Lost your keys lately? Forgotten where you parked your car? Can’t quite summon up that word you want to use? Our thinking abilities tend to peak as early as our 20s or 30s and then, in the decades that follow, brain power heads into a slow decline. From age 60, it can fall more precipitously as the brain continues shrinking. Beyond 80, the cracks really start to show – as President Joe Biden seems to be finding out – and it may become more obvious that we are not performing cognitively as we used to.
For a long time, this was accepted as the normal ageing trajectory. What science has now proved is that it doesn’t have to be that way. Some people are different. Their brains don’t suffer the same degree of shrinkage and they remain mentally sharp even when very elderly.
Neuroscientist Emily Rogalski is leading efforts to understand why. For more than a decade, she and a team of researchers have been studying a group of people they define as super-agers, looking inside their brains and probing how they live their lives.
“Super-agers are individuals who are over 80 and have a memory performance at least as good as people in their 50s and 60s,” says Rogalski, a professor of neurology at the University of Chicago.
Finding super-agers to participate in her research has proved challenging. Fewer than 10% of the people they screen have a memory performance that is considered good enough. So far, 500 individuals have been enrolled in the study – the oldest living super-ager just turned 110 – and some have donated their brains to be further investigated after death.
“One thing we’ve noticed is that super-agers tend to carry on living,” says Rogalski, whose work focuses mainly on cognitive testing and brain imaging with participants. “My part of the study is going really well because people keep coming back. Whereas my colleagues who focus on the neuropathology are having to be more patient.”
In the past, most research on ageing brains has been concerned with what is going wrong with people suffering from dementia. Rogalski is much more interested in what is going right in the brains of super-agers. Using MRI scans to take 3D images, she is starting to find out.
She says, “We’re able to measure things like the volume and thickness of the brain. In general, our brains shrink across the decades, especially the outer layer – the cortex – where our brain cells live. That shrinkage is associated with changes in our thinking ability. What we see is that the super-agers’ brains look more like those of 50- or 60-year-olds. They show no significant thinning in comparison, despite the age difference. They even show a region that is thicker, the anterior cingulate, which we know is really important for attention. And attention supports memory – you have to be paying attention to something in order to remember it.”
Studying super-agers over time has confirmed that they do have a slower rate of brain atrophy or thinning during the course of their long lives. And later, when their brains are examined under a microscope, scientists find more differences. These people have an abundance of the spindle-shaped brain cells called von Economo neurons, which are found only in humans and other highly social species such as elephants, dolphins and apes.
Brain size seems to be the main thing super-agers have in common. Participants wear sensors that track their activity, social interaction and sleep, plus share information about diet and lifestyle. And what is most striking is all the many ways they differ.
She says, “For example, we don’t see that the super-agers all eat a perfect Mediterranean diet. And there are some who exercise quite a bit, while others have never exercised, or only very minimally.”
Among the super-agers, there is no shortage of smokers, which perhaps reflects levels of tobacco use common in that generation. Drinking is widely variable – some have never had alcohol and others are convinced that part of their secret to ageing well is enjoying a cocktail every day at 5pm.
The number and types of medications super-agers take have been assessed and they aren’t any different from other cognitively average elderly people. Education doesn’t seem to be a factor. And neither have all the super-agers been blessed with easy, trouble-free lives.
“We’ve had some people who have reported living in poverty,” says Rogalski. “A few are Holocaust survivors. One woman was in a concentration camp and everyone in her family died, apart from a sister who had been sent away to London. Others have lost children at a young age due to tragic accidents, or lost spouses.”
It is likely there are genetic factors to explain why these people are living so well, but even that isn’t straightforward. Some super-agers carry the APOE4 gene variant, a red flag for Alzheimer’s disease. Nevertheless, they still have exceptional cognitive performance. So, how are they escaping their high risk? Rogalski believes there must be some other protective factor that is downregulating and keeping that risk at bay.
One thing that super-agers do have in common is that they tend to be extremely social, and have strong, positive relationships.
“Many of them are still working, and if they’re not, then they’re active in the community, volunteering or running non-profit organisations or are very engaged in their hobbies,” says Rogalski, who on the day we speak has been having trouble scheduling a catch-up session with one participant who has pickleball commitments.
This tallies with findings in the Blue Zones – regions around the world where people are living longer and healthier lives. The regions include Okinawa in Japan, Sardinia in Italy, Icaria in Greece; and a Seventh-day Adventist settlement in Loma Linda, southern California. In these locales, having a sense of purpose, strong relationships with others and belonging to a community have been identified as key factors in longevity.
And there is certainly evidence that poor mental health is tied to long-term risks of dementia. The latest research, Australia’s Hunter Community Study, followed more than 2000 people over 10 years and found that chronic anxiety significantly increases dementia risks, particularly when it begins before the age of 70.
However, there is a big chicken-and-egg question. Are the brains of super-agers healthier because they are so social? Or might it be that all those extra von Economo neurons they’ve been blessed with are resulting in their having stronger relationships in the first place?
