If this controversial idea gains acceptance, it could radically change the way we treat getting old.
By David Adam, MIT Technology Review
August 19, 2019 -- Each Cyclops had a
single eye because, legend has it, the mythical giants traded the other one
with the god Hades in return for the ability to see into the future. But Hades
tricked them: the only vision the Cyclopes were shown was the day they would
die. They carried this knowledge through their lives as a burden—the unending
torture of being forewarned and yet having no ability to do anything about it.
Since ancient times, aging has been
viewed as simply inevitable, unstoppable, nature’s way. “Natural causes” have
long been blamed for deaths among the old, even if they died of a recognized
pathological condition. The medical writer Galen argued back in the second
century AD that aging is a natural process.
His view, the acceptance that one can
die simply of old age, has dominated ever since. We think of aging as the
accumulation of all the other conditions that get more common as we get
older—cancer, dementia, physical frailty. All that tells us, though, is that
we’re going to sicken and die; it doesn’t give us a way to change it. We don’t
have much more control over our destiny than a Cyclops.
But a growing number of scientists are
questioning our basic conception of aging. What if you could challenge your
death—or even prevent it altogether? What if the panoply of diseases that
strike us in old age are symptoms, not causes? What would change if we
classified aging itself as the disease?
David Sinclair, a geneticist at Harvard
Medical School, is one of those on the front line of this movement. Medicine,
he argues, should view aging not as a natural consequence of growing older, but
as a condition in and of itself. Old age, in his view, is simply a
pathology—and, like all pathologies, can be successfully treated. If we labeled
aging differently, it would give us a far greater ability to tackle it in
itself, rather than just treating the diseases that accompany it.
“Many of the most serious diseases today
are a function of aging. Thus, identifying the molecular mechanisms and
treatments of aging should be an urgent priority,” he says. “Unless we address
aging at its root cause, we’re not going to continue our linear, upward
progress toward longer and longer life spans.”
It is a subtle shift, but one with big
implications. How disease is classified and viewed by public health groups such
as the World Health Organization (WHO) helps set priorities for governments and
those who control funds. Regulators, including the US Food and Drug
Administration (FDA), have strict rules that guide what conditions a drug can
be licensed to act on, and so what conditions it can be prescribed and sold
for. Today aging isn’t on the list. Sinclair says it should be, because
otherwise the massive investment needed to find ways to fend it off won’t
appear.
“Work to develop medicines that could
potentially prevent and treat most major diseases is going far slower than it
should be because we don’t recognize aging as a medical problem,” he says. “If
aging were a treatable condition, then the money would flow into research,
innovation, and drug development. Right now, what pharmaceutical or biotech
company could go after aging as a condition if it doesn’t exist?” It should, he
says, be the “biggest market of all.”
That’s precisely what worries some
people, who think a gold rush into “anti-aging” drugs will set the wrong
priorities for society.
It “turns a scientific discussion into a
commercial or a political discussion,” says Eline Slagboom, a molecular
epidemiologist who works on aging at Leiden University Medical Center in the
Netherlands. Viewing age as just a treatable disease shifts the emphasis away from
healthy living, she says. Instead, she argues, policymakers and medical
professionals need to do more to prevent chronic diseases of old age by
encouraging people to adopt healthier lifestyles while they are still young or
middle-aged. Otherwise, the message is “that we can’t do anything with anybody
[as they age] until they reach a threshold at the point where they get sick or
age rapidly, and then we give them medication.”
Another common objection to the
aging-as-a-disease hypothesis is that labeling old people as diseased will add
to the stigma they already face. “Ageism is the biggest ism we have today in
the world,” says Nir Barzilai, director of the Institute for Aging Research at
the Albert Einstein College of Medicine in New York. “The aging community is
attacked. People are fired from work because they are old. Old people cannot
get jobs. To go to those people with so many problems and now tell them,
‘You’re sick, you have a disease’? This is a no-win situation for the people we
are trying to help.”
Not everyone agrees it has to be a
stigma. “I am clearly in favor of calling aging a disease,” says Sven
Bulterijs, cofounder of the Healthy Life Extension Society, a nonprofit
organization in Brussels that considers aging a “universal human tragedy” with
a root cause that can be found and tackled to make people live longer. “We
don’t say for cancer patients that it’s insulting to call it a disease.”
