, and it may turn out that delaying aging actually does push the limit of life farther out.
Others expect more radical extensions of human life; British gerontologist Aubrey DeGray talks about people living for 1000 years, and people who call themselves transhumanists imagine replacing body parts as they wear out, or merging our minds with computers to make us essentially immortal. Brian Green, an ethicist at Santa Clara University in California, finds that concept horrifying. He fears it would make people value their own lives too highly, demoting other moral goods such as self-sacrifice or concern for the environment. "It kind of lends itself to a moral myopia," he says. "Humans work better if they have a goal beyond their own survival." And people who live for centuries might become averse to risk, because with longer lives they have more to lose if they were to accidentally die, and might be resistant to change, draining the world of creativity.
Most researchers are focused on "extending the 'healthspan,' so that the people who live into their 90s are vigorous and disease-free."
He's not too worried, though, that that's where studies such as the Mayo Clinic's are headed, and supports that sort of research. "Hopefully these things will work, and they'll help us live a little bit longer," Green says, "but the idea of radical life extension where we're going to live indefinitely longer, I think that is very unrealistic."
Most of the researchers working on combatting aging don't, in fact, talk of unlimited lifespans. Rather, they talk about extending the "healthspan," so that the people who live into their 90s are vigorous and disease-free up until nearly the end of their lives.
If scientists can lengthen life while reducing the number of years people suffer with dementia or infirmity, that could be beneficial, says Stephen Post, a professor of medicine and director of the Center for Medical Humanities, Compassionate Care, and Bioethics at Stony Brook University in New York. But even increasing the population of vigorous 90-somethings might have negative implications for society. "What would we do with all these people who are living so long?" he asks. "Would we stop having children? Would we never retire?"
Adding 2.2 healthy years to the U.S. life by delaying aging could benefit the economy by $7.1 trillion over 50 years.
If people keep working well past their 60s, that could mean there would be fewer jobs available for younger people, says Maxwell Mehlman, professor of bioethics at Case Western Reserve University's School of Law in Ohio. Mehlman says society may have to rethink age discrimination laws, which bar firing or refusing to hire people over a certain age, to make room for younger workers. On the other hand, those who choose to retire and live another two or three decades could strain pension and entitlement systems.
But a longer healthspan could reduce costs in the healthcare system, which now are driven disproportionately by older people. Jay Olshansky, an epidemiologist at the University of Illinois at Chicago School of Public Health, has estimated that adding 2.2 healthy years to the U.S. life by delaying aging would benefit the economy by $7.1 trillion over 50 years, as spending on illnesses such as cancer and heart disease drop.
For his part, Robbins says that the scientific conferences in the anti-aging field, which tend to focus on the technical research, should hold more sessions on social and economic impacts. If anti-aging therapies start extending healthy lifespans, as he and other researchers hope they will within a decade or so, society will need to adjust.
Ultimately, it's an extension of health, not just of longevity, that will benefit us. Extra decades of senescence do nobody any good. As Green says, "Nobody wants to live in a nursing home for 1000 years."
Questions remain about new drug for hot flashes
In May, a new drug, Fezolinetant, was approved by the FDA to treat hot flashes associated with menopause.
Vascomotor symptoms (VMS) is the medical term for hot flashes associated with menopause. You are going to hear a lot more about it because a company has a new drug to sell. Here is what you need to know.
Menopause marks the end of a woman’s reproductive capacity. Normal hormonal production associated with that monthly cycle becomes erratic and finally ceases. For some women the transition can be relatively brief with only modest symptoms, while for others the body's “thermostat” in the brain is disrupted and they experience hot flashes and other symptoms that can disrupt daily activity. Lifestyle modification and drugs such as hormone therapy can provide some relief, but women at risk for cancer are advised not to use them and other women choose not to do so.
Fezolinetant, sold by Astellas Pharma Inc. under the product name Veozah™, was approved by the Food and Drug Administration (FDA) on May 12 to treat hot flashes associated with menopause. It is the first in a new class of drugs called neurokinin 3 receptor antagonists, which block specific neurons in the brain “thermostat” that trigger VMS. It does not appear to affect other symptoms of menopause. As with many drugs targeting a brain cell receptor, it must be taken continuously for a few days to build up a good therapeutic response, rather than working as a rescue product such as an asthma inhaler to immediately treat that condition.