Although she doesn’t have an answer to that question, Rogalski still believes it is helpful to know how connected these individuals are.
“We can’t inject anything to make our brains plumper, but we can control our social interactions. It’s a relatively easy thing to call your best friend or find a connection with others,” she says.
Resilience and curiosity
Spending time with super-agers is one of the joys of her work. “Their stories, their resilience and curiosity, the approach they have to life, they have a vibrance.”
Some participants were keen to connect with one another, so there have been super-ager parties and one group gets together every month.
“A few weeks ago, a super-ager celebrated his 84th birthday and it just so happens that he’s been leading tours on a double-decker bus for the past 18 years, so he invited the other super-agers to come along, and that was a lot of fun,” says Rogalski.
The next step of her research is to go beyond the brain and analyse whether there is something else going on with these people that helps explain their enduring cognitive performance.
“We’re examining blood samples to look for inflammatory and immunologic biomarkers that can sometimes reflect brain health but can also reflect the health of other parts of our systems,” says Rogalski, who now heads the University of Chicago Healthy Aging & Alzheimer’s Research Care Centre. “The goal is to gather as much multidisciplinary information as possible. We want to understand the protective factors and how they might work together. It would be silly to think it was just one thing that got them there. It’s not going to be the 10 blueberries they ate every day.”
What seems most likely is that there are different pathways to becoming a super-ager. Some day, we may have a personalised system of longevity medicine, assessing each person’s risks and keeping them on their optimum pathway using a combination of lifestyle interventions and medicine. But science just isn’t there yet.
Rogalski says, “Every time we see something interesting, it opens a box to a whole series of new investigations that need to happen, so the answer is not going to come tomorrow. Still, I’m feeling optimistic while fully recognising that there is no shortage of things to be done.”
Traditionally, elderly people have been under-researched, so she is encouraged by the increased investment being directed towards healthy ageing. Globally, scores of scientists are exploring how and why we age, with the ultimate goal of finding ways to slow or even reverse it.
Auckland biotechnologist and author Greg Macpherson has travelled the world meeting and interviewing some of the leading longevity experts and this month published a book Age Less: The New Science of Slower and Healthier Ageing (Upstart Press, $39.99).
What sent Macpherson, 54, deep down the longevity rabbit hole was coming across a 2013 paper by Spanish researchers called “The Hallmarks of Ageing”. Another driver was that his father died at 51, so he really wanted to understand what he could do to slow his own ageing process. While busy on his research, the original nine hallmarks have been expanded to 12 (see side bar).
We are programmed to age in ways that are complex and interconnected, probably for reasons that are evolutionary. Macpherson hopes that at some point science will put the whole puzzle together and identify one upstream master switch that can be flipped to turn off the process. In the meantime, the war on ageing involves attacking it from different directions.
Repurposed drugs seem likely to be the first geroprotective treatments off the block, in particular an immunosuppressant called rapamycin, which has been shown to extend the lifespan of mice by acting on the mTOR signalling pathway that is involved in cell growth and metabolism – basically, it mimics calorie restriction. A common type 2 diabetes drug, metformin, is also being explored for its potential to reduce the risk of other age-related diseases.
An early adopter, Macpherson already takes both drugs as part of his “ageing hygiene” practice.
He also undergoes week-long fasts two or three times a year, meditates to manage stress, eats and sleeps well, stays as active as possible and takes supplements to support cellular health – he has developed his own range of formulas, marketed under the brand SRW (Science Research Wellness laboratories).
“I’m not perfect, I’m a work in progress,” he says. “Probably, I should enjoy less red wine, but I do enjoy it. And as I have Crohn’s [an inflammatory bowel disease], which has a fatigue element to it, exercising is a constant challenge.”
Longevity habits
While we are waiting for the sort of personalised prescription that will tell us precisely which longevity therapies and lifestyle measures will reduce our individual risk of age-related disease, Macpherson believes we can still start work on slowing our biological clocks.
Originally a pharmacist who founded the online Pharmacy Direct, he advises starting early and establishing good longevity habits in childhood. He also advocates what he calls “the longevity-focused work week”, structured to give people enough time for activity programmes to improve health and increase lifespan.
He says, “If governments and employers would get on board and we could just give people an hour and a half off at midday to go for a bike ride or a swim or do yoga, they would be healthier and more motivated. The benefits would be huge. When you want to attract a new employee, you could focus on this element. They’re not only going to get a great job and a good income, but also, they’ll come out of it with five to 10 years longer [in lifespan] as well.”
How well we are ageing is rapidly becoming more measurable. Last year, scientists at Stanford University in California revealed they had developed a test that could determine the age of a person’s organs by examining proteins in the blood. There are already a variety of other tests you can order online to measure biological age, and these are popular with biohackers.
