What if protecting our proteins allowed us to age well? The role of the proteonome could be absolutely central for the prevention of old age and, ultimately, for increasing human longevity.
It is in particular thanks to a small, ultra-resistant bacteria capable of “coming back to life” after extremely harmful attacks that existing theories on the chemistry of aging are being reworked.
It is Deinococcus radiodurans, one of the most resistant bacteria known to date, which lives in arid environments such as desert sand. It survives in canned meats 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 bacteria survives even if its DNA is damaged and broken into several hundred fragments due to violent stress. In just a few hours, she completely reconstitutes her genetic heritage and returns to life. Its DNA is not more resistant, it is simply repaired immediately by proteins that are indestructible in the face of this extreme radiation.
Thus, the secret of the robustness of this extremophilic bacteria depends on the robustness of its “proteome” – all of these proteins – and in particular its DNA repair proteins.
This suggests a new paradigm: to increase longevity, and in particular that of humans, it is the proteome – more than DNA – that we must protect.
Indeed, the survival of the organism depends on the activity of its proteins. If we act against the alteration of the proteome, which is at the origin of aging, we intervene simultaneously on all of its consequences: for example cell survival and functioning; and we avoid mutations induced by radiation.
Identify the causes of 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, telomere shortening, mitochondrial dysfunction and oxidative stress or even the chronic inflammation.
These different models all focus on trying to understand the consequences of aging, and not the causes. The central dogma “DNA -> RNA -> proteins”, which designates the relationships between DNA, RNA and proteins and which refers to the idea that this relationship is unidirectional (i.e. DNA to proteins via RNA), now deserves to be reconsidered.
Indeed, what if rather than being first interested in our DNA and seeking to protect it to slow down our aging, we protected our proteome?
What is the proteome?
The term “proteome” refers to all the proteins present in a cell or in an organism. Protein – from the Greek protos which means “first” – represent the second main constituent of the human body, after water, or around 20% of its mass.
The term “proteome” was constructed by analogy with the genome: the proteome being to proteins what the genome is to genes, that is to say the set of genes/proteins of an individual – this variant protein set depending on gene activity.
Indeed, the proteome is a dynamic entity, which constantly adapts 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 protein-protein interactive networks have been identified in various organisms, including approximately 250,000 in humans.
Proteins perform a wide variety of functions:
- A structural role: numerous proteins provide 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 cleaning of dysfunctional proteins and in desquamation), hormonal (for example, insulin regulates blood sugar), transport (for example, aquaporins transport water in the different layers of the skin) or defense (for example, immunoglobulins participate in the immune response). Thus, all vital functions are ensured by the activity of proteins.
What causes the irreparable alteration of 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 state of equilibrium is sensitive. It is even constantly threatened, because the synthesis and degradation of proteins depend… on proteins. With time and external attacks, the proteome is subject to various alterations, the most formidable of which is “carbonylation”, irreversible damage linked to protein oxidation.
Carbonylated proteins are permanently modified. They can no longer properly perform their biological functions; and sometimes even acquire toxic functions in the form of small aggregates.
When damaged beyond repair, proteins must be recycled or disposed of. With age, this elimination becomes more difficult, which can cause their accumulation in the form of toxic aggregates which hinder cellular physiology and accelerate aging. Beyond a certain threshold, these aggregates are harmful to the body: a state of proteotoxicity then sets in.
The loss of proteostasis, that is to say the balance between the synthesis of new proteins and their degradation, due to the accumulation of protein aggregates, constitutes the central cause in aging and degenerative diseases. These carbonylated protein aggregates are found in most age-related diseases, as well as in the main signs of skin aging.
Thus, while our vision of aging has until now been centered 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.
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.
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 can form, like ‘a human chaperone. In short, chaperones (protein or chemical) are the doctors of malformed proteins!
Back to the bacteria Deinococcus radiodurans, here, chaperones play a key role in protecting proteins against carbonylation, preventing their amino acids from being exposed to free radicals or ROS. Thus, they reduce their susceptibility to alterations and limit the formation of aggregates. At the same time, their antioxidant effectiveness neutralizes the causes of carbonylation.
These antioxidant chaperone proteins therefore constitute 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 effective protection of its proteome against oxidative damage by chemical chaperone molecules, rather than of its genome, its intact proteome is then able to repair the damage caused to its genome and ultimately to allow him to resuscitate in a few hours.
Beyond the genome, the protection of our proteome, that is to say our proteins, can be considered today as the key to our health and our longevity. Any other theory of aging is compatible with this theory, and can be interpreted by it.
Miroslav Radman, Professor, Inserm
This article is republished from The Conversation under a Creative Commons license. Read the original article.
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