80-year-old ‘Superager’ brains operate like those of a 50-year old. Here’s why

By Sandee LaMotte, CNN

(CNN) — The human brain shrinks as it ages, affecting the ability to remember — it’s part of life. Yet there are a lucky few, called “SuperAgers,” who possess a brain that fights back. For these people, memories stay as sharp as they were 30 or more years in the past.

Carol Siegler, who lives in the Chicago suburb of Palatine, is a SuperAger. At 82, she won the American Crossword Puzzle Tournament for her age group, which she said she entered “as a gag.”

“I’ve auditioned twice for ‘Jeopardy!’ and did well enough on it to be invited to the live auditions. Then Covid hit,” Siegler told me in 2022, when she was 85.

Today, Siegler is still going strong, well on her way to her 90th birthday, said Tamar Gefen, an associate professor of psychiatry and behavioral sciences at the Mesulam Institute for Cognitive Neurology and Alzheimer’s Disease at Northwestern University in Chicago.

Gefen conducts research at Northwestern’s SuperAging Program, which is currently studying 113 SuperAgers. Over the past 25 years, however, 80 SuperAgers have donated their brain tissue to the program, which has led to some fascinating discoveries.

CNN spoke to Gefen about those decades of work. She is a coauthor of a new analysis of the research that was published Thursday in Alzheimer’s & Dementia, the journal of the Alzheimer’s Association.

This interview has been lightly edited and condensed for clarity.

CNN: How do you define a SuperAger, and what have you found out about their behavior over the years?

Tamar Gefen: To be a SuperAger in our program at Northwestern, a person must be over 80 and undergo extensive cognitive testing. Acceptance in the study only occurs if the person’s episodic memory — the ability to recall everyday events and past personal history — is as good or better than cognitively normal people in their 50s and 60s.

We have screened close to 2,000 individuals who think they may be a SuperAger and less than 10% meet the criteria. Over the past 25 years, we have studied about 300 SuperAgers — a number of whom have donated their brain for research.

One key trait of SuperAgers is that they seem to be highly social people. They value connection and are often active in their communities. This is interesting because we know isolation is a risk factor for developing dementia, and so staying socially active is a known protective feature.

Another common thread in all SuperAgers is a sense of autonomy, freedom and independence. They’re making decisions and living their lives the way that they want to live.

I feel very strongly that successful aging is not just about sociability. If a person feels trapped, tethered or burdened, especially in a vulnerable state like poor health or older age, I think it can encroach on their entire psychosocial being.

But as far as healthy behaviors, SuperAgers run the gamut. We have SuperAgers with heart disease, diabetes, who aren’t physically active, who don’t eat any better than their similar age peers.

There is one SuperAger who drinks four beers every night. He laughs and says, “Maybe it’s done me wrong, but I’ll never know.” He doesn’t have an identical twin to compare his behavior to, so would he have lived to 108 instead of 98? We don’t know.

CNN: Many of your most intriguing discoveries have come from studying donor brain tissue. What have you discovered about the memory center of the SuperAger brain?

Gefen: Our studies have shown that an area of the brain that is responsible for attention, motivation, and cognitive engagement — known as the cingulate cortex — is thicker in SuperAgers, even compared with those of people in their 50s and 60s.

In the hippocampus, the memory center of the brain, we found SuperAgers have three times fewer tau tangles when compared to their “normal” peers. Abnormal formations of tau proteins are one of the key signs of Alzheimer’s.

In Alzheimer’s disease, tau also targets the neurons of the primary neurons of the cholinergic system — which is responsible for sustaining our attention in daily life. But that doesn’t happen in the brain of a SuperAger. Therefore, the cholinergic system appears to be stronger, and likely more plastic and flexible for reasons that we’re not sure about.

That’s interesting, because I see SuperAgers as focused. They can pay close attention, engage and actively listen. How else could they recall 13 out of 15 random words after 30 minutes? I picture them engraving the words on their cortex with a chisel.

SuperAger brains also have bigger, healthier cells in the entorhinal cortex, an area essential for memory and learning, that has direct connections to the hippocampus. The entorhinal cortex, by the way, is one of the first areas of the brain to get hit by Alzheimer’s disease.

In another study we examined every layer of cells within the entorhinal cortex of SuperAgers, and we painstakingly measured the size of the neurons. We found that in layer two, which is the layer that is most important for information transmission, SuperAgers had humongous, plump, intact, beautiful, gigantic entorhinal cortex neurons.

It was an incredible finding, because their entorhinal neurons were even larger than those in individuals who are much younger, some even in their 30s. That told us there is a structural integrity component at play — like the architecture, the bones, the skeleton of the neuron itself is sturdier.

We’re expanding the studies of these neurons to understand their biochemical signatures, determine what makes them special, and see if these signatures are found in other types of neurons in the brain of SuperAgers. Are these same neurons particularly vulnerable in those with Alzheimer’s disease, and if so, how and why?

CNN: What have you learned from your research about how the brain of a SuperAger reacts to injury, disease and stress?

Gefen: We’re looking at the inflammatory system in the brain of SuperAgers, with the goal of understanding how the immune cells in their brain respond to disease and adapt to stress. Inflammation, once it crosses a certain threshold, is a major component of cell loss in Alzheimer’s disease and nearly all other neurodegenerative diseases.

Compared with the brain of same-age peers, SuperAgers have fewer activated microglia, the resident immune cells of the brain, in their white matter. White matter is the brain’s super highway, transporting information from one part of the brain to another.

Here’s how it works: Microglia are activated because there is some kind of antigen or disease, typically something destructive in the brain. In some cases, however, microglia and other immune cells become hyperactive and go into overdrive, thus causing inflammation and possible damage.

The brain of a SuperAger, however, has fewer activated microglia. In fact, the levels of microglia were on par with people in their 30s, 40s and 50s. That could mean there is less junk or disease in the brain of a SuperAger so the microglia have no need to be active. Or it could mean microglia are responding efficiently to in clearing out disease or toxins, and because they are more plastic and adaptable, the microglia are able to activate, respond and then calm down.

All of this is fascinating — it may be that at the cellular level, the immune system of a SuperAger brain could be stronger or more adaptive, much like the layers of cells we found in the entorhinal cortex.

CNN: Whether or not you were born with the right genes to protect your brain sounds like the luck of the draw. What does that mean for the future?

Gefen: Genetics are tricky. It’s not just whether you have a gene or not, it about how your internal and external environment works together to influence how a gene is “turned on,” or expressed — some may be more highly expressed, some will have lower expression. This is the epigenetic part of the puzzle.

There is a list of candidate genes that we are starting to study very carefully, these are genes that also have a role in aspects of longevity, senescence, cell repair and cognitive reserve to name a few.

I’m excited about that, not only for the genetics that are heritable from parents, but also genetics at the cell level, that enable each neuron or immune cell to carry out its respective job within the brain. With the technology that’s advancing so rapidly, I’m certain we’re going to get to a point where prevention or modification at the genetic level will be part of the playbook.

Clearly, there is not a one target resolution for Alzheimer’s disease. I know we all want that one easy fix but it’s just simply not going to happen.

It’s going to take many teams and many specialists to come together and create a kind of personalized cocktail for prevention or treatment. I think it’s possible, but it’s going to take time.

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