Hot flashes vary greatly and naturally get better or resolve completely with time. That contributes to a placebo effect and makes it more difficult to judge the outcome of any intervention. Early this year, a meta analysis of 17 studies of drug trials for hot flashes found an unusually large placebo response in those types of studies; the placebo groups had an average of 5.44 fewer hot flashes and a 36 percent reduction in their severity.
In studies of fezolinetant, the drug recently approved by the FDA, the placebo benefit was strong and persistent. The drug group bested the placebo response to a statistically significant degree but, “If people have gone from 11 hot flashes a day to eight or seven in the placebo group and down to a couple fewer ones in the drug groups, how meaningful is that? Having six hot flashes a day is still pretty unpleasant,” says Diana Zuckerman, president of the National Center for Health Research (NCHR), a health oriented think tank.
“Is a reduction compared to placebo of 2-3 hot flashes per day, in a population of women experiencing 10-11 moderate to severe hot flashes daily, enough relief to be clinically meaningful?” Andrea LaCroix asked a commentary published in Nature Medicine. She is an epidemiologist at the University of California San Diego and a leader of the MsFlash network that has conducted a handful of NIH-funded studies on menopause.
Questions Remain
LaCroix and others have raised questions about how Astellas, the company that makes the new drug, handled missing data from patients who dropped out of the clinical trials. “The lack of detailed information about important parameters such as adherence and missing data raises concerns that the reported benefits of fezolinetant very likely overestimate those that will be observed in clinical practice," LaCroix wrote.
In response to this concern, Anna Criddle, director of global portfolio communications at Astellas, wrote in an email to Leaps.org: “…a full analysis of data, including adherence data and any impact of missing data, was submitted for assessment by [the FDA].”
The company ran the studies at more than 300 sites around the world. Curiously, none appear to have been at academic medical centers, which are known for higher quality research. Zuckerman says, "When somebody is paid to do a study, if they want to get paid to do another study by the same company, they will try to make sure that the results are the results that the company wants.”
Criddle said that Astellas picked the sites “that would allow us to reach a diverse population of women, including race and ethnicity.”
A trial of a lower dose of the drug was conducted in Asia. In March 2022, Astellas issued a press release saying it had failed to prove effectiveness. No further data has been released. Astellas still plans to submit the data, according to Criddle. Results from clinical trials funded by the U.S. goverment must be reported on clinicaltrials.gov within one year of the study's completion - a deadline that, in this case, has expired.
The measurement scale for hot flashes used in the studies, mild-moderate-severe, also came in for criticism. “It is really not good scale, there probably isn’t a broad enough range of things going on or descriptors,” says David Rind. He is chief medical officer of the Institute for Clinical and Economic Review (ICER), a nonprofit authority on new drugs. It conducted a thorough review and analysis of fezolinestant using then existing data gathered from conference abstracts, posters and presentations and included a public stakeholder meeting in December. A 252-page report was published in January, finding “considerable uncertainty about the comparative net health benefits of fezolinetant” versus hormone therapy.
Questions surrounding some of these issues might have been answered if the FDA had chosen to hold a public advisory committee meeting on fezolinetant, which it regularly does for first in class medicines. But the agency decided such a meeting was unnecessary.
Cost
There was little surprise when Astellas announced a list price for fezolinetant of $550 a month ($6000 annually) and a program of patient assistance to ease out of pocket expenses. The company had already incurred large expenses.
In 2017 Astellas purchased the company that originally developed fezolinetant for $534 million plus several hundred million in potential royalties. The drug company ran a "disease awareness” ad, Heat on the Street, hat aired during the Super Bowl in February, where 30 second ads cost about $7 million. Industry analysts have projected sales to be $1.9 billion by 2028.
ICER’s pre-approval evaluation said fezolinetant might "be considered cost-effective if priced around $2,000 annually. ... [It]will depend upon its price and whether it is considered an alternative to MHT [menopause hormone treatment] for all women or whether it will primarily be used by women who cannot or will not take MHT."
Criddle wrote that Astellas set the price based on the novelty of the science, the quality of evidence for the drug and its uniqueness compared to the rest of the market. She noted that an individual’s payment will depend on how much their insurance company decides to cover. “[W]e expect insurance coverage to increase over the course of the year and to achieve widespread coverage in the U.S. over time.”
