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What is autophagy?
The world’s easiest-to-understand explanation by UHA Mikakuto (The simplest explanation by UHA Mikakuto)

What if we could stay healthy longer and live joyfully?
What if we could slow skin aging and maintain a youthful, radiant appearance?

The key to unlocking such a dreamlike future might lie in autophagy, a process that is currently garnering significant attention.

What is autophagy?

Autophagy is an essential process that allows cells to break down and recycle substances to maintain cellular health, much like a recycling operator.

All Living Organisms Are Made of Cells

Before diving into autophagy, let’s first take a moment to understand cells.
All living organisms are composed of cells, including humans. Our bodies are made up of approximately 37 trillion cells, each one alive and functioning.
Cells are incredibly small and can only be observed under a microscope. Within each cell, there are various structures known as organelles, each performing specialized functions.
The activities within a cell are as intricate and dynamic as those of human society.
For example, organelles called mitochondria act as power plants, producing energy for the cell. Additionally, more than ten thousand different kinds of proteins work within the cell, each performing a specific role, much like individuals contributing to various tasks in a bustling city.

Autophagy: A Vital System

The malfunctioning of cells leads to impaired body functions and can result in various diseases.
In other words, being healthy means having healthy cells, while sickness occurs when cells become unhealthy.
To maintain cellular health, there is a crucial process known as autophagy, which acts like a recycling system within the cells. Autophagy breaks down and repurposes cellular components to ensure their proper function.
The term "autophagy" comes from the Greek words “auto” (meaning “self”) and “phagy” (meaning “eating”), as it describes cells consuming their own components to maintain balance.
Autophagy is an essential mechanism present in all cells.

How autophagy works

A membrane structure, resembling Pac-Man, forms within the cell. This structure engulfs various substances, such as proteins, and transports them to a "recycling plant." In this plant, degrading enzymes break down the substances, and the resulting components are recycled by the cell to synthesize new materials.

POINT

The health of our cells is maintained by a process called autophagy, which breaks down substances within the cells.

Why is autophagy necessary?

Why is autophagy necessaryin the first place?
We aim to uncover the much-anticipated hidden potential of autophagy, which holds promise for promoting longevity, maintaining health, and preventing aging.

01

Replacement of Cellular Contents

One of the roles of autophagy is to gradually decompose and "replace" the contents of cells on a daily basis.
Humans obtain proteins, a major nutrient, from food. However, approximately 240 grams of protein are synthesized by cells throughout the body each day—nearly four times the amount of protein typically consumed through food. This means that the protein intake from food alone is insufficient.
To bridge this gap, autophagy breaks down old proteins within cells into amino acids, which are then used as building blocks to synthesize new proteins.
Furthermore, autophagy breaks down not only proteins but also other macromolecules and organelles to create new ones.
In this way, autophagy plays a key role in renewing and replacing various cellular components. Just like automobiles last longer when their parts are gradually replaced, cells are "reborn" over several weeks through the mechanism of autophagy.

One of the roles of autophagy is to gradually decompose and "replace" the contents of cells on a daily basis.
Humans obtain proteins, a major nutrient, from food. However, approximately 240 grams of protein are synthesized by cells throughout the body each day—nearly four times the amount of protein typically consumed through food. This means that the protein intake from food alone is insufficient.
To bridge this gap, autophagy breaks down old proteins within cells into amino acids, which are then used as building blocks to synthesize new proteins.

Furthermore, autophagy breaks down not only proteins but also other macromolecules and organelles to create new ones.
In this way, autophagy plays a key role in renewing and replacing various cellular components. Just like automobiles last longer when their parts are gradually replaced, cells are "reborn" over several weeks through the mechanism of autophagy.

02

Elimination of hazardous substances

Autophagy decomposes substances in cells by encapsulating them randomly in a structure called an autophagosome during intracellular turnover.
In addition to performing random retrieval, autophagosomes also detect and eliminate hazardous substances that enter the cells.
For example, when cells are infected by pathogenic bacteria or viruses, autophagosomes isolate the bacteria or viruses by enclosing them, transporting them to lysosomes, where they are broken down and rendered harmless.
Autophagosomes also encapsulate damaged mitochondria. This is important because leaving broken mitochondria untreated can be dangerous, as they release reactive oxygen species, which are highly toxic. Autophagosomes are responsible for clearing a wide variety of harmful substances.
Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are caused by the death of brain cells due to the accumulation of protein clumps. Autophagosomes help clear and decompose the proteins that form these clumps, thereby preventing the onset of such diseases.

