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Aging Is Reversible--at Least in Human Cells and Live Mice

Karen Weintraub

Credit: Tim Flach Getty Images

New research suggests it is possible to slow or even reverse aging, at least in mice, by undoing changes in gene
activitythe 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 study published Thursday in Cell.

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
factorswhich 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.

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The new 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 studys 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 HutchinsonGilford 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 researchand 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 cellsso 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. Thats the wow factor, he explains.

Kaeberlein says the study suggests it may be possible not just to slow aging but to actually reverse it. Thats
really excitingthat 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 cellsthose that have lost function due to agingare 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

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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. Weve 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 Belmontes lab had shown that a normal mouse could live longer
after the gene tinkeringinstead of just reversing an aging-related illness.

Belmonte, like some other anti-aging researchers, says his initial goal is to increase the health spanthe
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 Alzheimers, 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 agingand when that goes bad, the entire
organism goes bad? He says they currently think the brains hypothalamusknown as the seat of control for
hormones, body temperature, mood, hunger and circadian rhythmsmay 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 parabiosisthe 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
degenerationbut 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

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so himself: Forty-seven years went by pretty quickly.

Karen Weintraub

Karen Weintraub is a freelance health and science journalist who writes regularly for the New York Times,
STAT (www.statnews.com) and USA Today, among others.

Credit: Nick Higgins

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