摘要：The discovery that faulty metabolism is at the root of many brain diseases suggests a surprising transplant could be the way to protect our brains from the ravages of ageing
IF YOU own a car, you will have noticed the engine getting less efficient with time. The further you drive it, the more fuel it takes to make the same journey – until, eventually, it becomes so underpowered that it needs a physical push to climb even a gentle hill.
Now, it is emerging that much the same is true of the human brain. Microscopic structures called mitochondria, found in every brain cell, are quite literally the engines of our thoughts and feelings. As we age, they find it harder and harder to produce sufficient energy to power our mental activities. Worse, in a similar way to an old car leaving clouds of smoke in its wake, the cell’s powerhouses start generating unwanted waste products that slowly poison our brains. This means that malfunctioning mitochondria may underlie many of the most devastating brain conditions, including Alzheimer’s, Parkinson’s, Huntington’s and motor neuron disease.
According to this “grand unified theory” of neurodegeneration, we could prolong our brain’s healthy functioning by recharging our neurons through restoration of their powerhouses. The idea is already inspiring some exciting new therapies for age-related brain conditions, with multiple drug candidates under investigation. Some researchers are even exploring the possibility of transplanting healthy mitochondria into damaged, ageing brains to re-energise them. “If you keep changing the parts of a car, it can last forever,” says Claudio Soto, a neurologist at the University of Texas Health Science Center at Houston. “So what happens if we try to do the same with the cell?” As audacious as this sounds, there are already indications that it might just work.
Neurodegeneration is an enormous health burden and, as the world’s population ages, the problem is becoming ever more serious. According to the latest estimates, around 152 million people will be living with dementia by 2050, with the major cause being Alzheimer’s disease. Parkinson’s disease, though less prevalent, is still thought to affect 1 in 37 people over their lifetime. Although some drugs can ease symptoms and slow the progression of these and certain other neurodegenerative diseases, scientists are desperately searching for a better understanding of the causes of these complex conditions.
Microscopic power plants
There is a growing realisation that mitochondria, the engines inside our cells, could be the key. Aside from the nucleus, these tiny organelles – each just a couple of micrometres in length – are the most complex element of cells. In deep evolutionary history, they are thought to have existed as independent life forms, before somehow entering bacteria and beginning a mutually beneficial relationship with them. Mitochondria’s ability to generate energy aided the evolution of the multicellular organisms, including humans, that would come to dominate Earth. Today, they are present in each of your cells – except red blood cells – with up to 2 million found in the most energetically active ones.
Like any power generator, mitochondria need fuel, in this case glucose. They use this sugar, after some initial processing in the cell’s cytoplasm, to synthesise a molecule called adenosine triphosphate (ATP) that provides useable energy for cellular processes. The brain is the hungriest of all your organs, consuming 20 per cent of the body’s energy, but comprising just 2 per cent of its mass. Neurons need a huge amount of energy to fuel electrical signalling and the constant fine-tuning of synapses, the junctions between neurons. That makes them particularly vulnerable to metabolic dysfunction. In recent decades, evidence has been growing that small disturbances in the efficiency of their mitochondria can trigger big problems.
Consider Alzheimer’s disease. It is characterised by the build-up of proteins – tangles of tau and amyloid plaques – that appear to be toxic to brain tissue. Historically, this observation has inspired multiple treatments to remove them. Yet several studies show that some people maintain normal cognitive function despite the proteins accumulating in their brains. There are lots of reasons why this might be so, but the most prominent is that these individuals have greater “cognitive reserve”, a sort of spare mental capacity that allows them to cope with more damage before showing signs of mental decline. What’s more, almost all treatments that remove plaques and tangles have failed. Despite many years of research, there is no consensus on what causes Alzheimer’s.
The possible involvement of mitochondria first came to light in the 1980s, when studies started to suggest that metabolic problems precede the build-up of the protein tangles and plaques associated with Alzheimer’s, which then disrupt energy generation further. Brain scans measuring glucose uptake, for example, show that people in the early stages of the condition have markedly slower metabolism. And post-mortem analyses of people who had Alzheimer’s reveal that their neurons have around half as many mitochondria as those of people of the same age without the disease.
