Add nature, art and religion to life's best anti-inflammatories

The awe we feel when we're in nature may help lower levels of pro-inflammatory proteins, a new study suggests.

Taking in such spine-tingling wonders as the Grand Canyon, Sistine Chapel ceiling or Schubert's "Ave Maria" may give a boost to the body's defense system, according to new research from UC Berkeley.

Researchers have linked positive emotions -- especially the awe we feel when touched by the beauty of nature, art and spirituality -- with lower levels of pro-inflammatory cytokines, which are proteins that signal the immune system to work harder.

"Our findings demonstrate that positive emotions are associated with the markers of good health," said Jennifer Stellar, a postdoctoral researcher at the University of Toronto and lead author of the study, which she conducted while at UC Berkeley.
While cytokines are necessary for herding cells to the body's battlegrounds to fight infection, disease and trauma, sustained high levels of cytokines are associated with poorer health and such disorders as type-2 diabetes, heart disease, arthritis and even Alzheimer's disease and clinical depression.

It has long been established that a healthy diet and lots of sleep and exercise bolster the body's defenses against physical and mental illnesses. But the Berkeley study, whose findings were just published in the journal Emotion, is one of the first to look at the role of positive emotions in that arsenal.

"That awe, wonder and beauty promote healthier levels of cytokines suggests that the things we do to experience these emotions -- a walk in nature, losing oneself in music, beholding art -- has a direct influence upon health and life expectancy," said UC Berkeley psychologist Dacher Keltner, a co-author of the study.

In two separate experiments, more than 200 young adults reported on a given day the extent to which they had experienced such positive emotions as amusement, awe, compassion, contentment, joy, love and pride. Samples of gum and cheek tissue, known as oral mucosal transudate, taken that same day showed that those who experienced more of these positive emotions, especially awe, wonder and amazement, had the lowest levels of the cytokine, Interleukin 6, a marker of inflammation.

In addition to autoimmune diseases, elevated cytokines have been tied to depression. One recent study found that depressed patients had higher levels of the pro-inflammatory cytokine known as TNF-alpha than their non-depressed counterparts. It is believed that by signaling the brain to produce inflammatory molecules, cytokines can block key hormones and neurotransmitters -- such as serotonin and dopamine -- that control moods, appetite, sleep and memory.

In answer to why awe would be a potent predictor of reduced pro-inflammatory cytokines, this latest study posits that "awe is associated with curiosity and a desire to explore, suggesting antithetical behavioral responses to those found during inflammation, where individuals typically withdraw from others in their environment," Stellar said.

As for which came first -- the low cytokines or the positive feelings -- Stellar said she can't say for sure: "It is possible that having lower cytokines makes people feel more positive emotions, or that the relationship is bidirectional," Stellar said.

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Environment, not genes, dictates human immune variation, study finds

A study of twins conducted by Stanford University School of Medicine investigators shows that our environment, more than our heredity, plays the starring role in determining the state of our immune system, the body's primary defense against disease. This is especially true as we age, the study indicates.

Much has been made of the role genes play in human health. Stunning advances in gene-sequencing technologies, in concert with their plummeting costs, have turned many scientists' attention to minute variations in the genome -- the entire toolbox of genes carried in virtually every cell in the body -- in the hope of predicting people's future health. Such studies have revealed a genetic contribution to health outcomes. But, with some notable exceptions, very few individual genetic variants contribute much to particular health conditions.

"The idea in some circles has been that if you sequence someone's genome, you can tell what diseases they're going have 50 years later," said Mark Davis, PhD, professor of microbiology and immunology and director of Stanford's Institute for Immunity, Transplantation and Infection. But while genomic variation clearly plays a key role in some diseases, he said, the immune system has to be tremendously adaptable in order to cope with unpredictable episodes of infection, injury and tumor formation.

"The immune system has to think on its feet," said Davis, senior author of the new study, which will be published Jan. 15 in Cell. Lead authorship is shared by former Stanford postdoctoral scholars Petter Brodin, MD, PhD, and Vladimir Jojic, PhD.

Nature versus nurture

"Unlike inbred lab mice, people have broadly divergent genetic heritages," said Davis, who is also the Burt and Marion Avery Family Professor. "And when you examine people's immune systems, you often find tremendous differences between them. So we wondered whether this reflects underlying genetic differences or something else. But what we found was that in most cases, including the reaction to a standard influenza vaccine and other types of immune responsiveness, there is little or no genetic influence at work, and most likely the environment and your exposure to innumerable microbes is the major driver."

