Today is World Alzheimer's Day, with 2050 million people living with dementia worldwide in 1

Replace cellular power plants, and new therapies promise to reverse brain aging?

9 September is World Alzheimer's Day. As an insidious neurodegenerative disease that develops progressively, Alzheimer's disease is becoming a huge burden on the global public health system. By 21, the number of Alzheimer's disease patients worldwide is expected to exceed 2050 million.

Neurodegeneration is a manifestation of the gradual loss of neuronal structure and function, which can lead to cognitive impairments such as dementia. Despite the lack of effective treatments and drugs, the "grand unified theory" of neurodegenerative diseases suggests that the devastating effects of aging on the brain may be reversed by restoring or replacing mitochondria.

■ Fang Lingsheng / Compilation

If you're a car owner, you'll probably notice that over time, car engines become less efficient and require more and more fuel for the same mileage. The same is true of the human brain, the researchers found. In cells, there is an organelle called a "mitochondria." As the power plant of human cells, the energy generated by mitochondria supports human thought activities and is also the energy engine for human experience and perception. However, as we age, there is less and less energy to support our brain activity. Worse, just as the tail of a classic car emits more exhaust gases, the aging human cell power plant also produces more waste that slowly poisons our brains.

Does this mean that mitochondrial dysfunction may be responsible for many of the most devastating brain diseases? These degenerative diseases of the brain include Alzheimer's disease, Parkinson's disease, Huntington's disease, and motor neurone disease.

As the world's population ages, neurodegenerative diseases are becoming a growing health problem. According to the latest estimates, by 2050, there will be 1 million people with dementia worldwide, most of them caused by Alzheimer's disease. Parkinson's disease is not as common as Alzheimer's disease, but it affects 52 in 37 people.

Regarding the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, although some drugs can reduce their symptoms and delay the development of the disease, they cannot be fundamentally cured. Today, scientists are looking for what causes such diseases and are trying to treat them by renewing their mitochondria.

Mitochondria miniature power plants within human cells

According to the "grand unified theory" (GUTs) of neurodegeneration, we can "recharge" neurons by restoring their energy pool, thereby extending the time it takes for the brain to perform healthy functions. The idea has inspired a number of new treatments for age-related brain diseases, and multiple drug candidates are being studied. Some researchers have tried transplanting healthy mitochondria into damaged or aging brains in hopes of exploring the possibility of rejuvenating the brain.

"If you keep changing car parts, your car may be able to keep driving." Claudio Soto, a neuroscientist at the University of Texas Health Science Center in Houston, said, "Can we also try to 'replace parts' cells?" Researchers are increasingly aware that to slow down aging and ward off neurodegenerative diseases, starting with mitochondria, known as cellular "generators," may be key.

Mitochondria are very tiny organelles, but they are the most complex elements in a cell. In the long evolutionary history of life, mitochondria, once considered independent forms of life, later somehow entered bacteria and began to establish a mutually beneficial relationship with bacteria. Mitochondria can produce energy for organisms and greatly assist the evolution of multicellular organisms, including humans. Today, mitochondria are found in each of our cells, and in addition to red blood cells, the number of mitochondria in the most active cells can be as high as 200 million.

Like any generator, mitochondria need fuel, but what they need is a special fuel, glucose. Mitochondria use glucose to synthesize a molecule called adenosine triphosphate (ATP) to provide usable energy to cells.

The brain is the most energy-intensive of all body organs, accounting for only 2% of body mass but consuming 20% of the body's energy. Because neurons require a lot of energy to maintain the activity of bioelectric signals and synapses (connection points between neurons), the brain is particularly vulnerable to metabolic dysfunction. In recent decades, there has been growing evidence that even minimal disturbances in mitochondrial efficiency can lead to serious health problems.

Energy crisis The vicious cycle leads to neurodegeneration

Alzheimer's disease, for example, is characterized by the accumulation of proteins that are harmful to brain tissue – tau protein and amyloid plaque tangled. Researchers have tried a variety of methods to try to remove these harmful proteins, but with little success. To this day, almost all treatments to remove plaque and tangles have not worked.

