delay the diseases of aging

On aging fish, folding proteins and a new route for the development of medicinal substances

Life expectancy increased significantly during the 20th century, and with it the rate of senile diseases also increased. With advancing age (and especially from the fifth decade of life), physical phenomena develop - such as cell degeneration, DNA damage, weakening of the immune system and malfunctions in protein folding (so that their structure is damaged). All of these lead to diseases, and damage to physical and mental health. Researchers are trying to find ways to slow down the rate of aging (for example, genetic or pharmaceutical treatment methods), to reduce or postpone the diseases of aging.What is the question? How and why do proteins in the body mimic proteins that fold incorrectly?

Dr. Itamar Harel and his team from the Institute of Life Sciences at the Hebrew University are studying the biology of aging in vertebrates using an innovative model for research in this field: an African turquoise killifish;

The life span of this fish lasts only four to six months, so it is relatively easy to study its aging. Dr. Harel: "Using this fish, it is possible to examine manipulations that may affect the rate of aging and delay devastating age-related diseases, including neurodegenerative diseases, such as Alzheimer's and Parkinson's, as well as cancer, diabetes, and cardiovascular diseases."

In their latest study, which won a research grant from the National Science Foundation, Dr. Harel and his team examined the protein folding process in this fish. For the most part, the proteins in the body - which are made from chains of amino acids - have a defined three-dimensional structure that allows them to function. There are many diseases that are caused by malfunctions in the folding of the amino acid chain into the three-dimensional structure, including those related to aging (such as Parkinson's and Alzheimer's). In addition to impairing their function, proteins that fold incorrectly can spread and infect other proteins. The researchers wanted to understand who those proteins are whose folding is damaged with age and if they accumulate in the organs. To this end, they isolated tissues from young and old fish, such as those taken from the brain, liver, intestine, muscle, reproductive organs and skin. They checked the identity of the proteins in these tissues using advanced genomic and molecular methods, and tried to locate those that undergo misfolding, and which, despite this, are not removed from the cell and accumulate ("aggregation"). They discovered in the tissues of the old fish many proteins that undergo increased aggregation, and each organ examined had a unique combination of such proteins. For example, the main defective protein discovered in the brain was DDX5, which is related to the processing of genetic material that is essential for brain function. No aggregation was detected in the tissues of the young fish. There are many diseases that are caused by malfunctions in the folding of the amino acid chain into the three-dimensional structure, including those related to aging (such as Parkinson's and Alzheimer's).

Later, the researchers introduced the damaged proteins into cultures of human cells and the brains of old mice, and found with molecular methods that the aggregation of DDX5 also occurs in mammals. Moreover, it turned out that it can infect other proteins and thus they too begin to fold incorrectly and their function is impaired. Next, the researchers plan to inject defective proteins such as DDX5 into the brains of fish and examine how they will be affected by this.

Dr. Harel says: "This research helps us understand that there are proteins that undergo increased aggregation with age and behave like prions (infectious proteins). Now it is important for us to find out why they behave this way and when it happens to them, at what stage in life. If we understand, for example, that at a certain time in the life cycle the proteins are affected by some process in the body that causes them to aggregate - we may be able to develop strategies that will stop this process; We will try to understand the biochemical basis of the damaged proteins - and develop medicinal substances that will inhibit it."

Life itself:

Dr. Itamar Harel, 40 years old, did a post-doctorate in the genetics of aging at Stanford University. He lives in Jerusalem, married to Guy (computer science researcher at the Hebrew University) and father to Alon (3 and a half years old). likes to dive, cook, eat, travel, draw and guide his group in the laboratory ("I enjoy looking at research discoveries through the eyes of young researchers").

More of the topic in Hayadan:

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• About aging - and the research that may show how to stop it