Research associates autophagy and age-related nervous system degradation

The in-built mechanism of recycling dead or poisonous material to preserve the health of human cells is critical to general health. Autophagy is a natural process that researchers are now interested in enhancing to see whether it will help prevent severe diseases of old age.

Research associates autophagy and age-related nervous system degradation
The worm C. elegans has a nervous system remarkably similar to that of humans. Researchers are studying it to better understand the link between autophagy and age-related degeneration of the nervous system. Image Credit: Nektarios Tavernarakis, 2022.

Can scientists postpone or perhaps prevent the emergence of age-related disorders by interfering in the mechanisms that cause the bodies and brains to fail as people age?

For thousands of years, people have believed in the legendary fountain of youth. Since 1889, while French doctor Charles-Édouard Brown-Séquard inject oneself with extraction from animal testicles, the issue of whether humans can drink from its waters has troubled modern academics working on the subject of biological aging (also known as senescence). Brown-Séquard said that both mental and physical health improved as a result of this.

In the Global North, age-related diseases such as Alzheimer’s and heart disease have attained pandemic levels, and the search for rejuvenation has not lost its attraction.

This increase in disease is mostly due to growing life expectancy, which is unsurprising. People born in Europe at this time may expect to live to be 81.3 years old, which is 35 years longer than those born in the late 19th century. However, doctors agree that the quality of life at an aging later age has not kept pace with longevity. Many of us spend their older years—sometimes decades—dealing with mental or physical problems that are virtually completely due to the aging process.

Our aim needs to shift from staying alive for longer to achieving a better quality of life in old age.”

Nektarios Tavernarakis, Professor and Bioscientist, University of Crete, Greece

Professor Tavernarakis, who researches aging, cell death, and neurodegeneration, says there are often no cures for the diseases of old age, and the symptoms can be “highly debilitating—sometimes devastating.”

Our aim needs to shift from staying alive for longer to achieving a better quality of life in old age,” says Professor Tavernarakis, who is also the principal coordinator of the MANNA project, which is sponsored by the European Union.

Cell detox

Professor Tavernarakis and his colleagues are working hard to figure out what causes biological deterioration at the cellular level—and how to reverse it. Society as a whole will profit by prolonging a person’s healthy years.

The burden of poor health in old age is enormous and rising on the social and healthcare systems. According to 2010 data, Alzheimer’s disease affects over 4.9 million individuals in Europe, and brain and neurological diseases cost Europe over €800 billion annually.

How can scientists hope to tackle the problem of physiological degeneration when there are so many seemingly unrelated ailments competing for their attention? There are several diseases related to aging, ranging from cancer to diseases of the internal organs, circulatory system, and brain system.

Essential housekeeping

Many people are hoping for a breakthrough, thanks to a biological mechanism known as autophagy (which means “self-eating” in Greek). To get rid of hazardous substances, all cells adopt autophagy (mostly unnecessary or damaged components).

As humans become older, this important housekeeping effort becomes less efficient, resulting in an accumulation of mistakes and malfunctions that cause disease-causing inflammation and, eventually, necrotic cell death (known as necrosis).

There is mounting evidence that defective autophagy is a common denominator in a wide range of age-related diseases. Tumors, liver disease, heart disease, stroke, and age-related neurodegenerative diseases including Alzheimer’s and Parkinson’s are all linked to necrosis.

Although research in this field is still in its infancy, a growing body of evidence shows that increasing autophagy might lengthen cell longevity and increase the chances of good health.

If we could target those underlying processes of aging, we might be able to slow down age-related degeneration and keep people healthier for longer. We see the prospect of developing a single pill that will target the biological pathways that also involve autophagy. The idea would be to have a polypill that prevents the underlying mechanisms involved in more than one aging-related condition.”

Professor Linda Partridge, Professor and Founding Director, Max Planck Institute for Biology of Aging, Germany

 “If we could target those underlying processes of aging, we might be able to slow down age-related degeneration and keep people healthier for longer. This would take us to a different place from where we are in now, where diseases are tackled one by one, as they arise,” Professor Partridge added.