03

Obtaining nutrition

Autophagy was first discovered in the liver of a rat placed in a state of starvation. This led to the hypothesis that autophagy plays a role in securing nutrition through self-consumption (auto-eating, or phagy) during times of hunger.
Subsequent research has shown that securing nutrients is the most fundamental role of autophagy in all living organisms.
Single-celled organisms, such as yeasts, cannot store large amounts of nutrients in their cells. Therefore, when external nutrients are depleted, cells break down their own contents to convert them into usable nutrients, directly preventing death.
While higher multicellular organisms, such as humans, can survive a certain level of starvation due to energy-storing cells like adipocytes, it is still crucial for autophagy to secure nutrition.
In fact, in newborn mammals, autophagy is the primary source of nutrition. It is known that newborn mice, for example, will die within a day of birth if autophagy is experimentally prevented.

POINT

Autophagy is required because of the three reasons:
[1] it replaces the contents of cells;
[2] it eliminates hazardous substances; and
[3] it obtains nutrition.
I totally understand!

What is the effect of autophagy?

What Effect Does Autophagy Have? Autophagy is essential for enriching life and brings the benefits we all desire:

●Longevity with maintained health
●Anti-aging
●Improved immunity
Let's take a closer look at how autophagy contributes to these benefits.

01

Longevity with maintained health

Longevity has been a common aspiration of humanity since ancient times. However, research on aging and longevity has only seen rapid progress in the past 30 years.
The breakthrough came in the 1980s with a study on the lifespan of nematodes. The study revealed that by modifying just one of their genes, the lifespan of nematodes could be nearly doubled, extending by two to three weeks. This discovery showed that life expectancy is programmed, shifting the understanding of aging and longevity from "a vague process" to "something that can be controlled" and "subject to scientific study."
As research progressed and numerous life-prolonging mechanisms were identified, scientists began to uncover common factors among these mechanisms. One of the key common denominators is the activation of autophagy.
Advances in these studies have also made it clear that autophagy's function weakens with aging.
As the term "age-related diseases" suggests, older individuals are more susceptible to various conditions. For example, age-related diseases include neurodegenerative diseases such as Alzheimer's and Parkinson's, age-related macular degeneration, age-related kidney disease, and osteoporosis. Many of these diseases may be caused or exacerbated by reduced autophagy.
An experiment with mice designed to preserve autophagy showed that these mice were less prone to age-related diseases. Activated autophagy helped mitigate the decline in activity, as well as conditions like Parkinson's disease, kidney disease, macular degeneration, and osteoporosis.

Longevity has been a common aspiration of humanity since ancient times. However, research on aging and longevity has only seen rapid progress in the past 30 years.
The breakthrough came in the 1980s with a study on the lifespan of nematodes. The study revealed that by modifying just one of their genes, the lifespan of nematodes could be nearly doubled, extending by two to three weeks. This discovery showed that life expectancy is programmed, shifting the understanding of aging and longevity from "a vague process" to "something that can be controlled" and "subject to scientific study."
As research progressed and numerous life-prolonging mechanisms were identified, scientists began to uncover common factors among these mechanisms. One of the key common denominators is the activation of autophagy.

Advances in these studies have also made it clear that autophagy's function weakens with aging.

As the term "age-related diseases" suggests, older individuals are more susceptible to various conditions. For example, age-related diseases include neurodegenerative diseases such as Alzheimer's and Parkinson's, age-related macular degeneration, age-related kidney disease, and osteoporosis. Many of these diseases may be caused or exacerbated by reduced autophagy.
An experiment with mice designed to preserve autophagy showed that these mice were less prone to age-related diseases. Activated autophagy helped mitigate the decline in activity, as well as conditions like Parkinson's disease, kidney disease, macular degeneration, and osteoporosis.