Notwithstanding Sinclair’s comment about
“linear, upward progress,” just how long humans could live remains bitterly
contested. The underlying, fundamental question: Do we have to die at all? If
we found a way to both treat and beat aging as a disease, would we live for
centuries—millennia, even? Or is there an ultimate limit?
Nature suggests that endless life might
not be inconceivable. Most famously, perhaps, the bristlecone pine trees of
North America are considered biologically immortal. They can die—chopped down
by an ax or zapped by a lightning bolt—but left undisturbed, they typically
won’t simply fall over because they get old. Some are reckoned to be 5,000
years young; age, quite literally, does not wither them. Their secret remains a
mystery. Other species appear to show signs of biological immortality as well,
including some sea creatures.
Such observations have led many to
contend that life span can be dramatically extended with the right
interventions. But in 2016, a high-profile study published in Nature argued
that human life has a hard limit of about 115 years. This estimate is based on
global demographic data showing that improvements in survival with age tend to
decline after 100, and that the record for human longevity hasn’t increased
since the 1990s. Other researchers have disputed the way the analysis was done.
Barzilai says efforts to tackle aging
are needed regardless. “We can argue about if it’s 115 or 122 or 110 years,” he
says. “Now we die before the age of 80, so we have 35 years that we are not
realizing now. So let’s start realizing those years before we’re talking about
immortality or somewhere in between.”
Whether or not they believe in either
the disease hypothesis or maximum life spans, most experts agree that something
has to change in the way we deal with aging. “If we don’t do something about
the dramatic increase in older people, and find ways to keep them healthy and
functional, then we have a major quality-of-life issue and a major economic
issue on our hands,” says Brian Kennedy, the director of Singapore’s Centre for
Healthy Ageing and a professor of biochemistry and physiology at the National
University of Singapore. “We have to go out and find ways to slow aging down.”
The aging population is the “climate
change of health care,” Kennedy says. It’s an appropriate metaphor. As with
global warming, many of the solutions rest on changing people’s behavior—for
example, modifications to diet and lifestyle. But, also as with global warming,
much of the world seems instead to be pinning its hopes on a technological fix.
Maybe the future will involve not just geoengineering but also
gero-engineering.
One thing that may underlie the growing
calls to reclassify aging as a disease is a shift in social attitudes. Morten
Hillgaard Bülow, a historian of medicine at the University of Copenhagen, says
things started to change in the 1980s, when the idea of “successful aging” took
hold. Starting with studies organized and funded by the MacArthur Foundation in
the United States, aging experts began to argue against Galen’s centuries-old
stoic acceptance of decline, and said scientists should find ways to intervene.
The US government, aware of the health implications of an aging population,
agreed. At the same time, advances in molecular biology led to new attention
from researchers. All that sent money flowing into research on what aging is and
what causes it.
In the Netherlands, Slagboom is trying
to develop tests to identify who is aging at a normal rate, and who has a body
older than its years. She sees anti-aging medicine as a last resort but says
understanding someone’s biological age can help determine how to treat
age-related conditions. Take, for instance, a 70-year-old man with mildly
elevated blood pressure. If he has the circulatory system of an 80-year-old,
then the elevated pressure could help blood reach his brain. But if he has the
body of a 60-year-old, he probably needs treatment.
Biomarkers that can identify biological
age are a popular tool in aging research, says Vadim Gladyshev of Brigham and
Women’s Hospital in Boston. He characterizes aging as the accumulation of
deleterious changes across the body, ranging from shifts in the populations of
bacteria that live in our gut to differences in the degree of chemical scarring
on our DNA, known as methylation. These are biological measures that can be
tracked, so they can also be used to monitor the effectiveness of anti-aging
drugs. “Once we can measure and quantify the progression through aging, then
that gives us a tool to assess longevity interventions,” he says.
Two decades on, the results of that
research are becoming apparent. Studies in mice, worms, and other model
organisms have revealed what’s going on in aging cells and come up with various
ways to extend life—sometimes to extraordinary lengths.
