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Longevity science is progressing slowly amid the anti-aging craze
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Jonathan An tries to ignore the hype about new life-extension
treatments, but it's caught up to him anyway.
He has heard the gospel of the longevity influencers, including that
one multimillionaire who has been on a media campaign for months
claiming that the 111 pills he takes each day will help him live
forever. An, an assistant professor of oral sciences at the University
of Washington, doesn't buy it. But he recently found himself
inadvertently ensnared by the fervor around anti-aging — thanks to his
mice.
An has studied mice suffering from periodontal disease, a bacterial-
induced inflammatory infection of the gums that can lead to tooth
loss. Mice (and more than 60 percent of human adults over 65) have to
deal with this uncomfortable oral illness — and they don't have much
choice but to cope. When people's teeth fall out, dentists like An
replace them. But he would rather not have to remove so many.
While studying for his doctorate in dentistry at the University of
Washington, An pursued a joint PhD to research preventive dental
measures. He experimented with giving mice chow infused with the drug
rapamycin each day to see if it would improve their oral health.
It worked. Mice treated for eight weeks with the drug — traditionally
used to help prevent organ-transplant rejection — not only experienced
delayed symptoms of periodontal disease, but saw regrowth of their
tooth-supporting jaw bones.
This year, An is planning to test rapamycin in humans. If it has the
same effect in adults as it did in mice, people might eventually be
able to pick up a drug at the pharmacy that helps them avoid unwanted
trips to the dentist's office.
Better dental health would be a pleasant effect, but that's not why
An's research drew an unusual amount of attention. Because the drug An
chose to test was rapamycin, the longevity field took notice. In
separate lab experiments over the past decade, rapamycin has been
found to extend the lifespan of yeast, nematodes, fruit flies, and
mice. It has helped mice delay or reverse immunity decline, muscle
decline, cognitive decline, and cancer growth.
This string of successes for rapamycin, which belongs to a class of
drugs that stifle one biological pathway for cell growth, has caught
the eyes of renowned longevity researchers. It's also attracted the
attention of wealthy lifehackers and the clinics, supplement
companies, and biotech investors who — out of true belief,
opportunism, or a combination — stand to make money from people
seeking an elixir for longer life.
Since An's study was published in 2020, longevity clinics from across
the country have asked him how they can incorporate rapamycin into
their practices. Some scientists consider rapamycin a strong candidate
for life-extension purposes both because it has helped lab species
live longer and because it has already been approved as an
immunosuppressant in humans. Today, doctors can and do prescribe
rapamycin for off-label use — including for longevity.
An wants to believe that these clinics — part of a fledgling longevity
industry that includes between 50 and 800 providers across the US,
according to the Wall Street Journal — are genuinely trying to improve
their clients' health. But he suspects that may not always be the
case.
He tells the longevity crowd what he does know, which is less exciting
than they might hope. When it comes to human health, "I don't know
what rapamycin does," he said. "But I always tell them to make sure to
have a dentist on hand because some of the side effects are oral-
related."
Other companies want him to help with their own studies, the results
of which they plan to keep private. An says no. "I'm a dentist," An
said. "Not a salesperson."
A longer, healthier life is one of the easiest products in the world
to sell. According to a Deloitte report, the 50 biggest longevity
companies raised more than $1 billion in venture capital funding as of
2020 — a number that the company said would rise "due to the growing
conviction that the longevity market could outstrip the existing
health care market." Altos Labs, a "rejuvenation" biotech whose
investors include Jeff Bezos, announced in 2022 that it had raised $3
billion in funding.
An astronomer's discovery of a neutron star has much less commercial
potential and therefore generates much less interest than a
researcher's discovery that the micronutrient resveratrol helps yeast
live longer — even if it's likely that neither ultimately affects
human lifespan. The attention paid to billionaire-funded research
risks obscuring whether the longevity field is genuinely on the verge
of a breakthrough or whether a clinic is just saying that to promote
their experimental blood transfusion.
In reality, longevity research is advancing — but slowly. Clinical
trials are moving forward on select uses for longevity drugs, younger
researchers are taking the field more seriously, and private
organizations are pledging significant support to research: The Saudi-
based Hevolution Foundation has promised up to $1 billion in funding
annually for biotech startups and academic researchers.