02

Anti-aging

In an era where many people live to be 100 years old, it’s no surprise that many are interested in anti-aging to maintain an independent life in old age.
As discussed above, focusing on cellular function is crucial for extending longevity while maintaining health. However, we are constantly exposed to various external factors that degrade cellular function, including ultraviolet rays, pollutants, stress, poor dietary habits, and viruses.
Moreover, after the age of 40, we often encounter health and beauty issues, such as gaining weight despite not overeating, experiencing shortness of breath when climbing stairs, and noticing changes in appearance like skin spots, wrinkles, and gray hair.
Traditional anti-aging methods typically address these external factors and deficiencies individually, through dietary supplements or cosmetics. However, such symptomatic treatments are limited because they cannot fully eliminate external stressors. As a result, cells with diminished function remain, and true improvement is not achieved.
It is often said that "there are limitations to anti-aging treatments for the skin" because cells with reduced functions cannot be restored even after nourishment.
However, comprehensive cell care now holds the potential to offer a new approach to anti-aging.

03

Improved immunity

Autophagy protects the health of cells through three key actions: intracellular turnover, elimination of hazardous substances, and securing nutrition during periods of starvation.
The discovery of autophagy's role in eliminating hazardous substances has not only expanded our understanding of its function but also highlighted its importance in a new immune system.
Living organisms have mechanisms to eliminate harmful substances, such as bacteria that invade the body. This process is part of the traditional immune system, which includes both innate immunity and acquired immunity. Innate immunity involves cells called macrophages that "eat" invading pathogens, for example, those entering the bloodstream. However, macrophages cannot act if the pathogens invade various types of cells. Previously, we thought there was no way to handle such a situation. However, autophagosomes were found to have the ability to capture and decompose these pathogens within cells.
As a result, it has been revealed that living organisms have a broader immune system than previously known—one capable of eliminating hazardous substances within each cell, independent of immune cells.
On the other hand, acquired immunity is characterized by its high specificity for pathogens, as it enables the body to retain long-term memory of certain invaders. This process involves B cells and T cells working together. B cells secrete proteins called antibodies that bind to specific pathogens, allowing the immune system to attack them. Additionally, killer T cells target and eliminate cells infected by specific pathogens. Autophagy plays a crucial role in maintaining the function of both B cells and T cells, making it essential for overall immunity in numerous ways.

POINT

With advances in autophagy research, we can transform longevity and aging from 'something uncontrollable' to 'something manageable.' It's truly amazing!

Elements that activate autophagy

What can we do to activate autophagy, which declines with aging?

01

Lifestyle modifications

First and foremost, improving your everyday lifestyle is crucial. For example, regular exercise is known to activate autophagy, with aerobic activities like walking being particularly effective.
Additionally, it is advisable to avoid high-fat meals, as they can reduce the liver's autophagy. Since calorie restriction has been shown to increase lifespan by activating autophagy, it's also beneficial to avoid overeating and minimize meals and snacks.
Autophagy is activated during sleep, so ensuring a good night's rest is important. Because autophagy is temporarily suppressed after nutrient intake, paying attention to your eating habits is essential—such as having your evening meal earlier in the day.
By making these dietary habits and exercise routines part of your daily life, you can potentially extend a life of maintained health by activating autophagy.

02

Nutrients that activate autophagy

Besides, resveratrol, which is contained in a large amount in red wine and grapes, astaxanthin, which is abundant in salmon, salmon roe, and shrimps and catechin, which is contained in green tea and powdered green tea, are also known as components that stimulate autophagy.
A number of dietary supplements that are concentrated from food components and activate autophagy have been developed. Dietary supplements like this would be one option to activate autophagy and extend a life with maintained health.
Recent research has identified food components that stimulate the activation of autophagy. Below, we will introduce some of the foods rich in these components.
•Urolithin A: A compound found in pomegranates, berries, and nuts such as walnuts. Urolithin A has garnered attention for its ability to eliminate damaged mitochondria and support autophagy. Studies have shown that urolithin A can increase the lifespan of nematodes by 1.5 times. It is also known to activate the "sirtuin gene," which is associated with longevity and healthy aging.
•Resveratrol: Found in large quantities in red wine and grapes, resveratrol is another component that stimulates autophagy.
•Astaxanthin: This powerful antioxidant is abundant in salmon, salmon roe, and shrimp, and has been recognized for its autophagy-activating effects.
•Catechins: Present in green tea and powdered green tea, catechins are also known to stimulate autophagy.
Additionally, many dietary supplements concentrated from these food components have been developed to activate autophagy. Such supplements could be an option for activating autophagy and promoting a life of sustained health.