Milestones in the history of aging
research
- 1934 Clive McCay discovers the concept of caloric restriction by finding that rats live longer if they consume limited diets.
- 1952 Zoologist and anatomist Peter Medawar proposes the idea of senescence—cellular aging—and argues that aging is linked to reproduction, in a theory he calls “early-life fitness.”
- 1961 Biologists Leonard Hayflick and Paul Moorhead discover that human cells derived from embryonic tissue divide a finite number of times: the “Hayflick limit.”
- 1977 Elizabeth Blackburn at Yale discovers that telomeres, the structures at the ends of chromosomes, have unusual properties and vary in size with age.
- 1980 James Fries argues that every person is born with a maximum potential life span, and the average is 85 years.
- 1981 Michael Rose at the University of California, Irvine, breeds a strain of fruit fly that can live four times longer than normal.
- 1993 Cynthia Kenyon and her colleagues at UCSF discover the daf-2 mutation, which doubles the life span of nematodes.
- 2000 Leonard Guarente and colleagues at MIT identify SIR2, a gene that can extend life span by about 30% in yeast. They also link it with NAD+, a molecule critical for metabolism.
- 2002 James Vaupel proposes that the average life span has no upper limit, and that 150-year-olds will be common by 2150.
- 2006 Matt Kaeberlein, formerly of Guarente’s lab and now at the University of Washington, shows that rapamycin, a drug isolated from soil bacteria on Easter Island, can increase the life span of yeast cells.
- 2010 GlaxoSmithKline halts research on resveratrol because it caused kidney damage in a clinical trial.
- 2016 Nir Barzilai and colleagues discover that metformin can prolong the life span of silkworms without reducing body weight.
- 2019 A research team from Mayo, Wake Forest, and the University of Texas, San Antonio, announces promising results from early human trials of senolytics.
Most researchers have more modest goals,
with a focus on improving what they call “health span”—how long people remain
independent and functional. And they say they’re making progress, with a
handful of possible pills in the pipeline.
One promising treatment is metformin.
It’s a common diabetes drug that has been around for many years, but animal
studies suggest it could also protect against frailty, Alzheimer’s, and cancer.
Giving it to healthy people might help delay aging, but without official
guidance doctors are reluctant to prescribe it that way.
One group of researchers, including
Einstein College’s Barzilai, is trying to change that. Barzilai is leading a
human trial called TAME (Targeting Aging with Metformin) that plans to give the
drug to people aged 65 to 80 to see if it delays problems such as cancer,
dementia, stroke, and heart attacks.
Although the trial has struggled to raise
funding—partly because metformin is a generic drug, which reduces potential
profits for drug companies—Barzilai says he and his colleagues are now ready to
recruit patients and start later this year.
Metformin is one of a broader class of
drugs called mTOR inhibitors. These interfere with a cell protein involved in
division and growth. By turning the protein’s activity down, scientists think
they can mimic the known benefits of calorie restriction diets. These diets can
make animals live longer; it’s thought that the body may respond to the lack of
food by taking protective measures. Preliminary human tests suggest the drugs
can boost older people’s immune systems and stop them from catching infectious
bugs.
Other researchers are looking at why
organs start to pack up as their cells age, a process called senescence. Among
the leading candidates for targeting and removing these decrepit cells from
otherwise healthy tissues is a class of compounds called senolytics. These
encourage the aged cells to selectively self-destruct so the immune system can
clean them out. Studies have found that older mice on these drugs age more
slowly. In humans, senescent cells are blamed for diseases ranging from
atherosclerosis and cataracts to Parkinson’s and osteoarthritis. Small human
trials of senolytics are under way, although they aren’t officially aimed at
aging itself, but on the recognized illnesses of osteoarthritis and a lung
disease called idiopathic pulmonary fibrosis.
Research on these drugs has highlighted
a key question about aging: Is there a common mechanism by which different
tissues change and decline? If so, could we find drugs to target that mechanism
instead of playing what Harvard’s David Sinclair calls “whack-a-mole” medicine,
treating individual diseases as they emerge? He believes there is, and that he
has found a stunning new way to rewind the aging clock.