Professor Partridge is the principal investigator for GeroProtect, an EU-funded initiative aimed at finding a good pharmacological candidate for a “geroprotective” polypill. Professor Patridge also explained, “We’re not looking to increase lifespan, but to solve the problem of the ever-growing period of ill-health at the end of life.”

Professor Tavernarakis’ MANNA aims to unravel the relationship between autophagy and nervous system deterioration as humans age. The worm Caenorhabditis elegans, which, maybe surprisingly, has a neurological system that is very comparable to that of humans, is the subject of most of the group’s research.

Through our work on both C. elegans and human brain tissue, we can confirm that mitophagy is downregulated in Alzheimer’s patients.”

Nektarios Tavernarakis, Professor and Bioscientist, University of Crete, Greece

The team has discovered some of the important genes and molecular actors involved in nerve-cell necrosis throughout the first four years of this investigation. Their findings show that a kind of autophagy termed mitophagy is required for the survival and long-term preservation of neurons.

Toxic build-up

Mitophagy (the process by which a cell converts glucose—or simple sugar—into useable energy) is employed by an organism in its prime to destroy aged or harmful mitochondria. However, when nerve cells age and mitophagy decreases, defective mitochondria begin to proliferate. This build-up is poisonous, causing an inflammatory reaction that results in cell death and damage. A neurodegenerative disease develops as a result of the gradual loss of functioning nerve cells.

Through our work on both C. elegans and human brain tissue, we can confirm that mitophagy is downregulated in Alzheimer’s patients,” stated Professor Tavernarakis.

Professor Tavernarakis said that while research into the specific processes underlying mitophagy failure is still ongoing, Tavernarakis is optimistic that complicated genetic treatments may one day be accessible to substitute gene sequences that promote necrosis with ones that enable healthy autophagy far into the old life. However, such treatments are still a long way off.

Eat less, live longer

Caloric restriction is one method for inducing autophagy. Researchers have discovered that ingesting less food or reducing an organism’s feeding hours within a particular day triggers autophagy in worms, flies, mice, chimpanzees, and humans.

Dietary restriction has also been demonstrated to lengthen longevity and prevent or postpone the onset of age-related diseases in nonhuman species. The most promising studies reveal lifetime extensions of 50–300% depending on the species. There is some promising evidence that food restriction helps animals age better, however, the consequences for humans are still up for debate.

Why going hungry may be beneficial? Simply put, when an organism’s food is constrained, its cells run out of glucose and start using their own superfluous material to create energy. To put it another way, cells are driven into a detoxifying state of autophagy in order to survive.

Disease prevention

Dietary limitations are problematic since most people dislike them, and any attempt to cut food intake in humans is usually short-lived. As a result, pharmacological therapies are a lot more practical option for improving autophagy (Professor Partridge emphasizes, however, that over-activating autophagy might be problematic since it can cause cells to destroy their contents at unfavorable rates).

There have already been a number of potential drug candidates discovered. The most well-known are Urolithin A (produced by certain gut bacteria after they have been fed ellagitannins, which can be found in raspberries, pomegranates, strawberries, and walnuts) and rapamycin (a natural antifungal developed by soil bacteria).

These two chemicals are known to play a role in autophagy upregulation. They have also been reported to enhance longevity in mice, worms, and fruit flies. These chemicals’ geroprotective qualities will soon be put to test in human clinical trials.

Professor Partridge, who has been researching the processes behind rapamycin’s ability to enhance autophagy in animal models, is optimistic that the findings of human trials will help the team get closer to generating their game-changing polypill.

Eventually we may end up with a drug that is taken very much like people today take statins (for cholesterol) or pills to lower blood pressure. Medicines that are taken over a very long period of time to prevent ill-health long before disease has even occurred,” Professor Partridge concluded.

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