Younger, longer

Until recently, few people gave much thought to senescent cells. They are cells that linger in the body even after they have lost the ability to divide. But on November 2, in what could be a landmark experiment in the study of ageing, researchers at the Mayo Clinic reported that if you purge the body of its senescent cells, the tissues remain youthful and vigorous.

The experiment was just in mice, and it cleared the cells with a genetic technique that cannot be applied to people. Like all critical experiments, it needs to be repeated in other labs before it can be accepted with confidence. But the startling result is plausible because it ties together an emerging body of knowledge about senescent cells. And it raises the possibility that attacks on the cells might postpone the diseases of aging and let people live out more of their lifespan in good health.

Senescent cells were discovered 50 years ago in a classic experiment by biologist Leonard Hayflick. He found that human cells cultured in glassware do not multiply indefinitely, as was then assumed, but can divide only 50 or so times before lapsing into senescence. But the finding was not followed up for many years; researchers assumed that it was something that occurred only in the laboratory, or that even if cells did become senescent in the body, there were too few to make a difference.

Only in the last few years have researchers come to realise that senescent cells do occur naturally and that they play central roles in both cancer and aging. Simple organisms live short lives and do not need cell division. More complex animals live longer because their tissues are renewable.

In humans, the cells lining the gut are renewed every five days. Red blood cells last 120 days. Even bone cells slowly turn over, with the result that the entire skeleton is renewed every 10 years or so. But the price for renewable tissues is cancer: If cells are capable of division, any damage to their control systems can lead to unconstrained growth. The body has therefore evolved two major systems to curb the risk of cancer – cell senescence and cell death. Both systems are set in motion by illicit cell divisions, like those caused by a virus; by damage to DNA; or by activation of tumor-causing genes.

Senescence: When does it occur?

Senescence can also be caused when cells run out of telomeres, the caps at the end of the chromosomes that get shorter at each cell division. This route to senescence, discovered in the 1990s, underlies the process observed by Hayflick. Cells thrown into senescence do not divide again but hang about in tissues until they are cleared by the immune system. In cell death, a cell is forced to set off a built-in suicide mechanism.

Researchers do not yet understand why there are two systems, or how the body chooses whether to assign a damaged cell to senescence or to death. But a benefit of senescence is that suspect cells can continue to perform vital functions, said Daniel Peeper, an expert on senescence at the Netherlands Cancer Institute in Amsterdam.

Byproduct of fight against cancer

Moles, for instance, are collections of senescent cells that continue to produce melanin and defend the skin from ultraviolet rays. Senescent cells thus seem to be a benign byproduct of the body’s defense against cancer. But researchers have developed growing suspicions of a less benign aspect: the cells’ culpability in aging. Senescent cells accumulate throughout life, probably because the immune system sweeps them away less efficiently as a person ages. Larger and flatter than normal cells, they are especially common in tissues showing signs of aging, like arthritic knees or the plaque in the arteries.

Despite being termed senescent, the cells are very active: They convert themselves into factories that churn out 100 different kinds of growth factors, along with cytokines, the inflammatory agents that stimulate the immune system. The evolutionary reason for this activity may be to provoke the immune system to attack patches of premalignant and malignant cells. But the process turns out to have some untoward side effects.

As it happens, many ageing tissues show signs of chronic inflammation, which can foster age-related diseases, including arthritis, Alzheimer’s and cancer. The relationship between aging and inflammation has so far been a mystery. “Does aging drive inflammation, or does something else cause chronic inflammation, which in turn drives aging?” Judith Campisi of the Buck Institute for Age Research asked in a review in the journal Cell last year.

The Mayo Clinic researchers, a team led by Jan M van Deursen and Dr. James L Kirkland, have come up with a clear and dramatic answer to this question:
It’s the senescent cells that inflame the tissues and cause them to age.

Senescence is induced in most cells by the activation of two genes, known as p53 and p16-INK4a, that are the guardians and enforcers of proper cell division. When they detect any damage in the cell’s controls, they force it into either senescence or death.

The role of p16-INK4a is to block the cell from dividing. The Mayo team genetically engineered a strain of mice in which whenever a cell became senescent by switching on its p16-INK4a gene, it also primed a cell suicide device.

The Mayo team used a special drug to activate this device and clear the mice of all their senescent cells. The researchers showed that mice purged of senescent cells could run much longer on a treadmill, had larger fat deposits – fat disappears from the skin as people age, causing wrinkles – and developed cataracts much later.

Much the same effect was seen in a second experiment, in which dosing did not start until the mice were middle-aged, except that cataracts that had already formed could not be reversed. The experiment “strongly suggests that accumulation of senescent cells does contribute to aging, and they show that by eliminating senescent cells they could delay premature aging,” Peeper said.

The finding was made in a strain of mice that age fast and usually die of heart arrhythmia. So despite their healthier tissues, the mice purged of senescent cells died at the usual age of heart problems. Van Deursen’s team is now testing to see whether normal mice will live longer when purged of senescent cells. The treatment was started when the normal mice were a year old, and they have now been treated for five months.

Next month they will run treadmill tests to see if they are in better shape than a comparison group of untreated mice, van Deursen said.

The genetic method used to purge mice of senescent cells cannot be used in people. Instead of trying to remove senescent cells from elderly people, Peeper believes, it may be more effective to identify which of the factors that the senescent cells secrete are the source of their ill effects and to develop drugs that block these factors. But van Deursen thinks it would be better to go after the senescent cells themselves. In his view it should be easy enough by trial and error to find chemicals that selectively destroy senescent cells, just like the targeted chemicals now used to treat certain kinds of cancer.

And unlike the cancer cells, which proliferate so fast that they soon develop resistance, the senescent cells cannot replicate, so they should be easy targets. Several companies and individuals have already approached the Mayo Clinic to explore developing such drugs.