As people age, it becomes more important to maintain a positive and predictable social environment. For example, maintaining close relationships with friends and family has been reported as one of the key factors in healthy aging.
While some decline in health, mind, and body is inevitable, research has shown that maintaining a positive social environment can help prevent some of the major stressors and challenges of aging.
Scientists have long been interested in exploring these underlying causes and investigating how the environment may provide a way to slow the rate at which our brains age.
We still don’t have a good grasp of how our social environment can “get under the skin” to affect our bodies and brains, but much recent work has pointed to changes at the level of gene regulation—how our genes are turned off and on. “
Noah Snyder-Mackler, assistant professor in Arizona State University’s Department of Life Sciences, Center for Evolution and Medicine and member of the Neurodegenerative Disease Research Center at ASU’s Biodesign Institute
And with new techniques available, scientists can begin to tease out the mysterious relationship between the dynamics of a person’s social environment and molecular changes in the brain.
But since human studies are difficult to conduct, and since aging processes have spanned decades of the typical human lifespan, researchers like Snyder-Mackler have turned to using our closest genetic cousins, the nonhuman primates, to better understand how our social environment can change our physiology—from the organismal level down to our genes.
Now, in a new study, Snyder-Mackler and first authors Kenneth Chiou (postdoctoral fellow at ASU) and Alex DeCasien (formerly of New York University, now postdoctoral fellow at the National Institute of Mental Health) led an international research team that showed that in a group of macaque monkeys women with higher social status had a younger, more resilient molecular profile, a key link between social environment and healthy brains.
This work was done in rhesus macaques, which “are the best-studied primate species in medicine. These animals also show some of the same age-related changes we see in humans, including a decrease in bone density and muscle mass, immune system changes and an overall decline in behavioral, sensory and cognitive functions,” 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 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 research builds on our team’s more than 15 years of work investigating the interactions between social behavior, genetics and the brain in Cayo macaques,” said Michael Platt, a professor at the Perelman School of Medicine, School of Arts and Sciences, and Wharton Business School at the University of Pennsylvania. “The discoveries our team has made demonstrate the value of all the work and money invested in this long-term study.”
“The study shows the value of building long-term collaborative networks across institutions,” added James Higham, professor of anthropology at New York University. “Long-term funding for such networks is key to enabling important interdisciplinary results in natural animal populations.”
Social environment and the biology of aging
The broad theme of Snyder-Mackler’s lab is to study the root and consequences of variation in the social environment, viewed at scales from tiny molecules all the way to the whole organism.
In the past decade, new genomic technologies have pushed scientists to study these interactions at an unprecedented level to explore this dynamic environment-genome interaction. 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 to show that individuals exposed to natural disasters, specifically hurricanes, have molecularly aged immune systems.
The group they have studied is a population of free-ranging rhesus macaques living on the isolated island of Cayo Santiago in 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 additional studies: 1) creating comprehensive gene expression datasets from 15 different brain regions and 2) focusing on one region in greater detail at one location. cellular level (in this case, a detailed analysis within one area of the brain, the dorsolateral prefrontal cortex (dlPFC), a brain region long associated with memory, planning and decision-making. This work was complemented by detailed behavioral observations and data collection of ten 36 research animals (20 females and 16 males).
When they sorted each brain region sample by age, 8 different gene clusters 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 highly consistent patterns across the brain,” Chiou said.
Next, they focused their analysis on expanding the prefrontal cortex region of the brain at the single-cell level.
“We complemented our brain gene expression data by measuring gene expression in 71,863 individual cells in the dlPFC across 24 female macaques spanning the lifespan,” said Chiou.
The gene expression data allowed them to group each individual cell into eight broad neuron types (eg, excitatory neurons, microglia, etc.) and then further group them into 26 different cell types and subtypes in the dlPFC brain region.
They also revealed strong parallels between macaque and human gene expression for age. Some of these changes were specific to regions associated with neurodegenerative diseases, while others reflected conserved neurological patterns associated with older age throughout the brain.
When comparing the mouse and brain data, the pathways that showed the most similarity in age-related variation between regions were central to brain cell-to-cell communication (chemical synaptic transmission, shared between five regions), brain growth (negative regulation of neurogenesis, shared between three regions ) and key regulatory genes for cell growth and death (positive regulation of pro-inflammatory cytokine tumor suppressor factor, divided into three regions).
But not all of the findings were paralleled in humans, suggesting that it may be at the root of some neurodegenerative diseases that are also part of what makes us uniquely human.
This key difference in 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 differences between regions were energy pathways (electron transport chain/oxidative phosphorylation, found in four regions). Interestingly, neurodegenerative diseases in humans, 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 sets of genes between humans and monkeys.
“This suggests that although neurodegenerative trajectories in humans differ from macaques in their age profile in some regions, they still show a high degree of overlap with social adversity, paralleling the epidemiological link in humans between social adversity and neurodegenerative diseases,” said DeCasien.
Aging is associated with changes in the social environment
Next, the team applied their data to the social aspects of aging macaques, which have some unique features. In female macaques, the level of dominance (the ape equivalent of social status) is inherited from their mother and remains constant throughout life. This is very different from the pattern found in male macaques, who leave their groups as they mature and enter their new groups at the bottom of the hierarchy before moving up the ranks as their tenure in the new group increases.
“Evidence in humans and other social species suggests that variation in the risk, onset, and progression of age-related diseases is 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 are similar to gene expression markers of aging in humans.”
Next, they wanted to find out if social adversity could be linked to molecular markers of age in the macaque brain. They found thatthe effect of sequencing on gene expression was esp driven by younger molecular profiles in high-ranking women, suggesting that the association between higher scores and younger brain age is not presented linearly along the social hierarchy but is specific to the highest-ranking women. High social status can bring a number of benefits, including increased access to resources, a more predictable environment, and less harassment from group members.
“Our findings provide some of the first evidence of molecular associations between aging and social adversity in the brain—providing a key mechanism linking harmful (or conversely, beneficial) environments to the earlier onset and accelerated progression of age-related brain hyperplasia and disease.” DeCasien said.
These atlases and findings will now provide valuable targets for future research in a tractable, clinically relevant model of human health and aging.
This relationship has a possible causal explanation; the chronic stress of social adversity, for example, has been suggested to accelerate aging by promoting chronic inflammation from a weakened immune system. Their work highlights 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 inextricably 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 may 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 findings from this study. “Taken together, our results provide a rich molecular resource documenting age-related molecular changes in the brain—in a nonhuman primate model living in a complex social and natural environment,” Snyder-Mackler said. “We hope they will provide new insights into how we can all live longer, healthier and happier lives.”
Chiou, KL, and more. (2022) Multiregional transcriptional profiling of the primate brain reveals features of aging and the social environment. Nature Neuroscience. doi.org/10.1038/s41593-022-01197-0.