Study provides an important link between social environment and healthy mind

As people age, maintaining a positive and predictable social environment becomes more and more important. For example, maintaining close relationships with friends and family has been identified as one of the key elements of healthy aging.

While some decline in health, mind and body is inevitable, studies have shown that maintaining a positive social environment can help ward off some of the major stresses and challenges of aging.

Scientists have long been interested in discovering these root causes, and studying how the environment may offer a way to slow down the aging of our brains.

We still don’t have a good handle on how our social environment can get ‘under the skin’ to affect our bodies and brains, but a lot of recent work has pointed to changes at the level of gene regulation — how our genes are turned on and off.”

Noah Snyder-Mackler, assistant professor in Arizona State University’s School of Life Sciences, Center for Development and Medicine and affiliated with the Neurodegenerative Disease Research Center at ASU’s Biodesign Institute

And with new techniques available, scientists can begin to tease apart the mysterious connection between the dynamics of one’s social environment and molecular changes in the brain.

But with human studies difficult to perform and with the process of aging in the decades of typical human lifespans, scientists like Snyder-McClure have turned to using our closest genetic cousins, nonhuman primates, to understand why. How our social environment can change our physiology – from the organismal level to our genes.

Now, in a new study, Snyder-Mackler and co-first authors Kenneth Chiu (a postdoctoral researcher at ASU) and Alex DeKassien (formerly at New York University, now a postdoctoral researcher at the National Institute of Mental Health) conducted an international research study. led. The team demonstrated that, in a population of macaque monkeys, females with higher social status had younger, more resilient molecular profiles, providing an important link between the social environment and healthy brains.

The work was conducted in rhesus macaques, “the best-studied nonhuman primate model species in medicine. These animals also show some of the same age-related changes we see in humans, including decreased bone density and muscle mass.” include decline in mass, immune system changes, and an overall loss of behavioral, sensory, and cognitive function,” Snyder-Mackler said.

The team included key collaborators from the Caribbean Primate Research Center/University of Puerto Rico, the University of Washington, the University of Pennsylvania, the University of Exeter, New York University, Central University of North Carolina, the University of Calgary and the University of Lyon. The study was published in the journal nature neuroscience (DOI: 10.1038/s41593-022-01197-0) and funded by the National Institute on Aging, the National Institute of Mental Health, the National Science Foundation, and the National Institutes of Health Office of Research Infrastructure Programs.

“This study builds on more than 15 years of work by our team examining the interactions between social behavior, genetics and the brain in Cayo macaques,” said Michael Platt, a professor in the Perelman School of Medicine, School of Arts and Sciences. Used to be.” Wharton Business School at the University of Pennsylvania. “The discovery made by our team demonstrates the value of all the hard work and resources invested in this long-term study.”

“The study shows the value in building long-term collaborative networks across institutions,” said James Higham, professor of anthropology at New York University. “Long-term funding for such networks is key to enabling important multidisciplinary findings in natural animal populations.”

Social environment and biology of aging

A broad theme of Snyder-Mackler’s lab is to investigate the root causes and consequences of variation in social environments, examined at scales ranging from small molecules to whole organisms.

Over the past decade, new genomic techniques have prompted researchers to probe these interactions at an unprecedented level to explore this dynamic interaction between the environment and the genome. Can a social or environmental adversity mimic aging at the molecular level? The answer is definitely yes. Snyder-Mackler’s team recently published (10.1073/pnas.2121663119) one of the first studies to show that individuals who experienced a natural disaster, especially hurricanes, had molecularly older immune systems.

The group they studied is a population of free-range rhesus macaques living on the isolated island of Cayo Santiago, Puerto Rico. The animals have lived on the island since 1938 and are managed by the Caribbean Primate Research Center (CPRC).

To make the connection between social status and the brain’s inner workings, the team conducted two complementary studies: 1) generating comprehensive gene expression datasets from 15 different brain regions, and 2) focusing on a single region in greater detail focusing on the cell level (in this case, a detailed analysis within a region of the brain, the dorsolateral prefrontal cortex (dlPFC), a brain region associated with memory, planning, and decision-making. This task involved detailed behavioral observations and data collection was supplemented by 36 studies on animals (20 females and 16 males).

emerging patterns

When they grouped each sampled brain region by age, eight distinct clusters of genes emerged. Among the most interesting were those involved in metabolic processes, cell signaling and immune and stress responses.

“We identified thousands of genes showing age-associated differences in expression patterns, including roughly 1,000 that show highly consistent patterns across the brain,” Chiu said.