To determine nature's and nurture's relative contributions, Davis and his colleagues turned to a century-old method of teasing apart environmental and hereditary influences: They compared pairs of monozygotic twins -- best known to most of us as "identical" -- and of dizygotic, or fraternal, twins. Monozygotic twins inherit the same genome. Despite inevitable copying errors when cells divide, which cause tiny genetic divergences to accumulate between monozygotic twins over time, they remain almost 100 percent genetically identical. Dizygotic twins are no more alike genetically than regular siblings, on average sharing 50 percent of their genes.

Because both types of twins share the same environment in utero and usually share the same environment in childhood, they make excellent subjects for contrasting hereditary versus environmental influence.

About two decades ago, study co-author Gary Swan, PhD, who was then at SRI Inc. and is now a consulting professor of medicine at Stanford, began curating a registry of twins for research purposes. The registry now includes about 2,000 twin pairs. For the new study, the researchers recruited 78 monozygotic-twin pairs and 27 pairs of dizygotic twins from the registry. They drew blood from both members of each twin pair on three separate visits.

The Stanford team then applied sophisticated laboratory methods to the blood samples to measure more than 200 distinct immune-system components and activities. All samples were sent immediately to Stanford's Human Immune Monitoring Core, which houses the latest immune-sleuthing technology under a single roof.

The power of environment

Examining differences in the levels and activity states of these components within pairs of monozygotic and dizygotic twins, the Stanford scientists found that in three-quarters of the measurements, nonheritable influences -- such as previous microbial or toxic exposures, vaccinations, diet and dental hygiene -- trumped heritable ones when it came to accounting for differences within a pair of twins. This environmental dominance was more pronounced in older identical twins (age 60 and up) than in younger twins (under age 20).

Davis and his associates also observed considerable environmental influence over the quantities of antibodies produced in members of twin pairs who had been vaccinated for influenza in a separate Stanford investigation directed by study co-author Cornelia Dekker, MD, professor of pediatric infectious disease and medical director of the Stanford-Lucile Packard Children's Hospital Vaccine Program. While many previous studies have suggested a powerful genetic component in vaccine responsiveness, Davis noted that those studies typically were performed in very young children who had not yet undergone the decades of environmental exposure that appears to reshape the immune system over time.

In a striking example of the immune system's plasticity, the Stanford scientists found that the presence or absence of a single chronic viral infection could have a massive effect on the system's composition and responsiveness. Three out of five Americans and as many as nine out of 10 people in the developing world are chronic carriers of cytomegalovirus, which is dangerous in immune-compromised people but otherwise generally benign. In 16 of the 27 monozygotic twin pairs participating in the study, one member of the pair had been exposed to cytomegalovirus but the other had not. For nearly 60 percent of all the features Davis' group measured, cytomegalovirus' presence in one twin and absence in another made a big difference.

"Nonheritable influences, particularly microbes, seem to play a huge role in driving immune variation," said Davis. "At least for the first 20 or so years of your life, when your immune system is maturing, this amazing system appears able to adapt to wildly different environmental conditions. A healthy human immune system continually adapts to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more, overshadowing the influences of most heritable factors."

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Baby cells learn to communicate using the lsd1 gene

We would not expect a baby to join a team or participate in social situations that require sophisticated communication. Yet, most developmental biologists have assumed that young cells, only recently born from stem cells and known as "progenitors," are already competent at inter-communication with other cells.

New research from Carnegie's Allan Spradling and postdoctoral fellow Ming-Chia Lee shows that infant cells have to go through a developmental process that involves specific genes before they can take part in the group interactions that underlie normal cellular development and keep our tissues functioning smoothly. The existence of a childhood state where cells cannot communicate fully has potentially important implications for our understanding of how gene activity on chromosomes changes both during normal development and in cancerous cells. The work is published in Genes and Development.

The way that the molecules that package a cell's chromosomes are organized in order to control gene activity is known as the cell's "epigenetic state." The epigenetic state is fundamental to understanding Spradling and Lee's findings. To developmental biologists, changes in this epigenetic state ultimately explain how the cell's properties are altered during tissue maturation.

"In short, acquired epigenetic changes in a developing cell are reminiscent of the learned changes the brain undergoes during childhood," Spradling explained. "Just as it remains difficult to map exactly what happens in a child's brain as it learns, it is still very difficult to accurately measure epigenetic changes during cellular development. Not enough cells can usually be obtained that are at precisely the same stage for scientists to map specific molecules at specific chromosomal locations."

Lee and Spradling took advantage of the unsurpassed genetic tools available in the fruit fly to overcome these obstacles and provide new insight into the epigenetics of cellular development.

