12 March 2012

A fresher mind

Understanding how the brain ages may hold clues to keeping our minds sharp and spry for longer.
brain ageing anti-ageing neuroscience

With each generation, medical advances and improved living conditions have ensured out bodies continue to function further into old age. Now the challenge is to keep our minds working well for longer too. Credit: iStockPhoto

It’s 1981. A frail old woman looks up as I sit down next to her and introduce myself. “Hello Mrs Pain, how are you? I’m Clare, I’m Ralph’s girlfriend.”

“Who, dear?” she asks, looking vague.

“The girlfriend of your grandson Ralph.”

“Oh yes, dear. How lovely,” she replies. “What a nice face you have. Now, tell me all about yourself.”

It’s a wonderful response, or would be, except we’ve had the same exchange more times than I care to remember. Each meeting with Ralph’s grandmother is pretty much the same. She has no memory of me, yet I’ve been part of the family for more than a year. I tell her about my day, choosing simple words and speaking slowly, emphasising the pleasant experiences. She seems to enjoy the conversation.

Mrs Pain wasn’t always like this. A doctor’s wife, she raised three children, wrote two books and was a pillar of her local town. But now, in her eighties, inside her head is a brain that’s literally shrinking. Nerve cells are dying and she is struggling to function with what remains.

Mrs Pain died in 1987, having spent her last decade confused and dependent. When her problems began, in the mid-1970s, she was diagnosed as having ‘senile dementia’. It’s a term no longer in vogue in medical circles. Today she would probably be classified as having Alzheimer’s disease (AD), and although it’s one of the most common diseases of old brains, it’s an extreme consequence of ageing. Most elderly people, nevertheless, have some decline in memory and thinking skills. Can science prevent, restrict or
even reverse this decline?

A picture is emerging that shows the effects of age are not due necessarily to the mere passage of time. Rather, they result from the accumulation of ‘insults’ caused by damage, over ‘benefits’ created by regeneration. The good news is there are simple things we can do to increase our chances of a lucid old age.

There are two key areas to work on in the quest for a better brain in later life: ‘plasticity’ and blood supply. Plasticity – a relatively recent and revolutionary concept – is the brain’s ability to modify itself in response to its environment. Michael Valenzuela of the University of New South Wales Regenerative Neuroscience Group in Sydney says it means “a person can modify their brain by choosing to do certain activities”. That’s quite an amazing thought: simply by taking up a new activity, we can actually alter our brains.

Brain plasticity occurs on many levels, Valenzuela explains. “Changes at the molecular level happen within hours of undergoing a new activity, as genes switch on or off. Then there is synaptic plasticity, where changes occur at the cellular level with nerve cells making stronger or weaker connections with each other. That takes days or weeks. Finally there is neurogenesis – the birth of new brain cells – in the two neurogenic niches. That takes weeks.”

Neurogenesis is somewhat of a buzzword in brain science. For most of the 20th century, research was handcuffed by the dogma that you were born with a certain number of nerve cells and that was it – for life. The brain was regarded as static. Then in the early 1990s, mounting evidence that two specialised parts of the adult brain were able to generate new nerve cells (neural stem cells) began to be accepted.

Scientists used to think the deterioration found in old brains was due to the death of nerve cells. It’s now thought the loss of synaptic connections between nerve cells matters more. Studies are showing that, to retain the quality of our thinking and memory, we need to keep our brains plastic.

The question is how? The brain responds plastically to stimulation, and this can come from physical and mental exercise and social interaction.

Brain plasticity also requires good nutrition from a diet including essential vitamins, minerals and fatty acids (especially omega-3 fatty acids, found in oily fish and flax seed oil). Antioxidants found in berries and vegetables also seem to be valuable.

Our knowledge of neurogenesis comes mainly from mice studies. In 2009, neuroscientist Daniel Blackmore discovered that exercise can make a big difference to the usually dramatic decline in the number of neural stem cells as mice age.