In unpublished work described in his
coming book Lifespan, he says the key to his lab’s work in this area is
epigenetics. This fast-moving field focuses on how changes to the way genes are
expressed, rather than mutations to the DNA itself, can produce physiological
changes such as disease. Some of the body’s own epigenetic mechanisms work to
protect its cells, repairing damage to DNA, for instance; but they become less
effective with age. Sinclair claims to have used gene therapy to effectively
recharge these mechanisms in mice, and he says he can “make damaged optic-nerve
cells young again” to restore sight to elderly blind animals.
We have been here before. Many
scientists thought they had found a fountain of youth in animal studies, only
to have the results dry up when they turned their attention to people. But
Sinclair is convinced he is on to something. He says he’ll soon publish the
results in a scientific journal for other researchers to examine.
Because aging isn’t officially a
disease, most research on these drugs exists in a gray area: they don’t—or
can’t—officially tackle aging. For example, Barzilai’s metformin project, the
closest the world has right now to a clinical trial for a drug that targets
aging, aims to prevent diseases associated with aging rather than aging itself,
as do the trials on senolytics. “And one of the side effects is you might live
longer,” he says.
Barzilai won’t go so far as to say aging
should be reclassified as a disease, but he does say that if it were,
discoveries might happen faster. Studies like TAME have to give people a drug,
then wait years and years to see if it prevents some of them from developing an
age-related disease. And because that effect is likely to be relatively small,
it takes huge numbers of people to prove anything. If aging were instead
considered a disease, trials could focus on something quicker and cheaper to
prove—such as whether the drug slows the progression from one stage of aging to
another.
The Healthy Life Extension Society is
part of a group that last year asked the WHO to include aging in the latest
revision of its official International Classification of Diseases, ICD-11. The
WHO declined, but it did list “aging-related” as an extension code that can be
applied to a disease, to indicate that age increases the risk of getting it.
To try to put research into treatments
that target aging on a more scientific footing, a different group of scientists
is preparing to revisit the issue with the WHO. Coordinated by Stuart
Calimport, a former advisor to the SENS Research Foundation in California,
which promotes research on aging, the detailed proposal—a copy of which has
been seen by MIT Technology Review—suggests that each tissue, organ, and gland
in the body should be scored—say, from 1 to 5—on how susceptible it is to
aging. This so-called staging process has already helped develop cancer
treatments. In theory, it could allow drugs to be licensed if they are shown to
stop or delay the aging of cells in a region of the body.
Reclassifying aging as a disease could
have another big benefit. David Gems, a professor of the biology of aging at
University College London, says it would provide a way to crack down on quack
anti-aging products. “That would essentially protect older people from the
swirling swamp of exploitation of the anti-aging business. They’re able to make
all sorts of claims because it’s not legally a disease,” Gems says.
In February, for instance, the FDA was
forced to warn consumers that injections of blood from younger people—a
procedure that costs thousands of dollars and has become increasingly popular
around the world—had no proven clinical benefit. But it couldn’t ban the
injections outright. By calling them an anti-aging treatment, companies escape
the strict oversight applied to drugs that claim to target a specific disease.
Like the Cyclops, Singapore has been
given a glimpse of what is to come—and officials there do not like what they
see. The island nation is on the front line of the gray surge. By 2030, if
current trends continue, there will be just two people working there for every
retired person (by comparison, the US will have three people in the workforce
for every resident over 65). So the country is trying to change the script, to
find a happier and healthier ending.
With the help of volunteer subjects,
Kennedy of Singapore’s Centre for Healthy Ageing is preparing the first
wide-ranging human tests of aging treatments. Kennedy says he’s aiming to trial
10 to 15 possible interventions—he won’t say which, for now—in small groups of
people in their 50s: “I’m thinking maybe three or four drugs and a few
supplements, and then compare those to lifestyle modifications.”
The Singapore government has prioritized
strategies to deal with the aging population and Kennedy wants to create a
“test bed” for such human experiments. “We have made great progress in
animals,” he adds, “but we need to begin to do these tests in people.”
[David Adam is a freelance writer and editor,
and the author of The Man Who Couldn’t Stop.]
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