An analysis of a quarter-century of SuperAger study – someone who is 80 or more but has the memory capacity of a person at least 20 or 30 years younger – has suggested that these people’s brains might be built differently, said the researchers.
Nearly 300 people have participated in the Northwestern University SuperAgeing Programme (NUSAP) since 2000, which has offered scientists interesting insights, reports NBC News.
One of the participants is Sel Yackley, who is a busy woman. She makes jewellery, sings in a choir and knits hats and scarves for the homeless. She also reads with her book club, goes to the gym a few times a week and is active in several civic organisations.
According to her Fitbit, she still manages to sleep an average of 7½ hours a night.
At 85, Yackley is one of the “SuperAgers”: someone who is 80 or older and retains the memory capacity, based on delayed word recall testing, of a person at least two to three decades younger.
Dr Marsel Mesulam, who founded the Mesulam Centre for Cognitive Neurology and Alzheimer’s Disease at the Northwestern University Feinberg School of Medicine in the late 1990s, first defined a SuperAger.
Recently, Mesulam Centre researchers reflected on 25 years of SuperAger study in an analysis published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.
Yackley, who is among the nearly 300 people who have participated in the NUSAP since 2000, is proof that impaired memory isn’t always a hallmark of ageing.
“We are going to be role models for other people who are getting older,” she said. “Take good care of your health and eat right and be sociable.”
Is SuperAgeing genetic?
Yackley acknowledges that genetic factors may be contributing to her youthful cognition. Her mother and father lived to be 86 and 88, respectively. On the other hand, she also feels her joie de vivre helps keep her mind sharp.
“I think it’s partly your determination to live a long life and your activities that enable you to do so,” she said, encouraging older adults to pursue “things that make you proud.”
Yackley’s peers in the SuperAger programme share a spirit of connection, according to Tamar Gefen, a co-author of the analysis and an associate Professor of Psychiatry and Behavioural Sciences at the Feinberg School.
“I don’t know if it’s necessarily social connections, it’s just connections in general,” Gefen said. “There are people who are connected to the land, there are people who are connected to their ancestry, people who are connected to their grandchildren, who are connected to their art.”
Gefen added: “You don’t see a lot of detached SuperAgers.”
That said, people can’t simply will themselves into “superageing”.
At 45, the lifetime risk of developing Alzheimer’s is one in five for women and one in 10 for men. SuperAgers are defying these odds.
“Genetics is a part of it, definitely,” Gefen said. “We know that there are major risk genes for Alzheimer’s disease, and SuperAgers don’t have those genes.”
For example, research has shown that people of European descent with two copies of a gene called APOE4 have a 60% chance of developing Alzheimer’s by 85.
“My interest is, are there genes that SuperAgers harbour that can actually protect them against getting Alzheimer’s?” Gefen said. “And is there a gene, let’s say that’s related to the immune system, that is over-expressed in SuperAgers that can be manipulated to then help individuals protect themselves?”
As she continues searching for such answers, Gefen said her team’s most exciting findings have stemmed from the brains of SuperAgers who have died.
SuperAgers’ brains may be built differently
Gefen and her colleagues have autopsied nearly 80 SuperAger brains and compared them with those of their “neurotypical” peers.
They focused on two indicators of Alzheimer’s: protein build-ups in the brain (amyloid plaques) and tau tangles.
“What we found in memory centres of the SuperAgeing brain is that there are far fewer tau tangles,” Gefen said. “But interestingly, amyloid or plaque pathology doesn’t really differ a whole lot.”
Because a number of Alzheimer’s treatments single out amyloid plaques, SuperAgers bring such treatment methods into question.
Gefen said: “Are we really targeting the right target if SuperAgers and their peers have similar amounts of amyloid?”
Other findings include that SuperAgers tend to have larger entorhinal neurons, which are nerve cells that are key to memory, and more von Economo neurons, which are nerve cells critical to social behaviour.
“Our guess is that (SuperAgers) are probably born with these kinds of structural protections,” Gefen said. “But we’re now going really deep into the molecular mechanisms of the cell to figure out what is keeping that cell strong.”
Dr Timothy Chang, who wasn’t involved in the SuperAger research, works on the opposite end of the spectrum. An assistant Professor of Neurology at the Mary S Easton Centre for Alzheimer’s Research and Care at UCLA, Chang studies and sees patients who have dementia.
“Those cases are really interesting,” he said. “They can teach us a lot about how, potentially, those people, based on genetics or other lifestyle factors, were able to avoid the disease.”
Though the prevalence of SuperAgers is unclear, they appear to be uncommon. Gefen and her co-authors noted that during the initial recruitment of study participants, just 10% met the criteria of SuperAgers.
Today, 101 SuperAgers ranging in age from 81 to 111 are actively involved in Mesulam Centre research.
Not all SuperAgers prioritise their health – on the contrary, some defiantly savour their vices – and many have lived difficult lives, Gefen said. But they don’t take their cognitive fitness for granted.
It’s all in the blood…
While SuperAgers, as such, are a smaller group, centenarians – once considered rare – have become commonplace. Indeed, they are the fastest-growing demographic group of the world’s population, with numbers roughly doubling every 10 years since the 1970s, and scientists say the blood of exceptionally long-lived people suggests some key differences.
Now, Swedish research – comparing biomarker profiles measured throughout life among exceptionally long-lived people and their shorter-lived peers – has unveiled some common biomarkers, including levels of cholesterol and glucose, in people who live past 90.
