Autophagy: Can we stay young and healthy longer by “cleansing” our cells? | science and technology

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By intervening in the dysfunctional processes of our body and our brain as we age, can we delay the onset of age-related disorders, or even completely prevent them from developing?

The mythical Fountain of Youth has been a popular legend for thousands of years. The question of whether we can drink its waters has plagued modern researchers working in the field of biological aging (known as senescence) since 1889, when French physician Charles-Édouard Brown-Séquard injected himself with extracts of animal testicles. Following this, he claimed that his mental and physical condition had improved.

Nearly 150 years later, age-related illnesses like Alzheimer’s and heart disease have reached epidemic levels in the global North, and the quest for rejuvenation has lost none of its appeal.

Unsurprisingly, the increase in life expectancy is largely responsible for this resurgence of the disease. People born in Europe today can expect to live to the age of 81.3, a good 35 years longer than those who entered the world at the end of the 19th century. However, doctors agree that the quality of life of the elderly has not kept pace with longevity. Many of us spend our senior years – sometimes decades – living with mental or physical disorders caused almost entirely by the aging process.

Often there is no treatment for the conditions of old age, and the symptoms can be “very debilitating – sometimes devastating”, according to Professor Nektarios Tavernarakisbioscientist at the University of Crete in Greece who studies aging, cell death and neurodegeneration.

“Our focus must shift from staying alive longer to having a better quality of life in old age,” said Tavernarakis, who is also lead coordinator of the EU-funded project. MANNA project.

Cellular detox

Tavernarakis and his colleagues aim to understand — and ultimately fix — the cellular causes of biological decline. The benefits of extending a person’s healthy years will be felt by society as a whole. The poor health of the elderly represents an enormous and growing burden on our social and health systems. Alzheimer’s disease alone affects more than 4.9 million people in Europeand diseases and disorders of the nervous system and brain represent an annual cost of around €800 billion for Europe, according to 2010 figures.

The question is, how can scientists hope to solve the problem of physiological decline when there is such an assortment of seemingly unrelated disorders vying for their attention? From cancers to diseases that affect internal organs, the circulatory system, and the nervous system, there are many conditions associated with aging.

Essential housekeeping

Many place their hopes in a biological process known as autophagy (meaning “self-eating” in Greek). All cells use autophagy to get rid of toxic materials (mainly useless or damaged components). As we age, this essential housekeeping task is performed less efficiently, leading to an accumulation of errors and problems that trigger pathogenic inflammation and ultimately necrotic cell death (known as necrosis).

There is growing evidence that defective autophagy is a common denominator in many age-related disorders. Necrosis contributes to the incidence of tumors, liver disease, stroke, heart disease, and age-related neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease.

Studies in this area are still in their infancy, but a growing body of research suggests that stimulating autophagy can prolong cell survival and improve our prospects for good health.

Looking to the future, Professor Linda Partridge, Founding Director of the Max Planck Institute for the Biology of Aging in Germany, said: “We are considering the possibility of developing a single pill that will target biological pathways also involving the autophagy. The idea would be to have a polypill that prevents the underlying mechanisms involved in more than one aging-related condition.

“If we could target these underlying aging processes, we might be able to slow down age-related degeneration and keep people healthier for longer. It would take us to a different place than where we are now, where illnesses are dealt with one by one as they arise.

Partridge is the Principal Investigator of GeroProtect, an EU-funded project that aims to find a suitable drug candidate for such a “geroprotective” polypill. “We are not looking to increase lifespan, but to solve the problem of the ever-increasing period of poor health at the end of life,” she said.

Tavernarakis’ MANNA focuses on unpacking the link between autophagy and age-related nervous system degeneration. Much of the group’s work is done on the worm Caenorhabditis eleganswho, perhaps surprisingly, has a nervous system remarkably similar to that of humans.

During the first four years of this project, the team discovered some of the key genes and molecular players involved in nerve cell necrosis. Their work confirms that the survival and long-term maintenance of neurons depends on a subtype of autophagy called mitophagy.

toxic buildup

At its peak, an organism uses mitophagy to eliminate old or toxic mitochondria (these are the organelles used by a cell to convert glucose – or simple sugar – into useful energy). But as age sets in and mitophagy slows, defective mitochondria begin to accumulate in nerve cells. This buildup is toxic, triggering an inflammatory response that leads to cell damage and death. It is this progressive loss of functional nerve cells that causes the onset of a neurodegenerative disease.

“Thanks to our work on both C.elegans and human brain tissue, we can confirm that mitophagy is downregulated in patients with Alzheimer’s disease,” said Professor Tavernarakis. He added that efforts to decipher the precise mechanisms involved in mitophagic failure are still ongoing, but he is confident that complex gene therapies will eventually become available to replace gene sequences that promote necrosis with those that support autophagy. healthy into old age. Such therapies, however, are many years old.

Eat less, live longer

A known way to induce autophagy is calorie restriction. In experiments with worms, flies, mice, chimpanzees, and humans, researchers found that consuming less food or restricting an organism’s feeding times in a given day activated the autophagy.

In non-human species, dietary restriction has also been found to prolong lifespan and reduce or delay the onset of age-related conditions. Depending on the species, the most promising results show lifespan extensions of between 50 and 300%. There is compelling evidence that dietary restriction also has positive effects on aging in primates, although the effects in humans remain controversial.

Why might being hungry help? Quite simply, when an organism’s diet is restricted, its cells starve themselves of glucose and begin to consume their own redundant material to generate energy. In other words, to sustain themselves, cells are forced into a detoxifying state of autophagy.

Disease prevention

The problem with dietary restrictions is that people generally don’t like them, and any attempt to reduce food intake tends to be short-lived in humans. Thus, when it comes to enhancing autophagy, pharmaceutical interventions are a much more realistic prospect (although Partridge points out that over-activation of autophagy can also be problematic, as it can lead to destruction by cells of their contents at unfavorably high levels).

A number of promising drug candidates have already been identified. Most notable are urolithin A (produced by certain gut bacteria after being fed ellagitannins, found in pomegranates, strawberries, raspberries and walnuts) and rapamycin (a natural antifungal produced by soil bacteria) .

Both of these compounds are known to be involved in the upregulation of autophagy. In mice, worms, and fruit flies, they have also been found to extend lifespan. Soon, the geroprotective properties of these compounds will be tested in human clinical trials.

Professor Partridge – who has studied the underlying mechanisms that make rapamycin effective in stimulating autophagy in animal models – hopes the results of the human trials will bring his team one step closer to developing their breakthrough polypill.

“Eventually, we could end up with a drug that is taken much like people today take statins (for cholesterol) or pills to lower blood pressure,” she said. “Drugs that are taken over a very long period of time to prevent health problems long before illness occurs.”

This article has been originally published in Horizonthe European magazine for research and innovation.

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