Superager brains excel at something scientists once thought was impossible

A new study published in the journal Nature reveals that the adult human brain continues to produce new neurons throughout life, a process that is highly active in older individuals with exceptional memories but severely limited in those with Alzheimer’s disease. The research suggests that preserving this neuron-generating capacity could be a key to protecting cognitive function in old age.

The human brain relies on billions of cells called neurons to process information, store memories, and coordinate movements. In certain animals like mice, researchers have repeatedly observed the birth of new neurons in the adult brain. This regenerative process is called neurogenesis.

For years, researchers debated whether adult humans also experience neurogenesis. Past studies produced mixed results, leading to questions about whether the human brain simply stops generating new neurons after childhood. The exact biological mechanisms controlling this cellular birth in humans remained unclear.

Researchers at the University of Illinois Chicago, Northwestern University, and the University of Washington set out to answer these lingering questions. The research team was led by Ahmed Disouky, a scientist investigating how the brain maintains its health over time. Disouky and his colleagues wanted to understand the biological differences between brains that age well and brains that succumb to dementia.

A major focus of the research involved a unique group of older adults known as superagers. These individuals are eighty years of age or older, but they possess the memory capacity of people thirty years younger. The team suspected that studying these remarkable individuals could reveal biological secrets to healthy aging.

“What’s exciting for the public is that this study shows the aging brain is not fixed or doomed to decline,” said Ahmed Disouky, the first author of the study. “Understanding how some people naturally maintain neurogenesis opens the door to strategies that could help more adults preserve memory and cognitive health as they age.”

To understand the biological roots of memory, the researchers focused on a specific region of the brain called the hippocampus. The hippocampus acts as a central hub for learning and memory formation. Diseases that erode memory, such as Alzheimer’s disease, typically attack this region early on.

The researchers also wanted to explore the concept of epigenetics, which involves changes in how DNA is packaged and read by the cell. Inside the nucleus of a cell, DNA is wrapped tightly in a structure called chromatin. When chromatin is open and accessible, specific genes can be turned on, allowing the cell to perform new functions or mature into a different type of cell.

“Modern medicine has revolutionized health care such that life expectancy is greater now than ever before,” said co-lead author Jalees Rehman, the Benjamin J. Goldberg Professor and head of the department of biochemistry and molecular genetics at UIC. “We need to ensure that this overall increased life expectancy goes along with a high quality of life, including cognitive health.”

To achieve this goal, the team needed a comprehensive view of how chromatin accessibility and gene expression affect the hippocampus. They gathered post-mortem brain tissue from five distinct groups of human donors. These groups included healthy young adults, healthy older adults, superagers, individuals with early signs of cognitive decline, and people diagnosed with Alzheimer’s disease.

The researchers analyzed the donated brain tissue using advanced single-cell sequencing techniques. This technology allows scientists to examine the genetic material inside individual cells one at a time. By looking at hundreds of thousands of individual cells, the team could identify rare cell types that might otherwise be lost in a larger sample.

To map out the biology of these tissues, the team used two distinct measurements for each individual cell. First, they looked at which specific genes were actively producing instructions, a process known as gene expression. Second, they measured the physical shape of the DNA to see which regions were unwound and available for use.

This dual approach allowed the scientists to see both the current activity of the cell and its future potential. If a gene is switched off but the DNA remains open, the cell retains the capacity to reactivate that gene later. If the DNA is tightly coiled and closed, that biological capacity is lost entirely.

The team specifically searched for cells at three different stages of development. The first stage involved neural stem cells, which act as blank slates that can develop into mature brain cells. The second stage involved neuroblasts, which are adolescent cells that have begun the transition into neurons.

The third stage consisted of immature neurons that are just on the verge of becoming fully functional. Finding cells in these three stages would prove that the brain is actively building new circuitry.

“Think of the stages of adult neurogenesis like a baby, a toddler and a teenager,” said Orly Lazarov, a professor in UIC’s College of Medicine and director of the Alzheimer’s Disease and Related Dementia Training Program. “All are signs that these hippocampi are growing new neurons.”

In previous years, some scientists struggled to tell the difference between developing neurons and other types of brain cells. Young neurons can look remarkably similar to support cells that produce brain insulation. By mapping the exact genetic profile of hundreds of thousands of cells, the research team finally separated these cellular identities.

The results confirmed that the adult human brain does indeed produce new neurons. The researchers detected neural stem cells, neuroblasts, and immature neurons in all five groups of donors. However, the abundance and health of these developing cells varied wildly depending on the cognitive status of the individual.