Epidemiologist Karin Modig writes in The Conversation that how long humans can live, and what determines a long and healthy life, have long been of interest, but the pursuit of understanding the secrets behind exceptional longevity isn’t easy, however.
It involves unravelling the complex interplay of genetic predisposition and lifestyle factors and how they interact throughout a person’s life.
She writes:
Nonagenarians and centenarians have long been of intense interest to scientists as they may help us understand how to live longer, and perhaps also how to age in better health.
So far, however, studies of centenarians have often been small scale and focused on a selected group, for example, excluding centenarians who live in care homes.
Huge dataset
We compared the biomarker profiles of people who went on to live past 100, and their shorter-lived peers, and investigated the link between the profiles and the chance of becoming a centenarian.
Our research included data from 44 000 Swedes who underwent health assessments at ages 64 to 99 – they were a sample of the so-called Amoris cohort.
These participants were then followed through Swedish register data for up to 35 years. Of these people, 1 224, or 2.7%, lived to be 100-years-old. The vast majority (85%) of the centenarians were female.
Twelve blood-based biomarkers related to inflammation, metabolism, liver and kidney function, as well as potential malnutrition and anaemia, were included. All of these have been associated with ageing or mortality in previous studies.
The biomarker related to inflammation was uric acid – a waste product in the body caused by the digestion of certain foods.
We also looked at markers linked to metabolic status and function including total cholesterol and glucose, and ones related to liver function, such as alanine aminotransferase (Alat), aspartate aminotransferase (Asat), albumin, gamma-glutamyl transferase (GGT), alkaline phosphatase (Alp) and lactate dehydrogenase (LD).
We also looked at creatinine, which is linked to kidney function, and iron and total iron-binding capacity (TIBC), which is linked to anaemia. Finally, we also investigated albumin, a biomarker associated with nutrition.
Findings
We found that, on the whole, those who made it to their 100th birthday tended to have lower levels of glucose, creatinine and uric acid from their 60s onwards.
Although the median values didn’t differ significantly between centenarians and non-centenarians for most biomarkers, centenarians seldom displayed extremely high or low values.
For example, very few of the centenarians had a glucose level above 6.5 mmol/L earlier in life, or a creatinine level above 125 µmol/L.
For many of the biomarkers, both centenarians and non-centenarians had values outside the range considered normal in clinical guidelines.
This is probably because these guidelines are set based on a younger and healthier population.
When exploring which biomarkers were linked to the likelihood of reaching 100, we found that all but two (alat and albumin) of the 12 biomarkers showed a connection to the likelihood of turning 100. This was even after accounting for age, sex and disease burden.
The people in the lowest out of five groups for levels of total cholesterol and iron had a lower chance of reaching 100 years than those with higher levels.
Meanwhile, people with higher levels of glucose, creatinine, uric acid and markers for liver function also decreased the chance of becoming a centenarian.
In absolute terms, the differences were rather small for some of the biomarkers, while for others the differences were somewhat more substantial.
For uric acid, for instance, the absolute difference was 2.5 percentage points. This means that people in the group with the lowest uric acid had a 4% chance of turning 100 while in the group with the highest uric acid levels only 1.5% made it to age 100.
Even if the differences we discovered were overall rather small, they suggest a potential link between metabolic health, nutrition and exceptional longevity.
The study, however, does not allow any conclusions about which lifestyle factors or genes are responsible for the biomarker values.
However, it is reasonable to think that factors such as nutrition and alcohol intake play a role.
Keeping track of your kidney and liver values, as well as glucose and uric acid as you get older, is probably not a bad idea.
That said, chance probably plays a role at some point in reaching an exceptional age. But the fact that differences in biomarkers could be observed a long time before death suggests that genes and lifestyle may also play a role.
Karin Modig – Associate Professor, Epidemiology, Karolinska Institutet
Study details
The first 25 years of the Northwestern University SuperAgeing Programme
Sandra Weintraub, Tamar Gefen, Changiz Geula, M-Marsel Mesulam.
Published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association on 7 August 2025
Abstract
During late life, “average” does not mean “intact.” For example, cross-sectional data from a common word list learning test show that average delayed word recall raw score at age 80 (5/15) is approximately half that at age 56 to 66 (9/15). Cognitive and neurobiological dissolution is therefore implicitly incorporated into concepts of the ageing brain. This position is being challenged through investigations on “superageing”, a term that was coined at the Northwestern Alzheimer's Disease Research Centre (ADRC) to define persons ≥ 80 years with delayed word recall raw scores at least equal to those of individuals 20 to 30 years younger. During the first 25 years of this programme we established that superagers constitute not only a neuropsychological but also a neurobiological phenotype distinctive from cognitively average age peers. With respect to brain structure, superagers have cortical volumes no different than neurotypical adults 20 to 30 years younger in contrast to neurotypical peers who do show such age-related shrinkage; they also have a region in the cingulate gyrus that is thicker than younger neurotypical adults. With respect to cellular biology, superagers have fewer Alzheimer's disease–type changes in the brain, greater size of entorhinal neurons, fewer inflammatory microglia in white matter, better preserved cholinergic innervation, and a greater density of evolutionarily progressive von Economo neurons. In the future, deeper characterisation of the superageing phenotype may lead to interventions that enhance resistance and resilience to involutional changes considered part of average (i.e., “normal”) brain ageing. This line of work is helping to revise common misperceptions about the cognitive potential of senescence and has inspired investigations throughout the United States and abroad.
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