A new study from researchers at the Salk Institute for Biological Studies offers one of the most detailed looks yet at how the brain’s molecular landscape shifts over time. By examining tens of thousands of individual brain cells, the team created a large-scale atlas showing how aging alters the brain’s genetic control systems across different cell types and regions.
The atlas spans eight brain regions and 36 distinct brain cell types, providing a detailed look at the biological changes of the aging brain at the genetic level. Epigenetic changes are chemical tags that act as switches controlling which genes are active or silent. The changes don’t alter the DNA sequence itself, but they determine how cells behave. As these switches deviate with age, cells begin to malfunction.
The study was published on March 11 in the journal Cell. Scientists hope this resource will lead to better understanding of how aging contributes to the development of neurodegenerative diseases.
“Aging is the most significant contributing factor to these neurodegenerative diseases,” said Joseph Ecker, Ph.D., director of the Genomic Analysis Laboratory at Salk and co-corresponding author of the study. “You don’t see these diseases in children. So understanding the age component is what we’re getting at.”
Why this Matters
Journalists should become familiar with basic scientific research like this to better understand how it impacts translational research and ultimately the development of new drug therapies. Alzheimer’s currently affects about 7.2 million people in the U.S. 65 and older, and incidence of Alzheimer’s, Parkinson’s, frontotemporal dementia, and ALS is projected to roughly double every 20 years. This will place enormous strain on an already over-strained health system, shortage of programs and services, and family caregivers.
Neurodegenerative diseases often develop slowly, with biological changes occurring for years or even decades before symptoms appear. By the time most people receive an Alzheimer’s diagnosis, their brain has already degenerated for years. The few existing therapies only help some people, some of the time, and come with serious risks, including brain bleeds and stroke.
Epigenetic changes may be among the earliest steps that push cells toward dysfunction, according to Ecker. The new atlas offers a way to examine these processes cell by cell, giving researchers a clearer picture of which cells are most vulnerable and what molecular changes occur first.
Identifying those early shifts could be critical for developing treatments that intervene before irreversible damage occurs. This could help scientists design more precise therapies earlier in the disease process, ideally preventing or slowing the underlying damage from Alzheimer’s disease, Parkinson’s disease and ALS, which all become more common with aging.
These therapies can be developed to work on the exact part of the brain that is affected, explained study lead author Rachel Zeng, a graduate researcher at Salk. That distinction matters enormously for treatment.
“If we are looking for specific diseases like Alzheimer’s, even if it’s the same cell type, taking into consideration which brain region to target for certain treatment is very crucial,” she said. “If you treat a brain region that is not affected, that’s not going to work.”
The study also found that brain aging is not uniform. Some brain regions and cell types change much faster than others. The atlas offers a kind of “parts list” for other researchers, akin to how a mechanic might approach repairing a car.
If you don’t understand all the parts, you’re never going to figure out how to fix it. You don’t want to change the oil when you need to change the transmission fluid.
Joseph Ecker, Ph.D.
Using mice for consistency
The researchers used mice rather than human tissue. That may seem like a limitation; it’s actually a scientific advantage, according to Ecker.
That’s because human aging studies include many confounders.
“Their genetic background may be different. Their lifestyle, health conditions or medications they took might have affected their brain,” Ecker said. Lab mice, however, are genetically identical. They live in controlled conditions, eat the same food and face none of the environmental chaos that complicates human data.
The uniformity allows researchers to isolate the molecular fingerprints of aging itself. And since epigenetic mechanisms are broadly conserved across mammals, insights from a mouse brain are relevant to human biology.
“We start with the mouse and then we try to translate what we find to a human,” Ecker said. “We can say, these kinds of cells are most vulnerable during aging, but don’t all have the same changes over time.”
Other researchers can now use the atlas as a reference to ask whether those same age-related changes appear in human brains, or in mouse models of specific diseases, such as frontotemporal dementia, Lewy body dementia or other neurodegenerative conditions.
Future efforts
The team is collaborating with Massachusetts General Hospital, which houses donated brains, plus blood and skin samples collected from those same donors over time. They hope to determine how early the epigenetic signature of Alzheimer’s appears, and which specific genes it implicates, long before symptoms are apparent.
“Right now, we have a pretty primitive understanding of the early stages of a lot of these diseases,” Ecker said. “What we need is to understand the early events that are happening in the epigenome. Once we have that kind of information, then you can design the kinds of therapies we’re going to need.”
