As people age, maintaining a positive and predictable social environment becomes more important. For example, maintaining close relationships with friends and family has been identified as one of the key components of healthy aging.
While some decline in health, mind, and body is 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 provide a pathway to slow the rate at which our brains age.
We still don’t have a good handle on how our social environment ‘gets under the skin’ to affect our bodies and brains, but much recent work has pointed to changes at the level of genetic regulation – how our genes are switched on and off.”
Noah Snyder Mackler, MD, Associate Professor in ASU’s College of Life Sciences and Center for Evolution and Medicine of the Neurodegenerative Disease Research Center at ASU’s Biodesign Institute
And as new technologies become available, scientists can begin to discover the mysterious relationship between the dynamics of an individual’s social environment and molecular changes in the brain.
But with human studies difficult to conduct and with aging processes drawn out over decades of the normal human lifespan, scientists like Snyder McClare have turned to using our closest genetic cousins, the nonhuman primates, to better understand how our social environment changes our functions. From the organic level down to our genes.
Now, in a new study, Snyder-Mackler and senior co-authors Kenneth Chew (a postdoctoral researcher at ASU) and Alex Decassin (formerly at NYU, now a postdoctoral researcher at the National Institute of Mental Health) led international research. The team shows that in a group In macaques, females with higher social status had younger and more flexible molecular profiles, providing a key link between social environment and healthy brains.
This work was done on rhesus macaques, which are “the best-studied non-human primate species in medicine. These animals also show some of the age-related changes we see in humans, including decreases in bone density and muscle mass, and immune system changes, and general impairment in behavioral, sensory and cognitive functions,” said Snyder-McLair.
The team included key collaborators at the Caribbean Primate Research Center/University of Puerto Rico, the University of Washington, the University of Pennsylvania, the University of Exeter, New York University, North Carolina Central University, the University of Calgary, and the University of Lyon. The study has been published in the journal Natural neuroscience (DOI: 10.1038/s41593-022-01197-0) and funded by the National Institute on Aging, National Institute of Mental Health, National Science Foundation, and NIH Office of Research Infrastructure Programs.
“This study builds on more than 15 years of work our team has done investigating interactions between social behavior, genetics, and the brain in cayo macaques,” said Michael Platt, MD, a professor in the Perelman School of Medicine, College of Arts and Sciences. Wharton School of Business, University of Pennsylvania. “The findings of our team demonstrate 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, a professor of anthropology at NYU. “Long-term funding of such networks is key to enabling important multidisciplinary outcomes in natural animal populations.”
Social environment and the biology of aging
One of the general themes of the Snyder-Mackler Lab is to investigate the root causes and consequences of variability in the social environment, examining them at levels from small molecules all the way up to the whole organism.
In the past decade, new genome technologies have prompted researchers to probe these interactions on an unprecedented level to explore this dynamic interaction between the environment and the genome. Can social or environmental adversity mimic aging at the molecular level? The answer is a decided yes. The Snyder-Mackler team recently published (10.1073/pnas.2121663119) one of the first studies showing that individuals who have experienced a natural disaster, specifically a hurricane, have molecularly older immune systems.
The group they studied is a group of rhesus macaques that live on the isolated island of Cayo Santiago, Puerto Rico. The animals have lived on the island since 1938 and it is managed by the Caribbean Primate Research Center (CPRC).
To make connections between social status and the inner workings of the brain, the team conducted two complementary studies: 1) creating comprehensive gene expression datasets from 15 different regions of the brain, and 2) focusing on a single region in greater detail than in a single region. The cell level (in this case, a detailed analysis within one region 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. The study was performed on 36 animals (20 females and 16 males).
When they grouped the brain regions of each sample by age, 8 distinct groups of genes stood out. Among the most interesting were those involved in metabolic processes, cell signaling, immune responses and stress.
“We ended up identifying thousands of genes that show age-related differences in expression patterns, including about 1,000 genes that show very consistent patterns across the brain,” Chiu said.
Next, they primed for their analysis to zoom in on a region of the brain’s prefrontal cortex on a single cell level.
