Harvard 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, a Harvard Medical School (HMS) professor of genetics, 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 for 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, a research fellow in medicine 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, DePinho said 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 mice. 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 drug.
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 León effect,” noted DePinho, referring to the Spanish explorer who sought the mythical Fountain of Youth.
“When we flipped the telomerase switch on and looked a month later, the brains had largely returned to normal,” said DePinho. 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 neurons.
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’ life spans 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.”
Premature ageing can be reversed by reactivating an enzyme that protects the tips of chromosomes, a study in mice suggests.
Mice engineered to lack the enzyme, called telomerase, become prematurely decrepit. But they bounced back to health when the enzyme was replaced. The finding, published online today in Nature1, hints that some disorders characterized by early ageing could be treated by boosting telomerase activity.
It also offers the possibility that normal human ageing could be slowed by reawakening the enzyme in cells where it has stopped working, says Ronald DePinho, a cancer geneticist at the Dana-Farber Cancer Institute and Harvard Medical School in Boston, Massachusetts, who led the new study. “This has implications for thinking about telomerase as a serious anti-ageing intervention.”
Other scientists, however, point out that mice lacking telomerase are a poor stand-in for the normal ageing process. Moreover, ramping up telomerase in humans could potentially encourage the growth of tumours.
After its discovery in the 1980s, telomerase gained a reputation as a fountain of youth. Chromosomes have caps of repetitive DNA called telomeres at their ends. Every time cells divide, their telomeres shorten, which eventually prompts them to stop dividing and die. Telomerase prevents this decline in some kinds of cells, including stem cells, by lengthening telomeres, and the hope was that activating the enzyme could slow cellular ageing.
Two decades on, researchers are realizing that telomerase’s role in ageing is far more nuanced than first thought. Some studies have uncovered an association between short telomeres and early death, whereas others have failed to back up this link. People with rare diseases characterized by shortened telomeres or telomerase mutations seem to age prematurely, although some tissues are more affected than others.
When mice are engineered to lack telomerase completely, their telomeres progressively shorten over several generations. These animals age much faster than normal mice — they are barely fertile and suffer from age-related conditions such as osteoporosis, diabetes and neurodegeneration. They also die young. “If you look at all those data together, you walk away with the idea that the loss of telomerase could be a very important instigator of the ageing process,” says DePinho.
To find out if these dramatic effects are reversible, DePinho’s team engineered mice such that the inactivated telomerase could be switched back on by feeding the mice a chemical called 4-OHT. The researchers allowed the mice to grow to adulthood without the enzyme, then reactivated it for a month. They assessed the health of the mice another month later.
“What really caught us by surprise was the dramatic reversal of the effects we saw in these animals,” says DePinho. He describes the outcome as “a near ‘Ponce de Leon’ effect” — a reference to the Spanish explorer Juan Ponce de Leon, who went in search of the mythical Fountain of Youth. Shrivelled testes grew back to normal and the animals regained their fertility. Other organs, such as the spleen, liver and intestines, recuperated from their degenerated state.
The one-month pulse of telomerase also reversed effects of ageing in the brain. Mice with restored telomerase activity had noticeably larger brains than animals still lacking the enzyme, and neural progenitor cells, which produce new neurons and supporting brain cells, started working again.
“It gives us a sense that there’s a point of return for age-associated disorders,” says DePinho. Drugs that ramp up telomerase activity are worth pursuing as a potential treatment for rare disorders characterized by premature ageing, he says, and perhaps even for more common age-related conditions.
The downside is that telomerase is often mutated in human cancers, and seems to help existing tumours grow faster. But DePinho argues that telomerase should prevent healthy cells from becoming cancerous in the first place by preventing DNA damage.
David Sinclair, a molecular biologist at Harvard Medical School in Boston, agrees there is evidence that activating telomerase might prevent tumours. If the treatment can be made safe, he adds, “it could lead to breakthroughs in restoring organ function in the elderly and treating a variety of diseases of aging.”
Other researchers are less confident that telomerase can be safely harnessed. “Telomere rejuvenation is potentially very dangerous unless you make sure that it does not stimulate cancer,” says David Harrison, who researches ageing at the Jackson Laboratory in Bar Harbor, Maine.
Harrison also questions whether mice lacking telomerase are a good model for human ageing. “They are not studying normal ageing, but ageing in mice made grossly abnormal,” he says. Tom Kirkwood, who directs the Institute for Ageing and Health at Newcastle University, UK, agrees, pointing out that telomere erosion “is surely not the only, or even dominant, cause” of ageing in humans.
DePinho says he recognizes that there is more to ageing than shortened telomeres, particularly late in life, but argues that telomerase therapy could one day be combined with other therapies that target the biochemical pathways of ageing. “This may be one of several things you need to do in order to extend lifespan and extend healthy living,” he says.