Next, they focused their analysis on enlarging the prefrontal cortex region of the brain at the single cell level.

“We complemented our brain-wide gene expression data with measures of gene expression in 71,863 different cells in the DLPFC in 24 females spanning the macaque lifespan,” Chiu said.

The gene expression data allowed them to classify each individual cell into eight broad neural cell types (eg, excitatory neurons, microglia, etc.) and then parse them into 26 different cell types and subtypes in the dlPFC brain region.

They also revealed strong similarities between the macaque and human gene expression signatures of age. Some of this variation was specific to regions associated with degenerative neurological diseases, while others reflected conserved neurological patterns associated with aging throughout the brain.

Comparing mouse and human brain data, the pathways showing the greatest similarity in age-associated variation across different regions were brain cell-to-cell communication (chemical synaptic transmission, shared across five regions), brain growth (negative regulation), and brain growth (negative regulation). neurogenesis, shared among the three regions) and a key brain regulatory gene for cell growth and death (positive regulation of the proinflammatory cytokine tumor necrosis factor, shared among the three regions).

But not all of the findings found parallels in humans, suggesting that some neurodegenerative disease may have root causes that are also part of what makes us uniquely human.

These important differences between the effects of age in macaques and humans may help to explain the unique mechanisms underlying some human neurodegenerative diseases.

Among the biochemical pathways showing the most age divergence across regions were energy pathways (electron transport chain/oxidative phosphorylation found in four regions). Interestingly, human neurodegenerative diseases, such as Parkinson’s disease (four regions), Huntington’s disease (three regions) and Alzheimer’s (one region), were associated with some of the most divergent gene sets between humans and monkeys.

“This suggests that, while neurodegeneration pathways in humans differ from macaques in their aging profiles in some areas, they still display strong overlap with social adversity, given the epidemiological relationship between social adversity and neurodegenerative diseases in humans.” parallelize the link,” DeKassian said.

Aging is associated with variation in social environment

Next, the team applied their data to the social aspects of macaque ageing, which have several unique features. In female macaques, dominance rank (the monkey analog of social status) is inherited from their mother and, for the most part, remains stable throughout their lives. This is very different from the pattern found in male macaques, who leave their groups when they mature and enter their new groups at the bottom of the hierarchy before rising in rank as their first term in the new group.

“Evidence in humans and other social species suggests that variability in the risk, onset, and progression of age-related morbidity is partially explained by variation in social adversity,” said Snyder-Mackler. “In female macaques, for example, low social status is associated with increased mortality, and its effect on immune cell gene expression is similar to the gene expression signature of aging in humans.”

Next, they wanted to determine whether social adversity could be associated with molecular signatures of age in the macaque brain. they found thatThe effect of rank on gene expression was specifically moderated by younger molecular profiles in higher-ranking females, suggesting that the association between higher rank and younger brain age is not expressed linearly along social hierarchy, but rather is specific to the highest-ranked females. Higher social status can provide a number of benefits, including increased access to resources, a more predictable environment, and decreased harassment from classmates.

“Our findings provide some of the first evidence of a molecular parallelism between aging and social adversity in the brain – an important link linking unfavorable (or conversely, beneficial) environments and age-related brain decline and the onset and rapid progression of disease.” provide mechanisms,” Dekasin said.

final thoughts

These atlases and findings will now provide valuable targets for future studies in clinically important models of human health and aging.

These links likely have a causal explanation; For example, the chronic stress of social adversity has been proposed to accelerate aging by promoting chronic inflammation from a weakened immune system. Their work underscores the importance of considering the social environment as a key modifier of aging and health.

“There is no doubt that the social lives of humans and other living animals are inextricably linked with their biology,” says Lauren Brent, an associate professor of psychology and animal behavior at the University of Exeter. “Exciting future research will show us why our interactions with others can affect how quickly we age, and whether these effects can be reversed.

And thanks to the data and findings of this study, we can move toward that goal. “Taken together, our findings provide a rich molecular resource cataloging age-associated molecular changes in the brain in a model nonhuman primate living in a complex social and natural environment,” said Snyder-Mackler. “We hope they will provide new insights into how we can all live longer, healthier and happier lives.”

Source:

Journal Reference:

Chiu, KL, and others. (2022) Multisector transcriptomic profiling of the primate brain reveals signatures of aging and the social environment. Nature Neuroscience. doi.org/10.1038/s41593-022-01197-0.

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