Solving a biological puzzle: How stress causes gray hair

Scientists uncover link between the nervous system and stem cells that regenerate pigment

January 22, 2020

Science Daily/Harvard University

Scientists have found evidence to support long-standing anecdotes that stress causes hair graying. Researchers found that in mice, the type of nerve involved in the fight-or-flight response causes permanent damage to the pigment-regenerating stem cells in the hair follicle. The findings advance knowledge of how stress impacts the body, and are a first step toward blocking its negative effects.

When Marie Antoinette was captured during the French Revolution, her hair reportedly turned white overnight. In more recent history, John McCain experienced severe injuries as a prisoner of war during the Vietnam War -- and lost color in his hair.

For a long time, anecdotes have connected stressful experiences with the phenomenon of hair graying. Now, for the first time, Harvard University scientists have discovered exactly how the process plays out: stress activates nerves that are part of the fight-or-flight response, which in turn cause permanent damage to pigment-regenerating stem cells in hair follicles.

The study, published in Nature, advances scientists' knowledge of how stress can impact the body.

"Everyone has an anecdote to share about how stress affects their body, particularly in their skin and hair -- the only tissues we can see from the outside," said senior author Ya-Chieh Hsu, the Alvin and Esta Star Associate Professor of Stem Cell and Regenerative Biology at Harvard. "We wanted to understand if this connection is true, and if so, how stress leads to changes in diverse tissues. Hair pigmentation is such an accessible and tractable system to start with -- and besides, we were genuinely curious to see if stress indeed leads to hair graying. "

Narrowing down the culprit

Because stress affects the whole body, researchers first had to narrow down which body system was responsible for connecting stress to hair color. The team first hypothesized that stress causes an immune attack on pigment-producing cells. However, when mice lacking immune cells still showed hair graying, researchers turned to the hormone cortisol. But once more, it was a dead end.

"Stress always elevates levels of the hormone cortisol in the body, so we thought that cortisol might play a role," Hsu said. "But surprisingly, when we removed the adrenal gland from the mice so that they couldn't produce cortisol-like hormones, their hair still turned gray under stress."

After systematically eliminating different possibilities, researchers honed in on the sympathetic nerve system, which is responsible for the body's fight-or-flight response.

Sympathetic nerves branch out into each hair follicle on the skin. The researchers found that stress causes these nerves to release the chemical norepinephrine, which gets taken up by nearby pigment-regenerating stem cells.

Permanent damage

In the hair follicle, certain stem cells act as a reservoir of pigment-producing cells. When hair regenerates, some of the stem cells convert into pigment-producing cells that color the hair.

Researchers found that the norepinephrine from sympathetic nerves causes the stem cells to activate excessively. The stem cells all convert into pigment-producing cells, prematurely depleting the reservoir.

"When we started to study this, I expected that stress was bad for the body -- but the detrimental impact of stress that we discovered was beyond what I imagined," Hsu said. "After just a few days, all of the pigment-regenerating stem cells were lost. Once they're gone, you can't regenerate pigment anymore. The damage is permanent."

The finding underscores the negative side effects of an otherwise protective evolutionary response, the researchers said.

"Acute stress, particularly the fight-or-flight response, has been traditionally viewed to be beneficial for an animal's survival. But in this case, acute stress causes permanent depletion of stem cells," said postdoctoral fellow Bing Zhang, the lead author of the study.

Answering a fundamental question

To connect stress with hair graying, the researchers started with a whole-body response and progressively zoomed into individual organ systems, cell-to-cell interaction and, eventually, all the way down to molecular dynamics. The process required a variety of research tools along the way, including methods to manipulate organs, nerves, and cell receptors.

"To go from the highest level to the smallest detail, we collaborated with many scientists across a wide range of disciplines, using a combination of different approaches to solve a very fundamental biological question," Zhang said.

The collaborators included Isaac Chiu, assistant professor of immunology at Harvard Medical School who studies the interplay between nervous and immune systems.

