Aging Is Reversible—at Least in Human Cells and Live Mice
Research suggests it is possible to slow or even reverse aging,
at least in mice, by undoing changes in gene activity—the same kinds of
changes that are caused by decades of life in humans.
By
tweaking genes that turn adult cells back into embryoniclike ones,
researchers at the Salk Institute for Biological Studies reversed the
aging of mouse and human cells in vitro, extended the life of a mouse
with an accelerated-aging condition and successfully promoted recovery
from an injury in a middle-aged mouse, according to a 2016 study.
The
study adds weight to the scientific argument that aging is largely a
process of so-called epigenetic changes, alterations that make genes
more active or less so. Over the course of life cell-activity regulators
get added to or removed from genes. In humans those changes can be
caused by smoking, pollution or other environmental factors—which dial
the genes’ activities up or down. As these changes accumulate, our
muscles weaken, our minds slow down and we become more vulnerable to
diseases.
The
study suggests the possibility of reversing at least some of these
changes, a process researchers think they may eventually get to work in
living humans. “Aging is something plastic that we can manipulate,” says
Juan Carlos Izpisua Belmonte, the study’s senior author and an expert
in gene expression at Salk. In their study Belmonte and his colleagues
rejuvenated cells by turning on, for a short period of time, four genes
that have the capacity to convert adult cells back into an embryoniclike
state.
In
living mice they activated the four genes (known as “Yamanaka factors,”
for researcher Shinya Yamanaka, the Nobelist who discovered their
combined potential in 2006). This approach rejuvenated damaged muscles
and the pancreas in a middle-aged mouse, and extended by 30 percent the
life span of a mouse with a genetic mutation responsible for
Hutchinson–Gilford progeria syndrome, which causes rapid aging in
children.
Because
the Yamanaka factors reverse changes made to gene regulators, some
scientists see the study as further evidence that aging is driven by
epigenetic changes. “I do think that epigenetic reprogramming is the
ultimate way to reverse aging,” says David Sinclair, a Harvard
University geneticist and anti-aging researcher who was not involved in
the study but is doing similar work. “My lab has a lot of evidence that
the primary driver of what we call the hallmarks of aging is the
epigenetic change.” Sinclair says his lab is preparing a paper
explaining what causes these changes as we age.
The
Salk study was conducted on middle-aged mice. But in theory,
reprogramming epigenetics should work on mice and people at any age,
says first author Alejandro Ocampo, adding that even cells from human
centenarians could eventually be rejuvenated. He and Belmonte say they
think they can improve the efficiency and results of the technique with
more research—and that they can undo the epigenetic changes responsible
for aging by using easier-to-handle chemicals instead of the Yamanaka
factors, hopefully moving toward the possibility of treatment for
people.
Matt
Kaeberlein, a molecular biologist at the University of Washington who
studies aging but was not part of the work, says other researchers have
found that the Yamanaka factors can rejuvenate cells—so in some ways
this study is not surprising. But Kaeberlein says no one else had yet
shown that the factors can treat age-related diseases in an animal by
making the same changes. “That’s the wow factor,” he explains.
Kaeberlein
says the study suggests it may be possible not just to slow aging but
to actually reverse it. “That’s really exciting—that means that even in
elderly people it may be possible to restore youthful function,” he
says. Plus, it is easier to imagine a treatment that makes changes to
the epigenome than to consider going into every cell and changing its
genes. He also notes that the results of the new study are very similar
to those seen when senescent cells—those that have lost function due to
aging—are removed from an organism. It is not yet clear, he says,
whether “this is another way to shut down or maybe reprogram senescent
cells.”
Manuel
Serrano, an expert on senescence at the Spanish National Cancer
Research Center in Madrid, was not associated with the new research but
says he is impressed with the study and its results. “I fully agree with
the conclusions. This work indicates that epigenetic shift is in part
responsible for aging, and reprogramming can correct these epigenetics
errors,” he wrote in an e-mail. “This will be the basis for future
exciting developments.”
The
study also showed how fine the line can be between benefit and harm.
When the researchers treated mice continually, some developed tumors and
died within a week. When the scientists cut the treatment to two days
out of seven, however, the mice benefited significantly. Sinclair says
this should be taken as a note of caution by anyone trying to increase
the human life span. “We’ve all been playing with fire,” he says, adding
that this fine line will make it challenging to get a drug approved by
regulatory agencies. “This is going to be what we spend the next 10
years figuring out: how to reprogram cells to be young again without
taking it too far so they become tumors.”
Both
Sinclair and Kaeberlein say they wish Belmonte’s lab had shown that a
normal mouse could live longer after the gene tinkering—instead of just
reversing an aging-related illness.
Belmonte,
like some other anti-aging researchers, says his initial goal is to
increase the “health span”—the number of years that someone remains
healthy. Extending life span, the number of years someone remains alive,
will likely take longer to achieve. Most major killers, including heart
disease, cancer and Alzheimer’s, are diseases of aging that become far
more common past middle age. “This is not just a matter of how many
years we can live but how well we can live the rest of our life,” Ocampo
says.
Belmonte
says his team is also trying to determine if aging is a process that
occurs simultaneously throughout the body. Or, as he puts it, “Is there
some tissue that regulates aging—and when that goes bad, the entire
organism goes bad?” He says they currently think the brain’s
hypothalamus—known as the seat of control for hormones, body
temperature, mood, hunger and circadian rhythms—may also act as a
regulator of aging.
Other
approaches that have been discovered to have anti-aging benefits in
animals include calorie restriction, the drug rapamycin and
parabiosis—the practice of giving old mice a blood supply from younger
ones. The fact that these diverse strategies all seem to work suggests
there may be more than one way to age, and that multiple complementary
therapies may be needed to significantly extend longevity, Kaeberlein
says.
Some
compounds such as resveratrol, a substance found in red wine that seems
to have anti-aging properties in high concentrations, appear to delay
epigenetic change and protect against damage from epigenetic
deterioration, Sinclair says. These approaches can reverse some aspects
of aging, such as muscle degeneration—but aging returns when the
treatment stops, he adds. With an approach like the one Belmonte lays
out in the new study, theoretically “you could have one treatment and go
back 10 or 20 years,” he says. If aging starts to catch up to you
again, you simply get another treatment.
“This
work is the first glimmer that we could live for centuries,” Sinclair
says, adding that he would happily do so himself: “Forty-seven years
went by pretty quickly.”