Losing Your Hair? You Might Blame the Great Stem Cell Escape.

Every person, every mouse, every dog, has one unmistakable sign of aging: hair loss. But why does that happen?

Rui Yi, a professor of pathology at Northwestern University, set out to answer the question.

A generally accepted hypothesis about stem cells says they replenish tissues and organs, including hair, but they will eventually be exhausted and then die in place. This process is seen as an integral part of aging.

Instead Dr. Yi and his colleagues made a surprising discovery that, at least in the hair of aging animals, stem cells escape from the structures that house them.

“It’s a new way of thinking about aging,” said Dr. Cheng-Ming Chuong, a skin cell researcher and professor of pathology at the University of Southern California, who was not involved in Dr. Yi’s study, which was published on Monday in the journal Nature Aging.

The study also identifies two genes involved in the aging of hair, opening up new possibilities for stopping the process by preventing stem cells from escaping.

Charles K.F. Chan, a stem cell researcher at Stanford University, called the paper “very important,” noting that “in science, everything about aging seems so complicated we don’t know where to start.” By showing a pathway and a mechanism for explaining aging hair, Dr. Yi and colleagues may have provided a toehold.

Stem cells play a crucial role in the growth of hair in mice and in humans. Hair follicles, the tunnel-shaped miniature organs from which hairs grow, go through cyclical periods of growth in which a population of stem cells living in a specialized region called the bulge divide and become rapidly growing hair cells.

Sarah Millar, director of the Black Family Stem Cell Institute at the Icahn School of Medicine at Mount Sinai, who was not involved in Dr. Yi’s paper, explained that those cells give rise to the hair shaft and its sheath. Then, after a period of time, which is short for human body hair and much longer for hair on a person’s head, the follicle becomes inactive and its lower part degenerates. The hair shaft stops growing and is shed, only to be replaced by a new strand of hair as the cycle repeats.

But while the rest of the follicle dies, a collection of stem cells remains in the bulge, ready to start turning into hair cells to grow a new strand of hair.

Dr. Yi, like most scientists, had assumed that with age the stem cells died in a process known as stem cell exhaustion. He expected that the death of a hair follicle’s stem cells meant that the hair would turn white and, when enough stem cells were lost, the strand of hair would die. But this hypothesis had not been fully tested.

Together with a graduate student, Chi Zhang, Dr. Yi decided that to understand the aging process in hair, he needed to watch individual strands of hair as they grew and aged.

Ordinarily, researchers who study aging take chunks of tissue from animals of different ages and examine the changes. There are two drawbacks to this approach, Dr. Yi said. First, the tissue is already dead. And it is not clear what led to the changes that are observed or what will come after them.

He decided his team would use a different method. They watched the growth of individual hair follicles in the ears of mice using a long wavelength laser that can penetrate deep into tissue. They labeled hair follicles with a green fluorescent protein, anesthetized the animals so they did not move, put their ear under the microscope and went back again and again to watch what was happening to the same hair follicle.

What they saw was a surprise: When the animals started to grow old and gray and lose their hair, their stem cells started to escape their little homes in the bulge. The cells changed their shapes from round to amoeba-like and squeezed out of tiny holes in the follicle. Then they recovered their normal shapes and darted away.

Sometimes, the escaping stem cells leapt long distances, in cellular terms, from the niche where they lived.

“If I did not see it for myself I would not have believed it,” Dr. Yi said. “It’s almost crazy in my mind.”

The stem cells then vanished, perhaps consumed by the immune system.

Dr. Chan compared an animal’s body to a car. “If you run it long enough and don’t replace parts, things wear out,” he said. In the body, stem cells are like a mechanic, providing replacement parts, and in some organs like hair, blood and bone, the replacement is continual.

But with hair, it now looks as if the mechanic — the stem cells — simply walks off the job one day.

But why? Dr. Yi and his colleagues’ next step was to ask if genes are controlling the process. They discovered two — FOXC1 and NFATC1 — that were less active in older hair follicle cells. Their role was to imprison stem cells in the bulge. So the researchers bred mice that lacked those genes to see if they were the master controllers.

By the time the mice were 4 to 5 months old, they started losing hair. By age 16 months, when the animals were middle-aged, they looked ancient: They had lost a lot of hair and the sparse strands remaining were gray.

Now the researchers want to save the hair stem cells in aging mice.

This story of the discovery of a completely unexpected natural process makes Dr. Chuong wonder what remains to be learned about living creatures.

“Nature has endless surprises waiting for us,” he said. “You can see fantastic things.”