As people age, maintaining a positive and predictable social environment becomes increasingly important. For example, maintaining close relationships with 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 show that maintaining a positive social environment can help prevent some of the major stressors and challenges of aging.
Scientists have long been interested in investigating these root causes and learning how the environment can provide a pathway to slowing the rate at which our brains age.
We still don’t have a good idea of how our social environment can ‘get under the skin’ to affect our bodies and brains, but very recent work points 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 Evolution and Medicine and an affiliate of the Center for Neurodegenerative Disease Research at ASU’s Biodesign Institute
And with new technologies available, scientists can begin to unravel the mysterious relationship between the dynamics of the social environment and molecular changes in the brain.
But with human studies difficult to perform and aging processes lasting decades beyond the typical human lifespan, scientists 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 all the way down to our genes.
Now, in a new study, Snyder-Mackler and co-authors Kenneth Chiu (a postdoctoral fellow at ASU) and Alex DeCassien (formerly at NYU, now a postdoctoral fellow at the National Institute of Mental Health) lead an international research team that demonstrates that in a population of macaque monkeys females of higher social status have younger, more resilient molecular profiles, providing a key link between social environment and healthy brains.
This work was done on rhesus macaques, which “are the best-studied nonhuman primate species models 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 overall impairment of behavioral, sensory and cognitive functions,” Snyder-Mackler said.
The team includes 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 Neurology (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 of Cayo macaques,” said Michael Platt, a professor at the University’s Perelman School of Medicine, School of Arts and Sciences, and Wharton Business School. of Pennsylvania. “The findings 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 of building long-term collaborative networks between institutions,” added James Higham, professor of anthropology at New York University. “Long-term funding of such networks is key to enabling important multidisciplinary discoveries in naturalistic animal populations.”
The social environment and the biology of aging
A broad theme of the Snyder-Mackler lab is to investigate the root causes and consequences of variation in the social environment, studied at scales from small molecules to the whole organism.
In the past decade, new genomic technologies have prompted researchers to explore these interactions at an unprecedented level to explore this dynamic interplay between the environment and the genome. Can social or environmental disadvantage mimic aging at the molecular level? The answer is a resounding yes. Snyder-Mackler’s team recently published (10.1073/pnas.2121663119) one of the first studies showing that people who survive a natural disaster, specifically a hurricane, have molecularly older immune systems.
The group they studied was 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 connections between social status and the inner workings of the brain, the team undertook two additional studies: 1) generating comprehensive gene expression data sets from 15 different brain regions and 2) focusing on one region in greater detail in the single a moment. cellular level (in this case, a detailed analysis within a single brain region, 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 on 36 animals studied (20 females and 16 males).
When they grouped each brain region in the sample by age, 8 distinct groups of genes stood out. Among the most interesting were those involved in metabolic processes, cell signaling, and immune and stress responses.
“Ultimately, we identified thousands of genes showing age-related differences in expression patterns, including approximately 1,000 that showed highly consistent patterns across the brain,” Chiu said.
They then turned their analysis to zoom in on the prefrontal cortex area of the brain at the single-cell level.
“We supplemented our whole-brain gene expression data with measures of gene expression in 71,863 individual cells in the dlPFC in 24 female macaques spanning the lifespan,” Chiu said.
The gene expression data allowed them to classify each individual cell into eight broad neuronal cell types (eg, excitatory neurons, microglia, etc.) and then further analyze 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 these variations are specific to regions associated with degenerative neurological diseases, while others reflect conserved age-related neurological patterns throughout the brain.
Compared with mouse and human brain data, the pathways showing the greatest similarities in age-related variation across regions are central to brain cell communication (chemical synaptic transmission shared among five regions), brain growth ( down-regulation of neurogenesis, shared between three regions) and a key brain regulatory gene for cell growth and death (up-regulated of the pro-inflammatory cytokine tumor necrosis factor, shared across three regions).
But not all of the findings find parallels in humans, suggesting that there may be root causes for some 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 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) are associated with some of the most different sets of genes between humans and monkeys.
“This suggests that while the pathways of neurodegeneration in humans differ from those of macaques in their age profiles in some regions, they still show strong overlap with social adversity, paralleling the epidemiological links in humans between social adversity and neurodegenerative diseases,” said De Cassien.
Aging is associated with a change in the social environment
The team then applied their data to the social aspects of aging in macaques, which have several unique characteristics. In female macaques, dominance rank (analogous to ape 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, which leave their groups as they mature and enter their new groups at the bottom of the hierarchy, before rising in rank as their stay in the new group lengthens.
“Evidence in humans and other social species suggests that age-related variability in the risk, onset, and progression of disease is explained in part by variation in social disadvantage,” 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 signatures of aging in humans.”
Next, they wanted to determine whether social distress could be linked to molecular signatures of age in the macaque brain. They found thatthe effect of rank on gene expression was esp driven by younger molecular profiles in high-ranking females, suggesting that associations between higher rank and younger brain age are not expressed linearly along the social hierarchy but are instead specific to the highest-ranking females . High social status can provide several advantages, including greater access to resources, a more predictable environment, and reduced harassment by teammates.
“Our findings provide some of the first evidence of molecular parallels between aging and social adversity in the brain – providing a key mechanism linking adverse (or conversely, beneficial) environments and the earlier onset and more rapid progression of age-related brain decline and disease ,” said De Cassien.
These atlases and findings will now provide valuable targets for future studies in a tractable, clinically relevant model of human health and aging.
These relationships potentially have a causal explanation; chronic stress from social disadvantage, for example, is thought 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 animals living in groups are inexorably intertwined with the rest of their biology,” says Lauren Brent, associate professor of animal psychology and 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 on our way to that goal thanks to the data and findings from this study. “Taken together, our findings provide a rich molecular resource cataloging age-related molecular changes in the brain—in a nonhuman primate model living in a complex social and naturalistic environment,” said Snyder-Mackler. “We hope they will provide new insights into how we can all lead longer, healthier and happier lives.”
Chiou, KL, et al. (2022) Multiregional transcriptomic profiling of the primate brain reveals signatures of aging and the social environment. Nature Neurology. doi.org/10.1038/s41593-022-01197-0.