"We know that peripheral neurons powerfully regulate organ function, blood vessels, and immunity, but less is known about how they regulate stem cells," Chiu said.

"With this study, we now know that neurons can control stem cells and their function, and can explain how they interact at the cellular and molecular level to link stress with hair graying."

The findings can help illuminate the broader effects of stress on various organs and tissues. This understanding will pave the way for new studies that seek to modify or block the damaging effects of stress.

"By understanding precisely how stress affects stem cells that regenerate pigment, we've laid the groundwork for understanding how stress affects other tissues and organs in the body," Hsu said. "Understanding how our tissues change under stress is the first critical step towards eventual treatment that can halt or revert the detrimental impact of stress. We still have a lot to learn in this area."

https://www.sciencedaily.com/releases/2020/01/200122135313.htm

Stimulating the vagus nerve in the neck might help ease pain associated with PTSD

February 13, 2019

Science Daily/University of California - San Diego

In a randomized, controlled pilot trial, researchers found that participants pre-treated with noninvasive vagus nerve stimulation experienced less pain after heat stimulus than mock-treated participants.

Post-traumatic stress disorder, or PTSD, is a mental condition caused by a traumatic event. People with PTSD may experience intrusive memories, negative thoughts, anxiety and chronic pain. The condition is typically treated with a combination of psychotherapy, anti-depressants and anti-anxiety medications.

It's this connection between mental health and pain that interests Imanuel Lerman, MD, associate professor at University of California San Diego School of Medicine, Jacobs School of Engineering and Qualcomm Institute, and a pain management specialist at UC San Diego Health and Veterans Affairs San Diego Healthcare System.

Lerman especially wants to know how the emotional pain experience may be influenced by the vagus nerve, which runs down both sides of our necks from the brainstem to the abdomen. The vagus nerve also plays a critical role in maintaining heart rate, breathing rate, digestive tract movement and many other basic body functions.

In a study published February 13, 2019 in PLOS ONE, Lerman and colleagues tested noninvasive vagus nerve stimulation as a method for dampening the sensation of pain.

"It's thought that people with certain differences in how their bodies -- their autonomic and sympathetic nervous systems -- process pain may be more susceptible to PTSD," Lerman said. "And so we wanted to know if we might be able to re-write this 'mis-firing' as a means to manage pain, especially for people with PTSD." Lerman led the study with Alan N. Simmons, PhD, director of the fMRI Research Laboratory at Veterans Affairs San Diego Healthcare System and associate professor of psychiatry at UC San Diego School of Medicine.

The team used functional magnetic resonance imaging (fMRI) to get a look at the brains of 30 healthy study participants after a painful heat stimulus was applied to their legs. To determine how the body's sympathetic nervous system responds to pain, they also measured the sweat on the skin of participants before the heat was applied, and at several points as the heat increased.

Half the participants were treated with noninvasive vagus nerve stimulation for two minutes -- via electrodes placed on the neck -- approximately 10 minutes before the heat stimulus. The other half received a mock stimulation.

Lerman and colleagues report three main findings from this study. First, vagus nerve stimulation blunted peak response to heat stimulus in several areas of the brain known to be important for sensory and discriminative pain processing, as well as in emotional pain centers. The treatment also delayed the pain response in these brain regions -- pain-related brain regions were activated ten seconds later in participants pre-treated with vagus nerve stimulation than in sham-treated participants.

Second, the sweat measurements revealed that vagus nerve stimulation altered autonomic responses to painful heat stimulus. For participants pre-treated with vagus nerve stimulation, the sweat response decreased over time, in contrast to the sham-treatment group.

Third, vagus nerve stimulation dampened the usual brainstem centers critical for the fight-or-flight-type responses, which are also known to control the sweat response to pain.