Like many new ideas in science, this one has taken a while to catch on – and was probably held back by the fixation on protein accumulations as the root cause of Alzheimer’s – but the research has now reached a critical mass that is hard to ignore. “There’s now a lot of evidence from animal models and cell cultures which prove that there’s reduced mitochondrial function with Alzheimer’s disease,” says Reham Abdel-Kader at the German University in Cairo, Egypt. Adding weight to this, we have also discovered that the main gene variant known to increase the risk of Alzheimer’s, ApoE4, reduces the efficiency of mitochondria. One study, for example, found that the neurons in mice with this gene variant produced less ATP, and their memory and ability to learn were compromised.
That still leaves the question of where protein tangles and plaques come in. According to one leading idea, the stress of meeting the neuron’s energy demands causes mitochondria to start producing more waste products, which triggers the production of tau and amyloid. To make matters worse, the cell’s energy crisis may prevent a rapid clean-up of these toxic proteins. “When a cell is metabolically stressed, a lot of the non-essential functions can be slowed down, one of which is clearance of waste macromolecules,” says Yashar Kalani at the University of Virginia. Experiments suggest that these piles of garbage can damage the mitochondria, which contributes to an even greater energy crisis, setting off a vicious cycle that descends into widespread neurodegeneration. Cognitive reserve may help some people cope better with this. But if the underlying mechanism does indeed relate to metabolism, that would explain why treatments to remove plaques usually fail to improve cognition in people with Alzheimer’s symptoms.
Parkinson’s disease may emerge through similar pathways. The condition is caused by a loss of neurons producing the neurotransmitter dopamine, which is used for communication with the part of the nervous system controlling the muscles. As these neurons die and dopamine dries up, people with Parkinson’s struggle to execute precise movements. The cell loss coincides with the build-up of a protein called alpha-synuclein, which forms sticky lumps known as Lewy bodies that are usually associated with Parkinson’s. Much like the research on Alzheimer’s, multiple lines of evidence now point towards mitochondrial dysfunction as the underlying cause of these changes.
Suspicions of a link were first aroused by the observation that some people develop Parkinson’s-like symptoms following exposure to certain pesticides, such as rotenone, which are known to impair mitochondrial function. Analyses of the main genes behind hereditary cases of Parkinson’s disease bolstered this hypothesis: PINK1, parkin and LRRK2 are all involved in the health and maintenance of mitochondria and their disposal when they are no longer functioning effectively. Once again, it seems that impairments in metabolism might lead to the formation of the toxic proteins in those Lewy bodies, which could then cause further stress to the mitochondria.
Evidence of mitochondrial dysfunction in Huntington’s disease and amyotrophic lateral sclerosis (a form of motor neuron disease also known as Lou Gehrig’s disease) further supports the idea that a dwindling energy supply may be an underlying cause in most neurodegenerative conditions. And the fact that mitochondrial efficiency drops as we age neatly explains why they tend to emerge in later life.
Malfunctioning mitochondria might also help us understand why long-term inflammation – arising from stress, poor diet or a disrupted immune system – increases vulnerability to neurological illness. Research shows that certain inflammatory chemicals called cytokines impair energy generation in mitochondria and, conversely, that mitochondrial dysfunction can trigger inflammation. In other words, inflammation seems to be another cog in the vicious cycle leading to brain deterioration. This idea can also help explain why certain lifestyles appear to slow brain ageing (see “How to have a younger brain“).
Unsurprisingly, neuroscientists are already looking for ways to bolster struggling mitochondria, with the hope of preventing neurodegeneration or at least slowing its progress once it starts. They have been excited to discover that a handful of existing drugs may achieve this. One is terazosin, commonly prescribed to treat the urinary problems that arise from an enlarged prostate. It transpires that the drug also binds to an enzyme called PGK1 that is involved in breaking down glucose and producing ATP. This boosts the enzyme’s activity and hence the overall productivity of mitochondria. Two related drugs, doxazosin and alfuzosin, offer a similarly unexpected increase to energy production.
The clincher came in 2021 with the discovery that men taking one of these three treatments for an enlarged prostate had an up to 37 per cent reduced risk of developing Parkinson's compared with those on another drug that didn't boost energy production. uWe also found that the longer the people were on these drugs, the lower their risk/* says Jacob Simmering at the University of Iowa. His colleagues are now planning a clinical trial to test the drugs on people who are at a high risk of Parkinson's. And their ambitions don,t end there. <(We don't think this is necessarily a Parkinson * s - specific intervention,n says Simmering.<( Given that our metabolism slows as we get older, could we reduce the risk of other age-related diseases through this mechanism? It>s something that we're considering as a plausible idea?)