“No one had looked at the ageing brain,” says Blackmore, from the Queensland Brain Institute at the University of Queensland. “We looked at the whole age process – mice from two months to 26 months – roughly like looking at an 80-year-old human. We showed that there was a massive decrease in the stem cells with age. By 26 months there was only 10-20% of the original cohort.

“In our experiments we found exercise could bring a one-year-old mouse’s
stem cell numbers back to the level of a six-month-old, and an 18-month-old’s back to the level of a one-year-old. It really did almost reverse the ageing process,” he says. “That’s exciting. If we can activate more stem cells in the ageing brain then hopefully we can improve memory.”

But why are fewer neural stem cells made as mice age? A somewhat macabre, but telling, experiment reported in Nature in September 2011 may hold a clue. Pairs of old and young mice were surgically joined along one side. After the operation their skin fused together, and their blood vessels became intimately connected. The result: an old and a young mouse sharing the same blood supply, with their hearts pumping mingled blood around their bodies. The researchers weren’t trying to make a monster. They were attempting to determine whether there are things in the blood that can make the brain age.

Saul Villeda, a Stanford University doctoral student and lead author of the study, couldn’t believe his luck when he later counted the neural stem cells in the mouse brains. A young mouse would normally have some 20,000 neural stem cells. After six weeks of exposure to the blood from an old mouse, they had only 16,000 – a 20% decline.

Aware that something in the old mice’s blood was ‘ageing’ the brains of young mice, Villeda screened for potential culprits. He narrowed it down to six candidates – all substances that tend to increase in the blood with time. Villeda has only looked at one so far, called CCL11. “I thought it was really curious that CCL11 turned up because it’s normally related to asthma”, says Villeda. “I thought ‘This is so weird, why would it be having an effect on the brain?’”

Through a carefully orchestrated series of experiments, Villeda showed that CCL11 is indeed a brain-ageing agent. It’s an exciting discovery, but Villeda thinks it’s just the beginning and that CCL11 may turn out to affect many more aspects of brain function than just neurogenesis. So, could there be several substances in the blood of old mice that damage the brain? “Absolutely. We only looked at a very small window. CCL11 has been a ‘proof of principle’ that changes in the blood can really affect the brain. There are probably lots of other factors and, taken all together, these factors could have really huge effects.”

If there are brain-ageing factors in the blood of old mice, are there similarly ‘brain-rejuvenating’ factors in that of young mice? When Villeda examined the brains of the old mice in the surgically joined pairs, he found their stem cell numbers had increased, apparently from the circulating younger blood. Admittedly, the increase was only from 350 to about 900 cells – paltry compared to the 20,000 in a young mouse’s brain – but it was a three-fold increase in just six weeks.

Spurred on by the thought of identifying rejuvenating factors, Villeda plans to do the reverse of what he’s done so far. “We are taking blood plasma from a young mouse and injecting it into old mice to see whether it works the other way round.” He prefers to call the rejuvenating factors he’s seeking ‘pro-neurogenic’ factors, which are at higher levels in young mouse blood. He has several potential candidates already.

How much of this can be extrapolated from mice to men? One encouraging point is that CCL11 is found in human blood and cerebrospinal fluid, and it increases with time just as it does in mice. On the other hand, some scientists, such as Valenzuela, are doubtful about whether neurogenesis plays as significant a role in human brain ageing as it appears to in mice.

“Ninety-nine per cent of what we know about neurogenesis is based on research in rats and mice,” says Valenzuela. “We really have no idea whether it is of functional significance in humans. There are an astonishingly small number of these cells. Whether these incredibly rare neurons have an important impact on the whole human brain remains to be seen.”

In humans, whether it’s neurogenesis or other aspects of brain function and activity that matter, plasticity does seem to be important for memory and thinking.

To measure the effects in people, Valenzuela and others are running a study called SMART that is following 100 older people at risk for Alzheimer’s, the disease that poor Mrs Pain suffered from. The participants are doing callisthenics, strengthening exercises and mental tasks that challenge their brains. The aim is to see whether their thinking skills and memories improve and if they go on to develop AD. By following the changes in their brains using neuro-imaging, Valenzuela thinks the study may reveal aspects of plasticity in the human brain.