“We supplemented brain-level gene expression data with measures of gene expression in 71,863 individual cells in the dlPFC across 24 females during the macaque’s lifespan,” Chiu said.
Gene expression data allowed them to classify each individual cell into eight broad neuron types (eg, excitatory neurons, microglia, etc.) and then analyze them into 26 distinct cell types and subtypes in the dlPFC brain region.
They also revealed strong similarities between macaques and human gene expression signatures of age. Some of this difference was specific to regions associated with neurodegenerative diseases, while others reflected preserved neural patterns associated with older age throughout the brain.
When compared with mouse and human brain data, the pathways showing the greatest similarities in age-related variance across regions were central to cell-to-cell communication (chemical synaptic transmission, shared across five regions), and brain development (negative cell regulation). neurogenesis, shared between three regions) and a key brain regulatory gene for cell growth and death (positive regulation of the proinflammatory cytokine tumor necrosis factor, shared across three regions).
But not all findings have found parallels in humans, suggesting that there may be root causes for certain neurodegenerative diseases that are also part of what makes us uniquely human.
These key differences between the effects of age in macaques and humans could help explain the unique mechanisms underlying some human neurodegenerative diseases.
Among the biochemical pathways showing the greatest difference in lifespan across regions were the energy pathways (electron transport chain/oxidative phosphorylation, present in four regions). Interestingly, human neurodegenerative diseases, such as Parkinson’s disease (four regions), Huntington’s disease (three regions) and Alzheimer’s disease (one region), have been associated with some of the most divergent combinations of genes in humans and monkeys.
“This suggests that while neurodegenerative pathways in humans and macaques differ in their age profiles in some areas, they still show strong overlap with social adversity, paralleling epidemiological links in humans between social adversity and neurodegenerative disease,” said Dekazian.
Aging is related to diversity in the social environment
Next, the team applied their data to the social aspects of macaque aging, which has several unique features. In female macaques, dominance rank (the monkey analogue of social status) is inherited from their mothers and, for the most part, remains stable throughout their lives. This is quite 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 moving up in rank as they lengthen their service in the new group.
“Evidence from humans and other social species suggests that variation in the risk, onset and progression of age-related disease is explained in part by variation in social adversity,” said Snyder-McCler. “In female macaques, for example, lower social status is associated with increased mortality, and its effects on immune cell gene expression are similar to gene expression signals for aging in humans.”
Next, they wanted to determine whether social adversity could be linked to molecular signatures of age in the macaque brain. They find thatThe effect of rank on gene expression was particularly significant Led by the youngest Molecular profiles in high-ranking females, suggesting that the associations between higher ranks and younger brain age are not expressed linearly along the social hierarchy, but are instead specific to higher-ranking females. Higher social status may confer many advantages, including increased access to resources, a more predictable environment, and less harassment from group mates.
“Our findings provide some of the first evidence of molecular similarities between aging and social adversity in the brain — providing a key mechanism linking adverse (or, conversely, beneficial) environments to earlier and faster progression of age-related brain deterioration and disease,” said DeCasien.
These atlases and findings will now provide valuable targets for future studies in a tractable and clinically important model of human health and aging.
These connections potentially have a causal explanation; For example, the chronic stress of social adversity has been suggested to accelerate aging by promoting chronic inflammation caused by a weakened immune system. Their work underscores the importance of viewing the social environment as a major modifier of aging and health.
“There is no longer any question that the social lives of humans and other living animals are inexorably intertwined with the rest of their biology,” says Lorraine 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.
We may be on our way to achieving this goal thanks to the data and findings of this study. “Together, our findings provide a rich molecular resource that typifies age-related molecular changes in the brain—in a non-human primate model living in a complex social and natural environment,” said Snyder-McLer. “We hope they provide new insights into how we can all live longer, healthier, happier lives.”
Chew, Kuala Lumpur, et al. (2022) Multigenerational transcriptional profiling of the primate brain reveals signs of aging and the social environment. Natural neuroscience. doi.org/10.1038/s41593-022-01197-0.