Leaps.org wrote to and followed up with nine of the largest health insurers/providers asking basic questions about their coverage of fezolinetant. Only two responded. Jennifer Martin, the deputy chief consultant for pharmacy benefits management at the Department of Veterans Affairs, said the agency “covers all drugs from the date that they are launched.” Decisions on whether it will be included in the drug formulary and what if any copays might be required are under review.
“[Fezolinetant] will go through our standard P&T Committee [patient and treatment] review process in the next few months, including a review of available efficacy data, safety data, clinical practice guidelines, and comparison with other agents used for vasomotor symptoms of menopause," said Phil Blando, executive director of corporate communications for CVS Health.
Other insurers likely are going through a similar process to decide issues such as limiting coverage to women who are advised not to use hormones, how much copay will be required, and whether women will be required to first try other options or obtain approvals before getting a prescription.
Rind wants to see a few years of use before he prescribes fezolinetant broadly, and believes most doctors share his view. Nor will they be eager to fill out the additional paperwork required for women to participate in the Astellas patient assistance program, he added.
Safety
Astellas is marketing its drug by pointing out risks of hormone therapy, such as a recent paper in The BMJ, which noted that women who took hormones for even a short period of time had a 24 percent increased risk of dementia. While the percentage was scary, the combined number of women both on and off hormones who developed dementia was small. And it is unclear whether hormones are causing dementia or if more severe hot flashes are a marker for higher risk of developing dementia. This information is emerging only after 80 years of hundreds of millions of women using hormones.
In contrast, the label for fezolinetant prohibits “concomitant use with CYP1A2 inhibitors” and requires testing for liver and kidney function prior to initiating the drug and every three months thereafter. There is no human or animal data on use in a geriatric population, defined as 65 or older, a group that is likely to use the drug. Only a few thousand women have ever taken fezolinetant and most have used it for just a few months.
Options
A woman seeking relief from symptoms of menopause would like to see how fezolintant compares with other available treatment options. But Astellas did not conduct such a study and Andrea LaCroix says it is unlikely that anyone ever will.
ICER has come the closest, with a side-by-side analysis of evidence-based treatments and found that fezolinetant performed quite similarly and modestly as the others in providing relief from hot flashes. Some treatments also help with other symptoms of menopause, which fezolinetant does not.
There are many coping strategies that women can adopt to deal with hot flashes; one of the most common is dressing in layers (such as a sleeveless blouse with a sweater) that can be added or subtracted as conditions require. Avoiding caffeine, hot liquids, and spicy foods is another common strategy. “I stopped drinking hot caffeinated drinks…for several years, and you get out of the habit of drinking them,” says Zuckerman.
LaCroix curates those options at My Meno Plan, which includes a search function where you can enter your symptoms and identify which treatments might work best for you. It also links to published research papers. She says the goal is to empower women with information to make informed decisions about menopause.
A company in England has made a test that picks out the compounds from breath that reveal if people have liver disease.
Every year, around two million people worldwide die of liver disease. While some people inherit the disease, it’s most commonly caused by hepatitis, obesity and alcoholism. These underlying conditions kill liver cells, causing scar tissue to form until eventually the liver cannot function properly. Since 1979, deaths due to liver disease have increased by 400 percent.
The sooner the disease is detected, the more effective treatment can be. But once symptoms appear, the liver is already damaged. Around 50 percent of cases are diagnosed only after the disease has reached the final stages, when treatment is largely ineffective.
To address this problem, Owlstone Medical, a biotech company in England, has developed a breath test that can detect liver disease earlier than conventional approaches. Human breath contains volatile organic compounds (VOCs) that change in the first stages of liver disease. Owlstone’s breath test can reliably collect, store and detect VOCs, while picking out the specific compounds that reveal liver disease.
“There’s a need to screen more broadly for people with early-stage liver disease,” says Owlstone’s CEO Billy Boyle. “Equally important is having a test that's non-invasive, cost effective and can be deployed in a primary care setting.”
The standard tool for detection is a biopsy. It is invasive and expensive, making it impractical to use for people who aren't yet symptomatic. Meanwhile, blood tests are less invasive, but they can be inaccurate and can’t discriminate between different stages of the disease.
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
The team is testing patients in the early stages of advanced liver disease, or cirrhosis, to identify and detect these biomarkers. In an initial study, Owlstone’s breathalyzer was able to pick out patients who had early cirrhosis with 83 percent sensitivity.
