Ronald DePinho, MD
Scientists at Dana-Farber Cancer Institute say they have for the
first time partially reversed age-related degeneration in mice,
resulting in new growth of the brain and testes, improved fertility, and
the return of a lost cognitive function.
In a report posted online by the journal Nature in advance of print publication, researchers led by Ronald A. DePinho, MD,
said they achieved the milestone in aging science by engineering mice
with a controllable telomerase gene. The telomerase enzyme maintains the
protective caps called telomeres that shield the ends of chromosomes.
As humans age, low levels of telomerase are associated with
progressive erosion of telomeres, which may then contribute to tissue
degeneration and functional decline in the elderly.
By creating mice with a telomerase switch, the researchers were able
to generate prematurely aged mice. The switch allowed the scientists to
find out whether reactivating telomerase in the animals would restore
telomeres and mitigate the signs and symptoms of aging.
The work showed a dramatic reversal of many aspects of aging, including reversal of brain disease and infertility.
While human applications remain in the future, the strategy might one
day be used to treat conditions such as rare genetic premature aging
syndromes in which shortened telomeres play an important role, said
DePinho, senior author of the report and the director of Dana-Farber's
Belfer Institute of Applied Cancer Science.
"Whether this would impact on normal aging is a more difficult
question," he added, "But it is notable that telomere loss is associated
with age-associated disorders and thus restoration of telomeres could
alleviate such decline."
The first author is Mariela Jaskelioff, PhD, in DePinho's laboratory.
Importantly, the animals showed no signs of developing cancer. This
remains a concern because cancer cells turn on telomerase to make
themselves virtually immortal.
DePinho said the risk can be minimized by switching on telomerase
only for a matter of days or weeks — which may be brief enough to avoid
fueling hidden cancers or cause new ones to develop. Still, he
observed, it is an important issue for further study.
In addition, said DePinho, these results may provide new avenues for
regenerative medicine, because they suggest that quiescent adult stem
cells in severely aged tissues remain viable and can be reactivated to
repair tissue damage.
"If you can remove the underlying damage and stresses that drive the
aging process and cause stem cells to go into growth arrest, you may be
able to recruit them back into a regenerative response to rejuvenate
tissues and maintain health in the aged," he said. Those stresses
include the shortening of telomeres over time that causes cells and
tissues to fail.
Loss of telomeres sends a cascade of signals that cause cells to stop
dividing or self-destruct, stem cells to go into retirement, organs to
atrophy, and brain cells to die. Generally, the shortening of telomeres
in normal tissues shows a steady decline, except in the case of cancer,
where they are maintained.
The experiments used mice that had been engineered to develop severe
DNA and tissue damage as a result of abnormal, premature aging. These
animals had short, dysfunctional telomeres and suffered a variety of
age-related afflictions that progressed in successive generations of
Among the conditions were testes reduced in size and depleted of
sperm, atrophied spleens, damage to the intestines, and shrinkage of the
brain along with an inability to grow new brain cells.
"We wanted to know: If you could flip the telomerase switch on and
restore telomeres in animals with entrenched age-related disease, what
would happen?" explained DePinho. "Would it slow down aging, stabilize
it, or even reverse it?"
Rather than supply the rodents with supplemental telomerase, the
scientists devised a way to switch on the animals' own dormant
telomerase gene, known as TERT. They engineered the endogenous TERT gene
to encode a fusion protein of TERT and the estrogen receptor.
This fusion protein would only become activated with a special form
of estrogen. With this setup, scientists could give the mice an
estrogen-like drug at any time to stimulate the TERT-estrogen receptor
fusion protein and make it active to maintain telomeres.
Against this backdrop, the researchers administered the estrogen drug
to some of the mice via a time-release pellet inserted under the skin.
Other animals, the controls, were given a pellet containing no active
After four weeks, the scientists observed remarkable signs of
rejuvenation in the treated mice. Overall, the mice exhibited increased
levels of telomerase and lengthened telomeres, biological changes
indicative of cells returning to a growth state with reversal of tissue
degeneration, and increase in size of the spleen, testes and brain.
"It was akin to a Ponce de Leon effect," noted DePinho, referring to
the Spanish explorer who sought the mythical Fountain of Youth.
"When we flipped the telomerase switched on and looked a month later,
the brains had largely returned to normal," said DePinho, who is also a
professor of medicine and genetics at Harvard Medical School.
More newborn nerve cells were observed, and the fatty myelin sheaths
around nerve cells — which had become thinned in the aged animals —
increased in diameter. In addition, the increase in telomerase
revitalized slumbering brain stem cells so they could produce new
To show that all this new activity actually caused functional
improvements, the scientists tested the mice's ability to avoid a
certain area where they detected unpleasant odors that they associated
with danger, such as scents of predators or rotten food.
They had lost that survival skill as their olfactory nerve cells
atrophied, but after the telomerase boost, those nerves regenerated and
the mice regained their crucial sense of smell.
"One of the most amazing changes was in the animals' testes, which
were essentially barren as aging caused the death and elimination of
sperm cells," recounted DePinho. "When we restored telomerase, the
testes produced new sperm cells, and the animals' fecundity was improved
— their mates gave birth to larger litters."
The telomerase boost also lengthened the rodents' lifespans compared
to their untreated counterparts — but they did not live longer than
normal mice, said the researchers.
The authors concluded, "This unprecedented reversal of age-related
decline in the central nervous system and other organs vital to adult
mammalian health justifies exploration of telomere rejuvenation
strategies for age-associated diseases."
Other authors include members of the DePinho research group and
Eleftheria Maratos-Flier, MD, of Beth Israel Deaconess Medical Center
and Harvard Medical School.
The research was supported by grants from the National Institutes of Health and the Belfer Foundation.