"Not everyone is the same -- some people may need more vagus nerve stimulation than others to achieve the same outcomes and the necessary frequencies might change over time -- so we'll need to personalize this approach," Lerman said. "But we are hopeful and looking forward to the next steps in moving this approach toward the clinic."

Next, Lerman and colleagues will launch a Veterans Affairs Healthcare System-funded clinical trial in San Diego with military veterans, with and without PTSD. They want to determine if at-home vagus nerve stimulation can reduce emotional pain and underlying neural inflammation associated with PTSD. To learn how to participate, please call 858-552-8585.

Vagus nerve stimulation is a form of neuromodulation, an approach to pain management that also includes spinal cord and dorsal root ganglion (DRG) stimulation. The U.S. Food and Drug Administration (FDA) has approved noninvasive vagus nerve stimulator for the treatment of episodic and chronic cluster headache and acute migraine, as well as an implantable device for epilepsy. An implanted vagus nerve stimulator is now being tested in a clinical trial for the treatment of rheumatoid arthritis. Side effects of implanted vagus nerve stimulation can include hoarseness, shortness of breath and nausea.

https://www.sciencedaily.com/releases/2019/02/190213142700.htm

Stress can impair memory, reduce brain size in middle age

October 25, 2018

Science Daily/University of Texas Health Science Center at San Antonio

Stress may be causing impaired memory and brain shrinkage in middle-age adults, even before symptoms of Alzheimer's or other dementia begin, according to a new study.

Adults in their 40s and 50s with higher levels of cortisol -- a hormone linked to stress -- performed worse on memory and other cognitive tasks than peers of the same age with average cortisol levels, research found. Higher cortisol in the blood also was associated with smaller brain volumes, according to the study, published Oct. 24 in Neurology, the medical journal of the American Academy of Neurology.

"In our quest to understand cognitive aging, one of the factors attracting significant interest and concern is the increasing stress of modern life," said study senior author Sudha Seshadri, M.D., professor of neurology at UT Health San Antonio and founding director of the university's Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases. "One of the things we know in animals is that stress can lead to cognitive decline. In this study, higher morning cortisol levels in a large sample of people were associated with worse brain structure and cognition."

The cognitive data are from 2,231 participants in the Framingham Heart Study, for which Dr. Seshadri is a senior investigator; 2,018 participants also underwent magnetic resonance imaging (MRI) to measure brain volume. The team included Framingham collaborators at Harvard Medical School; the National Heart, Lung, and Blood Institute; Boston University School of Medicine; the University of California, Davis, at Sacramento; and UT Health San Antonio.

Blood serum cortisol, which varies in level throughout the day, was measured in early morning (between 7:30 and 9 a.m.) in each fasting participant. The study featured a relatively young sample of male and female participants (mean age 48.5).

"Cortisol affects many different functions, so it is important to fully investigate how high levels of the hormone may affect the brain," said study lead author Justin B. Echouffo-Tcheugui, M.D., Ph.D., of Harvard Medical School. "While other studies have examined cortisol and memory, we believe our large, community-based study is the first to explore, in middle-aged people, fasting blood cortisol levels and brain volume, as well as memory and thinking skills."

Memory loss and brain shrinkage were found in the study's middle-age participants before the onset of any symptoms, Dr. Echouffo-Tcheugui noted. He said it is important for physicians to counsel people with higher cortisol levels on ways to reduce stress, such as getting enough sleep and engaging in moderate exercise.

"The faster pace of life today probably means more stress, and when we are stressed, cortisol levels increase because that is our fight-or-flight response," Dr. Seshadri said. "When we are afraid, when we are threatened in any way, our cortisol levels go up. This study adds to the prevailing wisdom that it's never too early to be mindful of reducing stress."

Findings were adjusted for factors including age, sex, smoking and body mass index. The team asked whether having APOE4, a genetic risk factor for cardiovascular disease and Alzheimer's disease, might be associated with higher cortisol level. This did not prove to be the case.

https://www.sciencedaily.com/releases/2018/10/181025084043.htm