But while there likely remain many promising treatment candidates that
have yet to be identified, they would take decades to reach clinical
trials. Even academics who are bullish on the promise of longevity
research fear that, for all the fanfare, the field has become too
fixated on a few drugs and lifestyle adjustments that have been under
investigation for years, while neglecting the basic research that
could reveal novel pathways to slow down human aging.
For now, the three best ways to extend your life remain boring: eating
a healthy diet, exercising regularly, and sleeping well. We aren't
going to add decades to human life any time soon; living to 150 or 200
remains in the realm of science fiction. But in decades to come,
advancements in the science of aging may still lead to therapeutic
breakthroughs that lengthen human healthspan — the period of life
spent in good health. Perhaps a few more people will become
centenarians, but the real success would be having more years when you
can live well.
### How longevity went mainstream in academia
Matt Kaeberlein, a longevity researcher at the University of
Washington, remembers a time when few in academia took the study of
aging — much less the idea of longevity — seriously.
"When I came into the field as a graduate student in 1998, there was
nobody who went to graduate school to study aging," he said. "The
perception among the broader scientific community was that it was
mostly snake oil and crap. There's still a lot of snake oil and crap,
but it is more accepted now than it used to be."
The field began gaining wider recognition in 1993 when Cynthia Kenyon,
a pioneer in aging research who now works at the Alphabet-owned life
sciences company Calico Labs, discovered that mutating a single gene
of the roundworm Caenorhabditis elegans doubled its lifespan. Other
scientists soon figured out why. Gary Ruvkun, a professor of genetics
at Harvard Medical School, and his colleagues found that the altered
gene regulated an insulin-signaling pathway similar to one in humans
that might play a role in slowing cell growth and metabolism.
Researchers like Andrzej Bartke found similar mechanisms in mice,
which have been the subject of much of the relevant research so far.
"One of the key things that's happened is that the evidence that you
can actually slow down and interfere with the aging process in mammals
… has become so overwhelming that only the willfully blind can ignore
it," Richard A. Miller, who leads the University of Michigan's Paul
Glenn Center for Biology of Aging Research, told me.
In the last two decades, scientists have performed hundreds of lab
experiments — mostly on animals — on drugs like rapamycin,
canagliflozin, acarbose, empagliflozin, metformin, and on
interventions like calorie restriction in diets and removal of
nondividing senescent cells. Instead of testing the effects of these
treatments on specific illnesses, many of these studies test whether
certain interventions slow down animals' aging processes and help them
live longer.
The expansion of longevity research has unearthed some potentially
useful information about which biological mechanisms control aging and
how to alter them. In mice and other species, changing a single
pathway has the power to extend life by significant margins, raising
hopes that if humans respond similarly, certain drugs could extend
human lives by years.
"We just have a better understanding of what those pathways are," said
Tom Rando, director of the UCLA Broad Stem Cell Research Center, "even
if we don't have a complete understanding of why they work and why
they extend lifespan."
Though most experiments with potential longevity drugs and other
interventions like blood transfusions are still being tested on lab
animals, two dozen candidate drugs have moved to clinical trials with
human patients. Daniel Promislow, a University of Washington professor
of medicine and pathology, told me that when he got into the field
three decades ago, researchers talked hopefully about early
developments someday making it to the lab. "Fast forward 25, 30 years,
and many of these lab-based discoveries are now at the heart of a
large number of clinical trials," he said.
The clinical trials could allow researchers to produce evidence for
interventions — besides diet, exercise, and sleep — that might help
people live longer. Coleen T. Murphy, professor of molecular biology
at Princeton, wrote in her 2023 book _How We Age_ that, "What drugs
can I take to live longer?" is becoming an increasingly tangible goal.
"A few years ago I might have chuckled at the naivety of this
question," she wrote, "but now it's not so crazy to think that we will
be able to take some sort of medicine to extend our healthy lifespans
in the foreseeable future."
The horizon for this future is still far off. Most researchers I spoke
to didn't believe that humans were going to experience a rapid
increase in life expectancy any time soon — or maybe ever. They
believed progress would instead be made in healthspan, helping people
stay healthier for longer and avoiding long periods of physical and
cognitive decline as they get older.
Such results probably won't lead to someone living an extra decade.
But they could make old age less burdensome. That would matter
enormously for individuals, who could enjoy more years in good health,
and society, by potentially reducing the high costs of late-in-life
medical care.