Using a variety of tools and techniques, they focused on cells in the fruit fly ovary and were able identify a specific gene called lsd1 that is needed for ovarian follicle progenitor cells to mature at their normal rate. The researchers found that the amount of the protein that is encoded by this gene, Lsd1, which is present in follicle progenitors decreases as the cells approach differentiation. What's more, the onset of differentiation could be shifted by changing the levels of Lsd1 protein that are present. They deduced that differentiation ensues when Lsd1 levels fall below a critical threshold, and that this likely corresponds to when genes can be stably expressed.

"The timing of differentiation is very important for normal development," Lee said. "Differentiation onset determines how many times progenitors divide, and even small perturbations in Lsd1 levels changed the number of follicle cells that were ultimately produced, which reduced ovarian function."

Previously, it was thought that the follicle cell progenitors started to differentiate based on an external signal they received from another kind of ovarian cells known as germ cells. Lee and Spradling found that while this germ cell signal was essential, it was already being regularly sent even before the progenitors responded. Instead, it was the Lsd1-mediated change in their epigenetic state that timed when progenitor cells started to respond to the signal and begun differentiating. Once they become competent, however, differentiating follicle cells communicate extensively with their neighbors, and continued to do so throughout their lives.

As is frequently the case in basic biological research, the molecules and mechanisms studied here are found in most multicellular animals and hence the researchers conclusions are likely to apply broadly throughout the animal kingdom, including in humans.

In addition, to the importance of this research for understanding how animal chromosomes change during normal development, it may also help clarify alterations in the epigenetic state that take place in some cancers. A minority of cells in such cancers begin to express high levels of Lsd1 and to behave like undifferentiated progenitors.

"Studying fruit fly follicle cell differentiation can teach us at a deeper level what Lsd1 is doing in both normal and cancerous progenitors," Lee added.

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Relationship between personality, health: Study sheds new light on link

Researchers report that "individuals who we would expect to be exposed to more infections as a result of their socially orientated nature (i.e., extraverts) appear to have immune systems that we would expect can deal effectively with infection. While individuals who may be less exposed to infections because of their cautious/conscientious dispositions have immune systems that may respond less well."

Researchers have found new evidence that explains how some aspects of our personality may affect our health and wellbeing, supporting long-observed associations between aspects of human character, physical health and longevity.

A team of health psychologists at The University of Nottingham and the University of California in Los Angeles carried out a study to examine the relationship between certain personality traits and the expression of genes that can affect our health by controlling the activity of our immune systems.

The study did not find any results to support a common theory that tendencies toward negative emotions such as depression or anxiety can lead to poor health (disease-prone personality). What was related to differences in immune cell gene expression were a person's degree of extraversion and conscientiousness.

The study used highly sensitive microarray technology to examine relationships between the five major human personality traits and two groups of genes active in human white blood cells (leukocytes): one involving inflammation, and another involving antiviral responses and antibodies.

A group of 121 ethnically diverse and healthy adults were recruited. These were comprised of 86 females and 35 males with an average age of 24 (range 18-59) and an average body mass index of 23. The participants completed a personality test which measures five major dimensions of personality -- extraversion, neuroticism, openness, agreeableness and conscientiousness -- (NEO-FFI McCrae and Costa, 2004). Blood samples were collected from each volunteer for gene expression analysis and their typical smoking, drinking and exercise behaviors were also recorded for control purposes. Gene expression analysis was carried out at the Social Genomics Core Laboratory at UCLA.

Leading the research, Professor Kavita Vedhara, from The University of Nottingham's School of Medicine, said: "Our results indicated that 'extraversion' was significantly associated with an increased expression of pro-inflammatory genes and that 'conscientiousness' was linked to a reduced expression of pro-inflammatory genes. In other words, individuals who we would expect to be exposed to more infections as a result of their socially orientated nature (i.e., extraverts) appear to have immune systems that we would expect can deal effectively with infection. While individuals who may be less exposed to infections because of their cautious/conscientious dispositions have immune systems that may respond less well. We can't, however, say which came first. Is this our biology determining our psychology or our psychology determining our biology?"

These two clear associations were independent of the recorded health behaviors of the participants and subsets of white blood cells which are the cells of the body's immune system. They were also independent of the amount of negative emotions people experienced. The study also found that expression of antiviral/antibody-related genes was not significantly associated with any personality dimension.

In the remaining three categories of personality, 'openness' also trended towards a reduced expression of pro-inflammatory genes and 'neuroticism' and 'agreeableness' remained unassociated with gene expression.

The research concludes that although the biological mechanisms of these associations need to be explored in future research, these new data may shed new light on the long-observed epidemiological associations between personality, physical health, and human longevity.

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