For the first time, researchers at the Icahn School of Medicine at Mount Sinai have been able to draw a link between structural changes in the brain and molecular signatures associated with aging in neurons. Their findings, published today in Cell, provide unprecedented insights into how cellular senescence may affect brain structures as we age, and the role these molecular processes could play in the development of neurodegenerative conditions such as Parkinson’s and Alzheimer’s.
“This is the first study to directly link senescence-related molecular networks in living human brain tissue to measurable differences in brain structure within the same individuals,” said Noam Beckmann, PhD, assistant professor of artificial intelligence and human health and director of data sciences at the Mount Sinai Clinical Intelligence Center. “By identifying molecular pathways that are engaged in both brain structure development and aging, our work highlights senescence as a fundamental biological feature of brain aging and neurodegenerative disease and helps prioritize targets for future experimental research aimed at protecting brain health.”
Although brain structures are known to change throughout life, the underlying molecular processes still remain largely unknown. Beckmann and colleagues set out to study how altered cellular states linked to senescence may influence brain structure changes by using data from patients in the Living Brain Project. This ongoing study includes the largest collection of brain samples sourced from living individuals, pairing brain imaging data with biopsies of the brain’s prefrontal cortex taken during deep brain stimulation procedures.
“This study addresses a major gap in the field by directly linking molecular features of the brain to neuroimaging measures in the same individuals,” said Alexander W. Charney, MD, PhD, director of The Charles Bronfman Institute for Personalized Medicine and vice chair of the Windreich department of artificial intelligence and human health at the Icahn School of Medicine at Mount Sinai. “By leveraging datasets from the Living Brain Project, we can begin to understand how senescence-related biology may differentially influence brain organization across cell types and across the lifespan.”
As part of the study, the researchers developed a new method to define senescence in different cell types found in the brain. They then investigated how senescent patterns of gene expression correlate with changes in brain structure, spanning from early development stages to late life.
Results showed the altered states of senescence can have different effects on brain structure depending on the cell type and stage of life. For instance, gene expression patterns linked to senescence in microglia were associated with a larger brain volume in the prefrontal cortex, while senescent excitatory neurons were associated with smaller brain volumes in aging brains. In the case of excitatory neurons, these findings were also observed in the early stages of life, providing new evidence that senescence processes are already active long before old age.
“Our results support brain cellular senescence as an example of ‘antagonistic pleiotropy’—the idea that some genes help survival or fertility early in life but cause harm later, contributing to aging and disease,” said Anina N. Lund, PhD, lead author of the study and now a postdoctoral fellow at the Icahn School of Medicine at Mount Sinai. “Most prior work links brain cellular senescence only to brain aging, but our finding of it during development shows this process is not just a marker of aging or disease; it also may play key roles in early brain development.”
While more work will be needed to fully understand the connection between senescence at the cellular level and brain structure changes, this study provides a framework for researchers worldwide to investigate how molecular processes influence aging and the development or prevention of neurodegenerative conditions.
“While brain ‘senescence’ or growing frail is largely accepted as a normal process of aging, this data set represents an opportunity to challenge that notion,” concluded Brian Kopell, MD, director of the Center for Neuromodulation at Mount Sinai and co-lead of The Living Brain Project.
Future work at Mount Sinai will involve larger, more diverse cohorts and establishing cause-and-effect relationships between senescent gene expression patterns and structural changes across a wide range of brain regions.