"I can't fathom saying, 'Yeah, we're going to try to extend someone's
lifespan by nine years,'" An told me. "There's really no way to do
that."
### Behind the hype, longevity research is moving — but slowly
In a way, some of the biggest improvements to human lifespans have
already been made. Initiatives in public health — water sanitation,
vaccination campaigns, sewage systems — have added decades to the
average person's life over the past few centuries. Since 1900, the
average lifespan of a newborn has more than doubled worldwide — from
32 years old to 71 years old.
But the very fact that humans already live far longer than a lab
animal is part of the reason that longevity research is so slow and
difficult. For experimental purposes, laboratory mice live less than
three years. Researchers have tested rapamycin in both young and old
mice at a range of doses and then waited for them to die. Doing the
same in humans would be far more expensive and take much longer. ****
It's also not strictly legal. **** The Food and Drug Administration
doesn't classify aging as a disease, which means that clinical trials
can't set out solely to test how much longer an intervention keeps
someone alive. Instead, researchers must study age-related indicators
like cardiovascular function and cognitive impairment instead of
"aging" itself.
To compensate, longevity researchers are looking for other ways to
measure aging that don't require a patient's death. They have
identified several biomarkers that could serve as surrogate endpoints,
but none have reached a scientific consensus. These include "aging
clocks," predictive models that purport to measure biological age or
the age of specific biological organs; Bryan Johnson, the
multimillionaire tech founder who calls himself a "professional
rejuvenation athlete," touts such data as proof that he has reversed
his aging.
These tests are ostensibly based on the research of Steve Horvath, a
former professor at UCLA who now works at Altos Labs. He has used age-
related DNA methylation to determine biological age. Though most
researchers I spoke to expressed cautious optimism about the potential
of Horvath's findings, they were skeptical of the extant consumer
tests.
"We're not really sure if the age we tell you is accurate and if it's
going to be the same tomorrow and whether it has any value," said Tony
Wyss-Coray, a Stanford professor of neurology who has found that
elderly mice given the blood of younger mice see improvements in brain
function. "And of course, no company wants to tell you that, but
that's just a fact."
Most longevity researchers think about their research environment the
same way: The flashiest stories are usually pretty removed from the
actual state of the field. A drug that just helped mice live 50
percent longer is unlikely to do exactly the same for humans, no
matter what a press release implies. Human bodies are much better at
repairing their DNA than mice are, which makes them less susceptible
to diseases like cancer. Plus, studies that would definitively prove a
certain intervention would aid human life would take decades, and
experts believe they could struggle to demonstrate their effectiveness
to the FDA.
"You'll rarely find a scientist funded by the [National Institutes of
Health] who's doing work in the biology of aging who would claim that
their research could or will allow people to live to 140," Rando told
me. "It's really coalesced around the idea that our main successes
will be in reducing the burden of disease."
It reflects a realism among the real experts. In longevity, there is
not going to be a moment when a chrysalis bursts and a butterfly flies
out, Miller said, a sudden leap forward in people's life expectancy.
"It's more like the evolution of land plants. Gradually, they creep up
over the beach, and then onto the meadow and then into the meadows.
This is sort of creeping through the scientific community — too
slowly."
According to many researchers, part of the reason for the relatively
slow progress in longevity treatments is lack of funding in the field.
For all the flashy announcements about companies like Calico and Altos
Labs, academic researchers struggle to find financial support. The
National Institute on Aging, the NIH division that funds research on
the aging process, projects that it will spend about 9 percent of its
budget on the biology of aging in 2024 and just under 60 percent on
neuroscience-specific research. (The NIA's total projected budget in
2024 is about $4.4 billion of the NIH's $47.1 billion.) Promislow and
Kaeberlein, who co-run a long-term study on biological and
environmental factors that could contribute to aging in dogs, are
currently fighting to keep their project alive with their NIH funding
expected to end in June.
"I think there's an assumption by a lot of people that there's a ton
of money in aging research," Murphy told me. "If you're an academic
trying to get funding from the NIH, it's actually not true."
The lack of funding also draws university researchers out of their
scholarly institutions and to companies like Calico and Altos Labs.
"The idea of working with very smart people with lots of resources,
all that's really attractive," Miller told me.
But that drift to the private sector could actually slow down aging
research, already a sluggish endeavor, even more in the long run. The
field is trending toward investor-driven research, while the basic
research studies necessary for the next generation of possible
interventions languish because they depend on public or philanthropic
funding.
