Gene trigger for stem cell shut down in ageing

Biologists have uncovered a gene that shuts down stem cells as people age.

They say the gene known as p16-Ink4a gradually reduces the ability of stem cells to proliferate, thus reducing the risk of cancer.

The discovery, reported in the scientific magazine Nature, was made in an experiment on mice, but the scientists believe that it applies to humans too.

The finding indicates that many degenerative diseases of ageing are caused by an active shutting down of the stem cells that renew the body’s various tissues and are not just a passive disintegration of tissues under daily wear and tear.

Senior author Dr Norman E Sharpless of the University of North Carolina said: “I don’t think aging is a random process — it’s a program, an anticancer program.”

The finding that stem cells are switched off with age is not encouraging for those who wish to use a patient’s own adult stem cells to treat disease.

The gene plays a central role in the body’s defenses against cancer, and it produces two quite different proteins that interact with the two principal systems for deciding whether a cell will be allowed to divide.

One of the proteins had also been noted to increase substantially with age. The cells of a 70-year-old produce 10 times as much of the Ink4 protein as those of a 20-year-old.

In the experiment the scientists genetically engineered a mouse strain with the gene knocked out. They found that the mouse cells had an extra ability to proliferate when the Ink4 protein was not present. At the same time the mice were highly prone to cancer which they developed as early as a year.

The researchers assume, but have not yet proved, that the increasing amounts of Ink4 as a person ages will thrust the stem cells into senescence, meaning that they can never divide again. The evolutionary purpose is evidently to avert the risk that a damaged stem cell might evade controls and proliferate into a tumor.

One implication is that therapists who hope to increase longevity have to tackle a system that may be hard to cheat. An intervention that reduces Ink4 production to prevent the age-related decline of stem cells will also increase the risk of cancer.

Dr Sharpless said that so far the only intervention known to increase lifespan was a calorically restricted diet which also reduced cancer, at least in laboratory mice. The reason, he said, is probably because such diets reduce cell division, the prime source of cancer risk.

For cell therapists, the dual activity of Ink4 may be “a hard box to get out of,” he said, unless they use cells that are somehow much younger than the patient.

Some proposals for stem cell therapy with adult stem cells envisage taking a patient’s stem cells, making them divide in the laboratory and putting them back in the patient to build new tissue.

The researchers said they did not yet know what stimulus makes cells increase their production of the Ink4 protein as a person grows older. Their suspicion is that the usual factors implicated in aging like mutation and oxidative damage to tissues would turn out to have a role in making cells produce more Ink4.