Can we prevent aging by ‘protecting’ our proteins?

  • Even if their DNA is damaged and broken into hundreds of fragments, certain bacteria can ‘survive’ by reconstructing their genetic heritage, according to our partner. The conversation.
  • This suggests that it is the proteome (a set of proteins), more than DNA, that we need to protect to extend our own lifespan.
  • This analysis was carried out by Miroslav Radmanprofessor of molecular biology at the National Institute of Health and Medical Research (Inserm).

It is largely thanks to a tiny, ultra-resistant bacterium that is able to ‘come back to life’ after extremely damaging attacks that existing theories about the chemistry of aging are being reworked.

It is about Deinococcus radiodurans, one of the most resistant bacteria known to date, which lives in dry environments such as desert sand. It survives in canned meat after the “shock” treatment of sterilization by gamma radiation. It can also survive a radiation dose 5,000 times greater than the lethal dose for humans.

Studies have shown that this bacterium survives even when its DNA is damaged by violent stress and broken into hundreds of fragments. In just a few hours, she completely restores her genetic heritage and returns to life. The DNA is not more resistant, it is simply immediately repaired by proteins that are indestructible in the face of this extreme radiation.

Deinococcus radiodurans is an extremophilic bacterium and one of the most radiation-resistant organisms known. Here it is seen by transmission electron microscopy – Michael Daly / Uniformed Services University -US Department of Energy

The secret of the robustness of this extremophilic bacterium thus depends on the robustness of its ‘proteome’ – all these proteins – and in particular its DNA repair proteins.

This suggests a new paradigm: to extend lifespan, and in particular that of humans, it is the proteome – more than DNA – that we must protect.

After all, the survival of the organism depends on the activity of its proteins. When we act against the change in the proteome, which is the basis of aging, we simultaneously intervene in all its consequences: for example, the survival and functioning of the cell; and we avoid mutations caused by radiation.

The keys to aging

Aging is characterized by the accumulation of events that deteriorate the functions of our organs, and by an exponential increase in the risk of death and disease over time.

Many models have been proposed to explain the molecular basis of aging, such as the theory of cellular senescence, the decrease in DNA repair capacity, the shortening of telomeres, mitochondrial dysfunction and oxidative stress or even the chronic inflammation.

These different models are all focused on trying to understand the consequences of aging, rather than its causes. The central dogma ‘DNA -> RNA -> proteins’, which denotes the relationships between DNA, RNA and proteins and refers to the idea that this relationship is unidirectional (i.e. DNA to proteins via RNA), now deserves reconsideration.

Triple helix of collagen, a structural protein that contributes to the skin’s resistance – Naos

What if, instead of first being interested in our DNA and trying to protect it to slow our aging, we protected our proteome?

What is the proteome?

The term ‘proteome’ refers to all proteins present in a cell or in an organism. Proteins – from the Greek protos meaning ‘first’ – represent the second main component of the human body, after water, or about 20% of its mass.

The term ‘proteome’ was constructed in analogy to the genome: the proteome is to proteins what the genome is to genes, i.e. the set of genes/proteins of an individual – this variant protein set is dependent on gene activity.

The proteome is indeed a dynamic entity, continuously adapting to the needs of the cell in relation to its environment. Proteins are essential molecules for the construction and functioning of all living organisms. Approximately 650,000 interactive protein-protein networks have been identified in various organisms, including approximately 250,000 in humans.

Proteins perform a wide range of functions:

  • A structural role: numerous proteins ensure the structure of each cell and the maintenance and cohesion of our tissues. For example, actin and tubulin participate in the architecture of the cell. Keratin is that of our epidermis, our hair and our nails. Collagen is a protein that plays an important role in the structure of bones, cartilage and skin.
  • A functional role: enzymatic (for example, proteases participate in the cleansing of dysfunctional proteins and in desquamation), hormonal (for example, insulin regulates blood sugar levels), transport (for example, aquaporins transport water in the different layers of the skin) or defense (for example, immunoglobulins take participate in the immune response). Thus, all vital functions are ensured by the activity of proteins.

“Carbonylation”, the main cause of irreversible changes to our proteome

The balance between the synthesis of new proteins and their breakdown is called proteostasis. This is necessary for the functioning of our body.

But this equilibrium state is sensitive. In fact, it is under constant threat because protein synthesis and breakdown depend on proteins. With time and external attacks, the proteome is subject to several changes, the most formidable of which is ‘carbonylation’, irreversible damage associated with protein oxidation.

Carbonylated proteins are permanently modified. They can no longer perform their biological functions properly; and sometimes even acquire toxic functions in the form of small aggregates.

When damaged beyond repair, proteins must be recycled or discarded. With aging, this elimination becomes more difficult, which can lead to its accumulation in the form of toxic aggregates that impair cellular physiology and accelerate aging. Above a certain threshold, these aggregates are harmful to the body: a state of proteotoxicity then arises.

The loss of proteostasis, that is, the balance between the synthesis of new proteins and their degradation, due to the accumulation of protein aggregates, is the central cause of aging and degenerative diseases. These carbonylated protein aggregates are found in most age-related diseases, as well as the major signs of skin aging.

Thus, while our view of aging has so far focused on the genome, recent research on the proteome introduces the importance of the accumulation of damaged proteins as a key factor in the aging process as a whole.

Antioxidant chaperone molecules, which act on the causes of aging

To fold properly, most proteins need help from specialized proteins called ‘chaperones’. Chaperone molecules are small proteins that help and assist in the normal folding of proteins after their synthesis by ribosomes, or in their correct folding after stress, such as heat stress.

Illustration of the extraction of bacterioruberins from the bacterium Arthrobacter agilis – bacterioruberins are antioxidant biological pigments with a chaperone effect, which protect the proteome – Naos

The term chaperone molecule – of French origin, although proposed by John Ellis and Sean Hemmingsen – was adopted because their role is to prevent unwanted interactions and break incorrect bonds that may form, such as in a human chaperone. In short, chaperones (protein or chemical) are the doctors of poorly formed proteins!

Back to the bacteria Deinococcus radiodurans : Here, chaperones play a key role in protecting proteins from carbonylation, preventing their amino acids from being exposed to free radicals or ROS. They thus reduce their sensitivity to changes and limit the formation of aggregates. At the same time, their antioxidant action neutralizes the causes of carbonylation.

These antioxidant chaperone proteins therefore provide an effective means of protecting the proteome, providing both physical protection of the functional structure of proteins and a protein-bound antioxidant shield that protects against damage such as carbonylation.

At the house of Deinococcus radioduransThanks to the effective protection of its proteome from oxidative damage by chemical chaperone molecules, rather than its genome, its intact proteome is then able to repair the damage to its genome and finally so that he can be resuscitated within a few hours.

In addition to the genome, the protection of our proteome, that is to say our proteins, can today be considered the key to our health and longevity. Every other theory of aging is compatible with this theory and can be interpreted by it.

This article was produced by The Conversation and hosted by 20 Minutes.

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