The harder scientists look for drugs to boost mitochondrial activity, the more they seem to find. Erythropoietin is another. Despite it being banned in sports, some athletes use it to enhance performance because it increases their number of red blood cells, which carry oxygen to muscles. But animal studies suggest that it can also reverse some of the mitochondrial damage in Parkinson’s and Alzheimer’s. Meanwhile, Abdel-Kader is exploring the potential of nitric oxide, a signalling molecule that has been shown to stimulate the growth of mitochondria when present at the right doses. She and her colleague Salma Tammam, also at the German University in Cairo, have designed biodegradable nanoparticles to deliver the gas to the brain in a controlled way. In early tests, their team found that nitric oxide improved the memory of mice with a form of neurodegeneration that is similar to Alzheimer’s disease.
Other researchers have set their sights on an even more ambitious solution to the brain’s energy deficit: a therapy known as mitochondrial transplantation, which involves harvesting organelles from healthier tissue and transferring them into damaged parts of the brain. That may sound far-fetched, but a team led by Keren Nitzan at Hadassah University Medical Center in Jerusalem has found that an injection of healthy mitochondria from humans can improve the memory and learning ability of mice with an Alzheimer’s-like illness, with cognitive benefits lasting at least 13 days. Furthermore, mitochondrial transplantation is already being trialled in humans – although not in the brain. In 2018, for instance, doctors at Boston Children’s Hospital in Massachusetts reported successfully using mitochondrial transplantation in the heart to aid recovery from oxygen starvation after cardiac surgery.
Kalani is one scientist seeking to use this therapy to treat ageing brains. He is first going to test mitochondrial transplantation in people who have had a stroke. The idea is to take a tiny piece of muscle tissue during surgery near the incision site. While the surgeon is operating, this will be centrifuged to extract mitochondria. “It can be done pretty rapidly – in about 20 minutes,” says Kalani. As muscle is rich in mitochondria, a small biopsy could provide around a billion of them. They will then be released directly into the brain through the same catheter used to break up the blood clot, in an attempt to help oxygen-starved brain tissue recover. If this works, the same method could be used to release mitochondria into the brains of people with neurodegenerative conditions like Parkinson’s or Alzheimer’s, says Kalani.
One major obstacle is getting mitochondria through the walls of blood vessels in the brain, which are notoriously impermeable. To get around this problem, Kalani has successfully used focused ultrasound to disturb the “blood-brain barrier” so it becomes temporarily more porous. Another possibility is to spray mitochondria into the nose or inhale them through it, where they can travel along the olfactory and trigeminal nerve pathways. “There’s a direct connection,” says Soto, which means the mitochondria would bypass the blood-brain barrier altogether. An early feasibility study, published in 2021, found that this technique reduced the symptoms of Parkinson’s in rats with a version of the disease.
There is also the question of where to get the mitochondria. Will it be good enough to take them from a patient’s muscle, as Kalani suggests, or should they come from a healthy donor or be cultivated from stem cells? Each has potential advantages and disadvantages that must be tested. We still need to determine the safety of these procedures and the size and duration of the benefits, says Kalani. But he is optimistic. “This has huge potential,” he says. “I think the opportunities are very exciting.”
It does look that way. As our understanding grows, we should be able to identify many other ways to keep the hungry “engines of thought” running smoothly. Even if only a few of these succeed, they will provide huge relief for millions of people at risk of developing neurodegenerative coditions. "There is a lot of promise," Says Soto.
How to have a younger brain
Your cells are powered by tiny organelles called mitochondria. There is evidence that when the mitochondria in the brain start producing less energy, the result may be neurodegeneration (see main story). Conversely, this may explain why some lifestyle changes help protect the brain from the effects of ageing.
The first is exercise. We tend to associate physical activity with heart health, but abundant research shows it can also reduce your risk of neurodegeneration. This may be because it stimulates mitochondria throughout the body, ensuring that they are in peak condition to meet the demands of our energy-hungry brains.
According to some studies, a calorie-restricted diet appears to have similar effects. This involves reducing energy intake by around 20 per cent and, in animal studies at least, is linked to greater longevity and improved brain health into old age. Experiments on animals suggest that this may be due to improved mitochondrial efficiency.
You may have also heard about the ability of resveratrol – a compound found in the skin of grapes – to promote healthier ageing. Studies show that it can stimulate the replacement of old, malfunctioning mitochondria with new ones, providing one possible explanation for its benefits. The same goes for some other supplements that seem to show promise in reducing the risk of neurodegenerative conditions, such as turmeric, ginseng and Ginkgo biloba.