Drugs like rapamycin have already taken decades to enter clinical
trials, but it's possible that none of the current leading longevity
candidates work. Researchers don't even agree on which of the current
drugs and interventions is the most promising: Miller, for example,
told me he thinks that rapamycin is "the wrong drug" and that more
funding should go to canagliflozin, which has increased median
survival age in male mice by 14 percent and for which human side
effects are better known due to its use in treating type 2 diabetes
since 2013. Still, he doesn't think it's easy, "from our limited
amount of knowledge, to be confident as to whether rapamycin, or
canagliflozin, or any other promising drug would produce major
benefits in people with acceptably low side effects." Most aging-
related biotechnology companies use investor money to test aging
interventions already proven in mice. Few are conducting the basic
research to find new possible pathways for future therapies.
The more aging-related pathways scientists can find, the more possible
targets for longevity drugs they would have. Each discovery opens the
possibility for new interventions. Kaeberlein said that though the
field has expanded in terms of the number of studies on certain drugs
and mechanistic pathways, it's also become in a sense more narrow.
"We think, 'This is how the system works. So we're going to test these
parts of the model,' instead of the more exploratory science that was
being done when I was a graduate student, which was, 'We have no
frickin' clue how the system works. Let's go do some unbiased screens
to figure out what's happening here,'" he said.
Longevity researchers may be playing in a tiny corner of the sandbox,
investigating just a few pathways while ignoring other possibilities.
Scientists blame such myopia for the long gap between breakthroughs.
The most consistently effective intervention for extending animal
lifespan has been known for decades: restricting the number of
calories they eat.
"I think that shift in mentality has led to more incremental results
and fewer big, exciting, new discoveries," said Kaeberlein, "and I
think, personally, that's why nobody has done better than rapamycin in
15 years and no one has done better than caloric restriction in 50
years."
There's also the possibility that drugs that have worked consistently
across different species will work for some humans but not others.
"The vast majority of studies in our field are done in one genetically
identical strain of mouse," Rando said. "It's sort of like running a
clinical trial in humans and only using identical twins. … Even if
something could work, it's likely to work in a subset of the
population and not in everybody."
Oddly, even the most brazen of the (non-expert) anti-aging boosters
have uninspiring perceptions of the current state of longevity
research. I was surprised when Bryan Johnson explained to me that,
despite having a team of doctors who track the age of his organs and
feed him a daily canister of pills, his choices weren't really made
based on today's advancements in health and wellness.
He instead puts his faith in the continued evolution of artificial
intelligence capabilities, which has advanced greatly over the past
few years. He sees AI continuing to develop at an exponential rate —
and longevity research eventually progressing at a more rapid speed
than human researchers could hope to replicate.
"It's an observation that we are baby steps away from super
intelligence," Johnson told me, "and it's improving at a speed that we
can't imagine."
It's that, he hopes, that will bring about eternal life. The mice
studies are less relevant.
### A more realistic future for the longevity field
Immortality is enticing, but it's not coming anytime soon. Neither is
living to 150. Some people — hopefully more than now — will live to
100, but they will still be the exception. The way longevity research
might push the field forward could look very similar to the treatments
we already have. For people with a high risk of cardiovascular
disease, statins are a sort of longevity drug. For those dealing with
certain cancers, chemotherapy can be considered a longevity treatment.
The future of longevity likely looks more like the world where we
discover that rapamycin — a drug that can extend the lives of mice and
help humans accept a new organ — can also treat elderly patients for
periodontal disease. It could mean that people take a blood sugar-
regulating drug like canagliflozin and suffer from fewer heart attacks
and cancers.
"I don't really care about life extension because there's no way to
measure it," An said. "It's really about your health."
Even in slow motion, the field keeps advancing. Murphy told me she was
excited to see trial results from the longevity company Unity
Biotechnology back in 2020. The drug UBX0101, which interacts with a
tumor-suppressing pathway, cleared a phase 1 clinical trial.
When it moved to phase 2, though, it failed to achieve its aim of
helping patients with osteoarthritis of the knee. A success could have
been a promising sign for treatments to get rid of non-dividing
senescent cells. But even a failure was valuable. It might not have
been the result that anyone wanted, but it was a result, and it was
public.
"That's progress for our field," she told me. "This is moving
forward."
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