In the brains of superagers, the neurogenic process was highly active. These individuals produced a massive number of immature neurons and neuroblasts compared to typical older adults. The researchers described this unique cellular profile as a signature of resilience against cognitive decline.

“Superagers had twice the neurogenesis of the other healthy older adults,” Lazarov said. “Something in their brains enables them to maintain a superior memory. I believe hippocampal neurogenesis is the secret ingredient, and the data support that.”

The situation looked vastly different in the brains of individuals suffering from cognitive decline. People with early stage memory issues showed a sharp drop in the production of new neurons. Those diagnosed with advanced Alzheimer’s disease generated almost no new neurons at all.

By looking at the molecular data, the researchers pinpointed exactly where the neurogenic process was breaking down. They found that the problem was largely rooted in the packaging of the DNA. In the Alzheimer’s disease group, the chromatin had become less accessible, effectively shutting down the genes required for a stem cell to mature into a working neuron.

These changes in chromatin accessibility happened very early in the disease process. The researchers noted that individuals with mild cognitive impairment showed restricted chromatin access even before their gene expression levels dropped. This suggests that the way DNA is folded might serve as an early warning sign of impending memory loss.

Inside the cells, proteins known as transcription factors act as master switches to control this entire system. They bind to the accessible chromatin and turn whole networks of genes on or off. The research revealed that superagers rely on a completely different set of transcription factors compared to people experiencing typical brain aging.

Because the superagers maintained accessible chromatin in specific areas, their brain cells could continue to form new connections. This ability to adapt and build new wiring is essential for forming new memories. The researchers observed that this biological resilience allowed superager brains to function like those of much younger individuals.

The researchers noticed that specific biological pathways remained highly active in superagers. For example, the genetic instructions for building cellular power plants, called mitochondria, continued to operate normally. This allowed the cells to generate the energy required for establishing new neural pathways.

The scientists also mapped out the chemical conversations happening between different types of brain cells. They looked closely at star-shaped support cells called astrocytes, which provide nutrients to neurons and help maintain a stable environment in the brain. In healthy aging, astrocytes and neurons engaged in a continuous biochemical dialogue to maintain the strength of their connections.

In brains affected by dementia, this chemical dialogue grew quiet, leaving the surviving neurons vulnerable to damage. The failure of these cellular support systems likely contributed to the decline of neurogenesis in the diseased brains.

“This is a big step forward in understanding how the human brain processes cognition, forms memories and ages. Determining why some brains age more healthily than others can help researchers make therapeutics for healthy aging, cognitive resilience and the prevention of Alzheimer’s disease and related dementia,” said Lazarov.

While the results provide a detailed map of human neurogenesis, the researchers acknowledged several limitations in their approach. The study relied on a relatively small number of brain samples. Human brain tissue is notoriously variable, and small sample sizes make it difficult to draw absolute conclusions across the entire population.

The researchers also pointed out that their results were not statistically significant in every single measurement comparing superagers to healthy adults. Some comparisons lacked statistical power due to the inherent variability from one tissue sample to the next. The team noted that future studies with much larger groups of donors will be necessary to confirm the exact rates of cellular birth.

Another limitation involves the use of post-mortem tissue. Analyzing brain tissue after death only provides a single snapshot in time. It is impossible to watch the actual progression of a single stem cell maturing into a functional neuron in a living human brain.

Despite these challenges, the study lays a strong foundation for future exploration. The research team plans to investigate how lifestyle choices influence the epigenetic signatures identified in this study. They hope to learn how external pressures can alter the chromatin in the hippocampus.

Next, this team will examine environmental and lifestyle factors like diet, exercise and inflammation that may work alongside neurogenesis to impact aging. By understanding these external influences, scientists might eventually design therapies that keep chromatin open and neurogenesis active. This approach could offer a new way to delay or prevent the onset of dementia in older adults.

The study, “Human hippocampal neurogenesis in adulthood, ageing and Alzheimer’s disease,” was authored by Ahmed Disouky, Mark A. Sanborn, K. R. Sabitha, Mostafa M. Mostafa, Ivan Alejandro Ayala, David A. Bennett, Yisha Lu, Yi Zhou, C. Dirk Keene, Sandra Weintraub, Tamar Gefen, M.-Marsel Mesulam, Changiz Geula, Mark Maienschein-Cline, Jalees Rehman & Orly Lazarov.