Boyle’s work is personally motivated. His wife died of colorectal cancer after she was diagnosed with a progressed form of the disease. “That was a big impetus for me to see if this technology could work in early detection,” he says. “As a company, Owlstone is interested in early detection across a range of diseases because we think that's a way to save lives and a way to save costs.”
How it works
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
Study participants breathe into a mouthpiece attached to a breath sampler developed by Owlstone. It has cartridges are designed and optimized to collect gases. The sampler specifically targets VOCs, extracting them from atmospheric gases in breath, to ensure that even low levels of these compounds are captured.
The sampler can store compounds stably before they are assessed through a method called mass spectrometry, in which compounds are converted into charged atoms, before electromagnetic fields filter and identify even the tiniest amounts of charged atoms according to their weight and charge.
The top four compounds in our breath
In an initial study, Owlstone captured VOCs in breath to see which ones could help them tell the difference between people with and without liver disease. They tested the breath of 46 patients with liver disease - most of them in the earlier stages of cirrhosis - and 42 healthy people. Using this data, they were able to create a diagnostic model. Individually, compounds like 2-Pentanone and limonene performed well as markers for liver disease. Owlstone achieved even better performance by examining the levels of the top four compounds together, distinguishing between liver disease cases and controls with 95 percent accuracy.
“It was a good proof of principle since it looks like there are breath biomarkers that can discriminate between diseases,” Boyle says. “That was a bit of a stepping stone for us to say, taking those identified, let’s try and dose with specific concentrations of probes. It's part of building the evidence and steering the clinical trials to get to liver disease sensitivity.”
Sabine Szunerits, a professor of chemistry in Institute of Electronics at the University of Lille, sees the potential of Owlstone’s technology.
“Breath analysis is showing real promise as a clinical diagnostic tool,” says Szunerits, who has no ties with the company. “Owlstone Medical’s technology is extremely effective in collecting small volatile organic biomarkers in the breath. In combination with pattern recognition it can give an answer on liver disease severity. I see it as a very promising way to give patients novel chances to be cured.”
Improving the breath sampling process
Challenges remain. With more than one thousand VOCs found in the breath, it can be difficult to identify markers for liver disease that are consistent across many patients.
Julian Gardner is a professor of electrical engineering at Warwick University who researches electronic sensing devices. “Everyone’s breath has different levels of VOCs and different ones according to gender, diet, age etc,” Gardner says. “It is indeed very challenging to selectively detect the biomarkers in the breath for liver disease.”
So Owlstone is putting chemicals in the body that they know interact differently with patients with liver disease, and then using the breath sampler to measure these specific VOCs. The chemicals they administer are called Exogenous Volatile Organic Compound) probes, or EVOCs.
Most recently, they used limonene as an EVOC probe, testing 29 patients with early cirrhosis and 29 controls. They gave the limonene to subjects at specific doses to measure how its concentrations change in breath. The aim was to try and see what was happening in their livers.
“They are proposing to use drugs to enhance the signal as they are concerned about the sensitivity and selectivity of their method,” Gardner says. “The approach of EVOC probes is probably necessary as you can then eliminate the person-to-person variation that will be considerable in the soup of VOCs in our breath.”
Through these probes, Owlstone could identify patients with liver disease with 83 percent sensitivity. By targeting what they knew was a disease mechanism, they were able to amplify the signal. The company is starting a larger clinical trial, and the plan is to eventually use a panel of EVOC probes to make sure they can see diverging VOCs more clearly.
“I think the approach of using probes to amplify the VOC signal will ultimately increase the specificity of any VOC breath tests, and improve their practical usability,” says Roger Yazbek, who leads the South Australian Breath Analysis Research (SABAR) laboratory in Flinders University. “Whilst the findings are interesting, it still is only a small cohort of patients in one location.”
The future of breath diagnosis
Owlstone wants to partner with pharmaceutical companies looking to learn if their drugs have an effect on liver disease. They’ve also developed a microchip, a miniaturized version of mass spectrometry instruments, that can be used with the breathalyzer. It is less sensitive but will enable faster detection.
Boyle says the company's mission is for their tests to save 100,000 lives. "There are lots of risks and lots of challenges. I think there's an opportunity to really establish breath as a new diagnostic class.”