Recently on reality TV show The Kardashians, some members of the family took the TruDiagnostic blood test to measure their pace of ageing. This uses a set of epigenetic markers and was based on an algorithm from the longitudinal Dunedin Multidisciplinary Health and Development Study (apparently, Kim is ageing 18% slower than others her age, and Khloe 28% slower)
Recently, researchers at TruDiagnostic and Stanford Prevention Research Center used biological age-testing methods in a twin study looking at the epigenetic impact of vegan versus omnivorous diets. Each of the 21 pairs of identical twins ate either an entirely plant-based diet or a healthy one that included animal products, for eight weeks. The vegans were found to have significantly less epigenetic age acceleration.
While there is debate about how worthwhile some of these age-measuring products are, Macpherson believes they are useful as motivators – his SRW company sells an at-home DNA saliva test that assesses cellular health.
“It’s nascent science, but it can give a really interesting insight into where you’re going. If you’re ageing biologically a bit faster, you might want to look at what behaviours you can change or what supplements you can take to slow it down,” he says. “Adopting a longevity mindset and strategy right now is hopefully going to get us to the point where we’re still around to benefit from some of these new technologies that are coming through.”
One technology that interests Macpherson is hyperbaric oxygen therapy, and he was particularly inspired by his interview with Israeli scientist Shai Efrati, whose studies have explored its impact on a range of conditions, including age-related cognitive decline.
“He’s worked out that you can trick the body into growing longer telomeres by inducing fluctuations in oxygen levels,” explains Macpherson.
“It pushes the body into stimulating repair mechanisms, because it thinks we’re under pressure.”
Other scientists are focused on eliminating senescent cells, repairing DNA or filtering aged blood to make it young again, without any harmful side effects. In a relatively short time, researchers have moved from longevity experiments with nematode worms and yeasts, to mammals and now increasingly humans as they seek to stop age-related disease in its tracks.
Says Macpherson, “These are exciting times to be living in. We know that we can slow ageing. It’s just a matter of translating the science into therapies and lifestyle changes. And I think younger people are starting to wake up to this and think about ageing well. I’m excited for that generation because they will probably reach their 80s and still be in really good health.”
An attitude rethink
As we learn more about what gives super-agers and Blue Zone inhabitants many more healthy years of life, there will likely be many more active old people around. Then society might have to seriously rethink its attitude towards being elderly.
“Ageism is a big deal,” says Macpherson. “We need to stop telling people that they can’t do things because they’re too old. We’ve got to separate ageing from disease.”
Emily Rogalski is of much the same mind. Her time spent with the super-agers has only deepened her conviction that we should value the contribution seniors can make. She cites a pioneering mental health programme in Zimbabwe, where there has been a lack of help for people suffering from depression. Psychiatrist Dixon Chibanda and his team trained hundreds of grandmothers to use a cognitive behavioural therapy-based approach.
The Friendship Bench, as the voluntary programme is called, has since helped thousands of people. Chibanda’s dream is of a global network of grandmothers helping their communities.
Says Rogalski, “That’s a glowing example of how you can value your older adults instead of looking at them as an economic drain on society. We have a tendency to have a huge amount of stigma around ageing and much lower expectations of the elderly. The longer we do that, the more likelihood that we lean into it.
“Then the first time we forget our keys or where we parked the car, we say, ‘Oh my goodness, I might just be getting old,’ instead of thinking that we were talking on the phone when we parked the car and doing a million other things and it’s not that our brain is broken, but we might just need to pay more attention.”
Rogalski doesn’t know if her own brain is ageing well but she believes that spending time with the super-agers and soaking up their outlook on life can’t be doing her any harm.
“What I hope is that if I just hang out with them for long enough that it will increase my odds.”
What are the 12 hallmarks of ageing?
Genomic instability – Accumulation of damage to our DNA over time.
Telomere attrition – The shortening of the protective caps at the ends of our chromosomes, which leads to a point where cells can no longer replicate.
Epigenetic alterations – The changes in the way our DNA works that may be influenced by environment and lifestyle and can lead to disorders.
Loss of proteostasis – The accumulation of damaged or misfolded proteins that is seen in neuro-degenerative diseases, such as Alzheimer’s.
Disabled macroautophagy – The body becomes less efficient at cleaning out and recycling the components of damaged cells and these accumulate, affecting cell function.
Deregulated nutrient sensing – The body’s ability to detect and respond to nutrients from food is disrupted.
Mitochondrial dysfunction – The powerhouses of our cells become less efficient at producing the energy the cells need to function.
Cellular senescence – Cells lose the ability to divide, but remain active. As these accumulate, they promote inflammation and damage surrounding tissues.
Stem cell exhaustion – Stem cells play an important role in regeneration and repair. As they decline, they start losing their ability to maintain the body’s tissues and organs.
Altered intercellular communication – Ageing cells change the way they communicate with each other, leading to a range of problems, including a weakening of the immune system’s ability to fight off disease.
Chronic inflammation – The immune system doesn’t efficiently switch off its response, causing widespread inflammation and eventually creating damage.
Dysbiosis – The balance of the gut microbiome changes.
(Research led by Carlos López-Otín and published in Cell magazine, 2023.)