It's worth noting, though, that some studies have shown that some people who have harmful protein accumulation in the brain can still maintain normal cognitive function. There could be a variety of reasons, not least that these people have a larger "cognitive reservoir," which gives them the ability to cope with harmful protein damage before signs of mental decline appear.

Like the initial encounter with many new scientific ideas, the theory of "cognitive reserve" went unnoticed for a long time. Today, research in this area has accumulated a wealth of evidence that is difficult to ignore.

Much evidence from animal models and cell cultures suggests that older people with dementia are often accompanied by decreased mitochondrial function. What's more, the primary genotype, AzpoE4, which increases the risk of developing Alzheimer's disease, reduces the efficiency of mitochondria. For example, one study found that neurons carrying this gene variant produced less ATP, and their memory and learning abilities were also impaired.

However, this evidence still does not solve the problem of protein tangles and plaques. One mainstream view is that the pressure to meet neuronal energy needs causes mitochondria to start producing more waste, triggering the production of tau and amyloid. To make matters worse, a cell's energy crisis can also affect the rapid removal of toxic proteins.

Yasar Kalani of the University of Virginia pointed out that when cells are subjected to metabolic stress, many non-essential functions are slowed down, one of which is the removal of waste macromolecules. Experiments have shown that these piles of garbage destroy mitochondria, leading to a more severe energy crisis, and the resulting vicious cycle eventually leads to widespread neurodegeneration. Adequate cognitive reserve can help some people cope better with this condition, but if the underlying mechanism is indeed related to metabolism, it may explain why plaque-removal treatment often does not improve cognitive performance in Alzheimer's patients.

Mitochondrial damage is an underlying cause of most neurodegenerative diseases

Similar to the pathogenesis of Alzheimer's disease, Parkinson's disease is caused by the loss of neurons that produce the neurotransmitter dopamine. Dopamine works by communicating with the nervous system that controls muscles, and with the death of these neurons and the decreasing amount of dopamine, it is difficult for Parkinson's patients to control muscles to perform precise movements.

This loss of neurons coincides with the accumulation of a protein called "α-synuclein," which forms sticky clumps called "Lewy bodies," which are often associated with Parkinson's disease. There is now multiple pieces of evidence that mitochondrial dysfunction is a potential cause of these changes.

This link was initially suspected because researchers observed that some people experienced Parkinson's-like symptoms after exposure to certain pesticides, such as rotenone, that are known to impair mitochondrial function. Analysis of the main genes responsible for hereditary Parkinson's disease supports the hypothesis that the PINK1, parkin, and LRRK2 genes are all implicated in mitochondrial dysfunction. Metabolic damage can lead to the formation of toxic proteins in Lewy bodies, putting more stress on mitochondria.

Reduced energy supply may be the underlying cause of most neurodegenerative diseases, a view further supported by evidence from mitochondrial dysfunction in Huntington's disease and amyotrophic lateral sclerosis, commonly known as "frostbite".

The fact that mitochondrial efficiency declines with age explains why neurodegenerative diseases tend to appear later in life. Dysfunction of mitochondria may also help us understand why long-term inflammation (often caused by stress, poor diet, or immune system disorders) increases the risk of neurological disorders. Studies have shown that certain inflammatory factors impair mitochondrial energy production, and mitochondrial dysfunction in turn triggers inflammation. Inflammation appears to be another important factor in the vicious cycle of brain degeneration, a view that helps explain why certain lifestyles help slow brain aging.

Anti-aging It is essential to increase mitochondrial activity

Neuroscientists have begun looking for ways to boost mitochondrial activity to prevent or delay neurodegeneration. They were excited to discover that some existing drugs might be effective.

One is terazosin, which is commonly used to treat urinary disorders caused by an enlarged prostate. The drug is known to bind to an enzyme called PGK1, which is involved in breaking down glucose and producing ATP, which improves the overall energy production of mitochondria by increasing PGK1 activity. Two other related drugs, doxazosin and furazosin, also increase mitochondrial energy production.

In 2021, researchers found that men who took all three drugs had a 37% lower risk of Parkinson's disease compared to men who took other drugs that did not promote energy production. "We also found that the longer we took these drugs, the lower the risk." Jacob Seamerlin of the University of Iowa said. In addition to Parkinson's disease, can age-related degenerative diseases also reduce risk through this pathway? Simerin thinks it's worth a try.

