New research reveals how cellular senescence, the process by which aging cells change function, shapes the structure of the human brain from development to old age, deepening our understanding of brain aging and neurodegenerative diseases.
researchers Icahn School of Medicine at Mount Sinai We discovered how cellular senescence, the biological process by which aging cells change their function, is relevant to humans. brain structure in both growing and late life stages. This study demonstrates how the molecular signatures of cellular aging reflect brain volume and cortical organization throughout the lifespan.
Deciphering brain structure and cellular aging
Understanding the structure of the human brain has always been an important challenge in neuroscience. Brain structure is known to change over time and to be associated with both aging and neurodegenerative conditions, but the molecular processes that drive these changes, including cellular senescence, are poorly understood.
Cellular senescence is known as a condition in which cells permanently stop dividing but do not die, but instead change in function. Although aging is thought to be related to aging and disease, the role of aging in the formation of human brain structure (both early in development and later) is also poorly understood.
“This is the first study to directly link aging-related molecular networks in living human brain tissue to measurable differences in brain structure within the same individual,” said Norm Beckman, Ph.D., director of data science and assistant professor of artificial intelligence and human health at the Icahn School of Medicine at Mount Sinai and co-senior author of the paper. “By identifying molecular pathways involved in both the development and aging of brain structures, our study highlights aging as a fundamental biological feature of brain aging and neurodegenerative diseases and helps prioritize targets for future experimental studies aimed at protecting brain health.”
New resource: Living Brain project
Key resources for this study include: living brain projectwhich combines prefrontal cortex biopsy and brain imaging data obtained during a deep brain stimulation procedure. This approach allowed researchers to study the molecular and structural features of living individuals. The research team developed a method to identify senescent cells in human brain tissue and investigated how aging-related gene expression correlates with brain structure.
“By leveraging the Living Brain Project’s dataset, we can begin to understand how the biology associated with aging differentially impacts brain tissue across cell types and across the lifespan,” said Alexander W. Charney, M.D., Ph.D., director of the Center. Charles Bronfman Institute for Personalized Medicine He is also co-senior author of this paper.
Cell type and life stage are important
One of the main findings of this study was that cellular aging plays different roles depending on cell type and stage of life. Aging-related genes in microglia, the brain’s main immune cells, were associated with larger brain volume, while aging-related genes in excitatory neurons were correlated with smaller brain volume in the aging brain. These neuron-associated patterns are also observed early in life, suggesting that aging-related processes are activated soon after embryonic development.
One of the main findings of this study was that cellular aging plays different roles depending on cell type and stage of life.
“We were excited to use our new method to see clear signs of aging in both the aging and developing brains,” said Annina N. Lund, Ph.D., a former neuroscience graduate student and current postdoctoral fellow at the Icahn School of Medicine and lead author of the study. “Our findings support the aging of brain cells as an example of ‘antagonistic pleiotropy,’ the idea that some genes benefit survival and fertility early in life but become harmful later in life, causing aging and disease. Most have only linked aging of brain cells to brain aging, but our findings in development show that this process is not just a marker of aging or disease, but may also play an important role in early brain development.”
Implications for future research
“Often the greatest advances in medicine are not the invention of entirely new tools, but a unique understanding of what is already achievable,” said Brian Kopel, MD, director of the Mount Sinai Neuromodulation Center and co-leader of the Living Brain Project. “This research represents a new milestone in the Living Brain Project’s ability to utilize a unique combination of known data types to pave the way for future treatments. Brain ‘aging’ or frailty is widely accepted as a normal aging process, but this dataset provides an opportunity to question that concept.”
The greatest advances in medicine often result not from the invention of completely new tools, but from unique understandings of what is already available.
Although this discovery does not immediately point to a cure, it provides a framework for understanding how brain structure evolves over time and how age-related differences arise. The authors acknowledge limitations, including the small, clinically specific cohort and focus on the prefrontal cortex, but stress that this study provides an important foundation for future research.
Next steps include expanding to larger and more diverse cohorts, refining cell type-specific definitions of aging, and conducting experimental studies to test whether aging-related pathways causally influence brain structure. Such research could reveal when aging supports brain health and contributes to vulnerability to aging and neurodegenerative diseases.