The other crucial factor in warding off AD is for your brain to have healthy blood vessels. Most of your several hundred billion nerve cells are as old as you are and, although they’re pretty tough overall, nerve cells are very sensitive to low oxygen levels and will die rapidly if their blood supply is interrupted.

Valenzuela, who has written a book called Maintain Your Brain, emphasises that brain and heart health are one and the same. One of the key things we can do for our brains is to try to avoid having a stroke – a potential cause of massive cell death in the affected area. Strokes spell death for the nerve cells normally supplied with oxygen by that vessel.

If the vessel involved is one of the major arteries that feed a large portion of the brain, the likely outcomes are death or severe brain damage. If the cause is a clot, a stroke can be thought of as a ‘brain attack’: like a heart attack, but happening in the brain. This means that all the things that promote heart health will help prevent strokes, too. What’s less well known is that, for stroke survivors, the ensuing months often involve a creeping decline in attention and cognitive skills even in areas of the brain that weren’t damaged by the initial stroke. It’s known as vascular dementia, it’s progressive, and its causes are not well understood.

Frail old Mrs Pain, who was in the middle stages of AD, provides a disturbing glimpse of the future. The disease is becoming more common as we live longer because the odds of developing it increase substantially with age. While a person aged between 60 and 65 has only a 2.5% chance of having AD, about 25% of people between 80 and 85 have it, and 50% of people over 90. This means many of us will face AD, either first-hand, or through the experiences of a close family member: eking out the final stages of life in a state of confusion.

Valenzuela sees AD becoming a huge financial burden to society in years to come. And support and advocacy group Alzheimer’s Australia predicts that, unless some breakthrough is made, by the 2060s spending on dementia will outstrip spending on any other health condition.

Karen Cullen, a neuro-anatomist at the University of Sydney, sees AD like heart disease. “We’ll all probably get a little bit of heart disease, but not everyone gets it to the extent that it impacts on your quality of life. AD might be connected with a general process that we all will suffer to some extent, but only some of us will go on to show the symptoms.”

Certainly some physical process is going on, as the brains of patients with AD look very different to healthy brains. Firstly, they shrink as brain cells die and, in severe cases, parts of an AD brain may have only 50% of the cells of a normal brain. AD-affected brains also form thousands of clumps of a protein called beta amyloid, known as amyloid plaques, and many nerve cells show peculiar knotted structures called neurofibrillary tangles.

For decades, much of AD research has centred on the amyloid plaques and the neurofibrillary tangles as the cause of the disease. But the crucial question is whether the amyloid plaques are a cause or consequence. Cullen says you can look at AD like a crime investigation: are the plaques the smoking gun or simply bloodstains on the carpet?

Valenzuela’s view about a link between heart and brain health fits well with an underlying theory implicating brain blood vessel damage in AD. He thinks it’s an important clue that all the factors that promote a healthy heart also reduce the risk of AD. “If you want to reduce your risk of getting dementia, go and have your blood pressure checked,” he advises. “If it is above the normal range, take steps to bring it down.” He points out that the only large-scale randomised clinical trial that has shown evidence of prevention of AD using a medication of any sort has come from a study of drugs that reduce blood pressure.

Cullen, too, thinks blood vessels are the crux of the issue. While studying the detailed anatomy of human brains during her PhD, she couldn’t help noticing a pattern in the brains of people who had died of AD. “It was just too obvious to me: the amyloid plaques were always near the blood vessels.”

In 2005 she and her team painstakingly demonstrated that post-mortem human AD brains show evidence of multiple ‘microbleeds’ (tiny haemorrhages) from capillaries and other blood vessels. They went on to show that the amyloid plaques occur next to the microbleeds far more often than would be expected by chance.