The harder researchers work to find drugs that boost mitochondrial activity, the more surprises they bring. Erythropoietin is another drug that increases mitochondrial activity. It is a drug that is banned in sports and is used by athletes to improve performance because it increases the number of red blood cells, which act as a driver of oxygen to the muscles. Animal studies have shown that the drug reverses mitochondrial damage caused by Parkinson's and Alzheimer's diseases.

Researchers at the German University in Cairo are studying the role of nitric oxide, which can promote mitochondrial biosynthesis and improve their biological function in the right dose. To do this, they designed biodegradable nanoparticles to deliver this gas to the brain in a controlled manner. Early tests found that nitric oxide could improve memory in neurodegenerative mice with Alzheimer's-like disease.

Mitochondrial transplantation or new treatment options for dementia

Other researchers have proposed a refreshing treatment option: Transplanting mitochondria to replenish brain energy, that is, extracting cells from healthy body tissue and transplanting them into damaged brains.

This may sound whimsical. A team led by Karen Nizan of the Hadassah University Medical Center in Jerusalem, Israel, found that injecting healthy mitochondria from humans improved memory and learning in mice with Alzheimer's-like disease for at least 13 days.

Currently, mitochondrial transplantation is in clinical trials, although not on the brain. For example, in 2018, doctors at Boston Children's Hospital in Massachusetts, USA, reported success in helping hypoxic patients recover after heart surgery through mitochondrial transplantation.

Kalani tried this therapy to treat aging brains, and he was the first scientist to try mitochondrial transplants in stroke patients. "In surgery, mitochondria can be extracted from a small piece of muscle near the incision in about 20 minutes." Muscles are rich in mitochondria, and a tiny slice of tissue can provide about 10 billion mitochondria, which can be transported directly into the brain through a special catheter to aid the recovery of oxygen-deprived brain tissue.

If this approach works, Kalani says, it could also be used in patients with neurodegenerative diseases such as Parkinson's or Alzheimer's to release mitochondria into the brains of such patients.

An important question is how to get mitochondria through the almost impermeable walls of blood vessels in the brain. To solve this problem, Kalani used focused ultrasound to interfere with the "blood-brain barrier," making it temporarily porous and permeable. Another possibility is to spray mitochondria into the nasal cavity or inhale it through the nose and enter the brain through olfactory cells and trigeminal nerve pathways.

His research experiments showed that mitochondria can bypass the blood-brain barrier and enter the brain. An early feasibility study published in 2021 found that mitochondrial transplantation reduced symptoms in rats with Parkinson's disease.

The last issue is the origin of mitochondria. There are several ways to extract from a patient's muscle, from a healthy donor, and from a stem cell, but the benefits and harms of each method need to be determined through experiments. Kalani noted that the safety, efficacy and duration of these procedures still need further research to determine, but he is optimistic about the potential and prospects of mitochondrial transplantation.

With a deeper understanding of the brain's mechanisms, researchers will also discover more ways to keep the brain running smoothly, and even if only a few of them are successful, it can greatly alleviate the symptoms of countless people with degenerative diseases. "We are confident that this day will come." Soto said.

Further reading

How to keep your brain young

A small organelle called a "mitochondria" is constantly fueling your body's cells. There is evidence that if the energy produced by mitochondria in the brain is reduced, it can lead to neurodegenerative diseases. Some beneficial lifestyles protect the brain from ageing.

The first is exercise. We often associate physical activity with heart health, but numerous studies have shown that regular exercise also reduces the risk of neurodegenerative diseases. This is because exercise stimulates the activity of mitochondria in all parts of the body, ensuring that mitochondria are in optimal condition to meet the brain's energy needs.

Limiting calories in the diet has a similar effect. Animal experiments and studies have found that calorie restriction can prolong life, improve brain health in old age, and help improve mitochondrial efficiency.

In addition, resveratrol, a compound found in grape skins, can also play an anti-aging role. Studies have shown that resveratrol boosts mitochondrial metabolism. Others such as turmeric, ginseng and ginkgo biloba can also play a role in reducing the risk of neurodegenerative diseases. (Wen Wei Po)