Study provides key link between social environment and healthy brains

As people age, it becomes more and more important to maintain a positive and predictable social environment. For example, keeping close ties to friends and family has been identified as one of the key ingredients for healthy aging.

While some declines in health, mind, and body are inevitable, studies have shown that maintaining a positive social environment can help stave off some of the major stressors and challenges of aging.

Scientists have long been interested in exploring these root causes and studying how the environment can be a way to slow the rate at which our brains age.

We still don’t have a good handle on how our social environment can “get under our 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 at Arizona State University’s School of Life Sciences, Center for Evolution and Medicine and affiliated with the Neurodegenerative Disease Research Center at ASU’s Biodesign Institute

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

But with human studies difficult to conduct and with aging processes protracted beyond decades of the typical human lifespan, researchers like Snyder-Mackler have turned to using our closest genetic cousins, non-human primates, to better understand , how our social environment can change our physiology – from the organismal level all the way down to our genes.

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

This work was done in rhesus macaques, which “are the best-studied non-human primate model species in medicine. These animals also show some of the same age-related changes we see in humans, including decreases in bone density and muscle mass, immune system changes and a general impairment of behavioral, sensory and cognitive functioning,” Snyder-Mackler said.

The team included key collaborators at the Caribbean Primate Research Center/University of Puerto Rico, University of Washington, University of Pennsylvania, University of Exeter, New York University, North Carolina Central University, University of Calgary and University of Lyon. The study was published in the journal Nature’s 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 investigating the interactions between social behavior, genetics, and the brain in the Cayo macaques,” said Michael Platt, professor at the Perelman School of Medicine, School of Arts and Sciences, and Wharton Business School at the University of Pennsylvania. “The discoveries made by our team show 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,” added James Higham, professor of anthropology at New York University. “Long-term funding of such networks is key to enabling important interdisciplinary findings in naturalistic animal populations.”

The social environment and biology of aging

A broad theme of Snyder-Mackler’s laboratory is to investigate the fundamental causes and consequences of variation in the social environment, examined at scales from small molecules all the way to the whole organism.

In the last decade, new genomic technologies have driven researchers to investigate these interactions at an unprecedented level to explore this dynamic interaction between the environment and the genome. Can social or environmental adversity mimic older age at the molecular level? The answer is a definite yes. Snyder-Mackler’s team recently published (10.1073/pnas.2121663119) one of the first studies showing that people who experienced a natural disaster, specifically a hurricane, had molecularly older immune systems.

The group they studied is a population of free-ranging 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 inner workings of the brain, the team conducted two complementary studies: 1) generate comprehensive gene expression data sets from 15 different regions of the brain and 2) focus on one region in more detail at the single cell level (in this case, a detailed analysis within a single region of the brain, the dorsolateral prefrontal cortex (dlPFC), a brain area long associated with memory, planning, and decision-making.This work was complemented by detailed behavioral observations and data collection on 36 study animals (20 females and 16 males).

Emergent patterns

When they grouped each sampled brain region by age, 8 different clusters of genes stood out. Among the most interesting were those involved in metabolic processes, cell signaling, and immune and stress responses.

“We ended up identifying thousands of genes that show age-related differences in expression patterns, including about 1,000 that show very consistent patterns across the brain,” Chiou said.

Next, they turned their analysis to zoom in on the prefrontal cortex area of ​​the brain at a single cell level.

“We supplemented our brain-wide gene expression data with measures of the expression of genes in 71,863 individual cells in the dlPFC across 24 females spanning the macaque’s lifespan,” said Chiou.

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

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

Compared with mouse and human brain data, the pathways that showed the greatest similarities in age-linked variation across regions were central to brain cell-to-cell communication (chemical synaptic transmission, shared across five regions), brain growth (negative regulation of neurogenesis, shared between three regions) and a central brain regulatory gene for cell growth and death (positive regulation of the proinflammatory cytokine tumor necrosis factor, shared across three regions).

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

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

Among the biochemical pathways that showed the greatest 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 apes.

“This suggests that although neurodegeneration pathways in humans differ from macaques in their age profiles in some regions, they still show strong overlap with social adversity, paralleling epidemiological links in humans between social adversity and neurodegenerative diseases,” DeCasien said.

Aging is associated with variation in the social environment

The team then applied their data to the social aspects of macaque aging, which has several unique features. In female macaques, dominance rank (the analog of social status) is inherited from their mother and remains mostly stable throughout their lives. This is very different from the pattern found in male macaques, which leave their groups as they mature and enter their new groups at the bottom of the hierarchy before rising in rank as their tenure in the new group be extended.

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

Next, they wanted to determine whether social adversity could be linked to molecular signatures of age in the macaque brain. They found thateffect of rank on gene expression was esp driven by younger molecular profiles in high-ranking women, suggesting that associations between higher rank and younger brain age are not expressed linearly along the social hierarchy, but instead are specific to the highest-ranking women. High social status can provide several benefits, including increased access to resources, more predictable environments, and less harassment from group mates.

“Our findings provide some of the first evidence of molecular parallels between aging and social adversity in the brain—providing a key mechanism linking negative (or conversely beneficial) environments and the earlier onset and faster progression of age-related brain decline and disease,” said DeCasien.

Final thoughts

These atlases and findings will now provide valuable targets for future studies in a manageable, clinically relevant model of human health and aging.

These links potentially have a causal explanation; the chronic stress of social adversity, for example, 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 longer any doubt that the social lives of humans and other gregarious animals are inexorably intertwined with the rest of their biology,” says Lauren Brent, 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 are reversible.

And we may be well on our way to that goal thanks to the data and results from this study. “Collectively, our findings provide a rich molecular resource cataloging age-associated molecular changes in the brain—in a nonhuman primate model living in a complex social and naturalistic environment,” Snyder-Mackler said. “We hope they will provide new insights into how we can all live longer, healthier and happier lives.”

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