POINT

A healthy lifestyle and diet help autophagy function properly, keeping the body healthy and youthful.

Previous studies of autophagy

Autophagy has been regarded as a promising factor for longevity with maintained health and aging prevention, something everyone desires. What kind of research has been conducted so far? Japan is a global leader in the field of autophagy. Let’s take a brief look at the history and details of this research.

In 1993, Yoshinori Ohsumi, a distinguished professor at the Institute of Science Tokyo, discovered 14 genes essential for autophagy and published a groundbreaking paper. His work was highly acclaimed, and he was awarded the Nobel Prize in Physiology or Medicine in 2016. He revealed the molecular mechanisms of autophagy, something that had never been uncovered before.

When starting his laboratory, Professor Ohsumi invited Tamotsu Yoshimori, a cell biologist specializing in mammals, to join as an assistant professor. Professor Yoshimori made a landmark discovery by identifying a protein essential for mammalian autophagy, laying the foundation for further research. His paper on the discovery of LC3 has been widely cited and is considered a cornerstone of the field.

UHA Mikakuto has been evaluating the effects of various food ingredients on the activation of autophagy using the tfLC3 method, a more accurate approach developed by Professor Yoshimori at the University of Osaka.

While most autophagy assessments evaluate the expression of the LC3 protein (static evaluation), the tfLC3 method allows for a precise evaluation of autophagy function (dynamic evaluation). This dynamic approach involves marking the LC3 protein and observing its movement to evaluate the activation state, enabling more accurate flax of autophagy. Using the tfLC3 method, UHA Mikakuto has assessed over one hundred components related to autophagy, discovering that substances such as resveratrol and astaxanthin may enhance autophagic activity, thus advancing the field of research.

POINT

Japan won the Nobel Prize for its groundbreaking research on autophagy! It’s truly remarkable!

Future of autophagy

So far, we have discussed the functions and benefits of autophagy. But what type of autophagy is expected to contribute to longevity with maintained health? What is the future vision for autophagy?

Professor Yoshimori, a leading researcher in the field, not only identified the role of LC3 but also developed a method to measure autophagy based on this discovery. This method is currently being used in studies exploring ways to regulate autophagy activity.

Autophagy has garnered attention not only for its potential in longevity, aging prevention, and beauty, but also for its transformative impact on the evolution of medical care.

Looking ahead, autophagy is expected to receive even greater attention for its potential in achieving longevity with maintained health. To bring the future of health and aging prevention that everyone desires closer to reality, research on autophagy will continue with passion.

Why is UHA Mikakuto focusing on autophagy research?

UHA Mikakuto follows the philosophy that “deliciousness means kindness.” Delicious foods are good for the body, and healthy foods are delicious. People who choose delicious, nutritious foods tend to improve their health. To enhance the health and beauty of people, UHA Mikakuto applies its expertise in creating “deliciousness” from candy and gummi manufacturing to develop gummi candy-shaped dietary supplements that make it easy to enjoy vitamins and minerals for a healthier daily life. At the same time, the company is actively researching “what is good for the body.”
As part of this mission, Mikakuto is focusing on autophagy, a key player in aging prevention, and is collaborating closely with AutoPhagyGo Inc., founded by Professor Tamotsu Yoshimori from the University of Osaka. Together, they aim to develop foods that can be easily incorporated into daily diets to activate autophagy.
Through this collaboration, it has been shown that the combination of urolithin A and resveratrol is particularly effective in enhancing autophagic activity.
Furthermore, we are working on developing our own method for measuring autophagy, as there is currently no established way to measure human autophagy activity. Once we are able to measure autophagy in humans, it may open up new possibilities for extending life with maintained health, including the potential for clinical studies in humans.

POINT

A collaborative study between UHA Mikakuto and AutoPhagyGO Inc. has revealed that the combination of urolithin A and resveratrol further enhances autophagy. We are continuously developing technologies for potential application in humans.

Supervisors
Taiji Matsukawa, Executive Officer, UHA Mikakuto Biodevelopment Division;
Director of the Japan Autophagy Consortium
Biodevelopment Section, UHA Mikakuto
Osaka Head Office: 4-12 Kanzaki-cho, Chuo-ku, Osaka-shi 540-0016 JAPAN