The question is: which comes first, the microbleed or the amyloid deposit? Cullen favours the ‘blood on the carpet’ view of amyloid and believes the bleed usually comes first, but says that when using post-mortem brains, the question can’t be properly answered. Suggestions that blood vessels are involved in AD have surfaced occasionally, but until recently, the theory was actively discouraged. Many AD researchers still see it as highly contentious. Cullen says her ideas have been frankly ridiculed in the past and she tells of journal articles being curtly rejected in the 1990s. A definition of AD that specifically precluded it from being diagnosed after stroke hasn’t helped.

“I see Alzheimer’s disease as being caused by lots of little blood vessel leaks – it’s as simple as that,” says Cullen. When you multiply this by tens of thousands over the longer term, effects start to show. “AD dementia is almost certainly due to a collection of mechanisms that significantly accelerate the leakiness,” adds Cullen.

One of the factors accelerating the leakiness may be beta amyloid itself.
Two years before Cullen was looking at leaks in human brains, Wilf Jefferies of the University of British Columbia in Canada was investigating ‘transgenic’ mice that produce far too much beta amyloid throughout their bodies. It’s a well-known animal model of the disease, incorporating an aberrant gene found in the inherited form of human AD. Jefferies’ discovery was that the excess beta amyloid in the blood of the mice was making their brain capillaries leak.

Furthermore, he found that the leaky capillaries appear in the mice very early, long before they show symptoms of AD and before amyloid plaques develop in the brain. In transgenic mice, at least, it seems the leaks precede the plaques.

Brain capillaries are unusual in that their cells are joined by ‘tight junctions’, which prevent many substances from entering or leaving the vessel. This arrangement constitutes the ‘blood-brain barrier’ (BBB). If the BBB becomes leaky, potentially toxic molecules can reach and damage nerve cells.

In Jefferies’ latest study, reported in the journal PLoS One in August 2011, he describes finding unusually high densities of blood vessels in his AD mice and in human AD post-mortem brains, suggesting that new blood vessels are being made. He favours a ‘smoking gun’ view of beta amyloid and thinks it causes increased blood vessel growth.

“We find that there’s a higher density of blood vessels in AD patients as well as in animal models of AD.” He believes the unusual blood vessel growth explains the increased leakiness. “It’s known that when blood vessel cells proliferate, the tight junctions are reorganised. There are similar specialised blood vessels in the testes and in the eye that behave in a similar way.”

He mentions an intriguing parallel with another disease of old age – macular degeneration of the eye – where unusual vessel growth resulting in increased vessel permeability and consequent disease has also been reported.

Neither scientist was aware of the other’s work – which illustrates the almost impossible task of keeping up with the vast flow of published research. The debate on the causes of AD is likely to rage for some time. “Scratch the surface in AD research and find a can of worms the size of Sydney Harbour,” says Cullen. But, even though there is no clear consensus yet on the causes, Valenzuela believes the actions we must take to try to avoid AD are simple and clear, and conveniently, they overlap with what is needed to encourage brain plasticity.

Experiments such as Villeda’s monster mice may eventually lead to drugs that block brain-ageing agents. We may find ways to take the neural stem cell levels of 80-year-olds back to what they had at 20.

In the future, we may routinely use brain ‘rejuvenation factors’ to keep our brains young. The debate about the causes of AD will one day be resolved. But we are a long way from this now. While we’re waiting, there are already simple steps we can take to improve our chances of a mind that continues working well in old age.

Perhaps it would be helpful to replace the word ‘ageing’ with ‘damaging’ in our minds. It’s probably not the mere passage of time, but the accumulation of damage, that is harming our brains as we get older. That means we can act to limit the damage right now – looking after our brain’s blood vessels with physical exercise, a healthy diet and by keeping our blood pressure low.

Even more encouraging, simply by taking mental and physical exercise – doing crosswords, playing board games with friends, dancing or learning something new – we can actually make our brains regenerate. It might not take a scientific breakthrough to protect your brain, but simply the discipline to stay fit and to keep on learning.

Clare Pain is a freelance writer based in Sydney.

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