The mechanism of record longevity
Longevity of mutant worms explained through mitochondria
Polina Loseva, N+1
Scientists have discovered a mechanism that allows nematodes – double mutants – to live five times longer than usual. It turned out that two signaling pathways, the work of which they have disrupted, "intersect" in the mitochondria. Together, both mutations inhibit the mitochondria's energy production, which triggers an anti-stress response in the body's cells. The study was published in the journal Cell Reports (Lan et al., Translational Regulation of Non-autonomous Mitochondrial Stress Response Promotes Longevity).
Among all the ways to prolong life that scientists are trying on different model organisms, genetic ones have been the most effective so far. Every time a worm or fly begins to live several times longer than usual, one or another mutation introduced by researchers is at the heart of its longevity.
The most successful are usually mutants in proteins that are responsible for growth and metabolism in the animal's body. The genes encoding them are extremely conservative, so it is convenient to study them on C.elegans nematodes – in humans they work according to the same principles. The leading role among them belongs to two proteins. The first is the TOR complex, which triggers the synthesis of proteins in the cell. The second is insulin–like growth factor-1 (IGF-1), which boosts metabolism, forcing the cell to absorb and spend more energy.
In 2013, a group of researchers led by Di Chen from Nanjing University has created a double mutant nematode, in which the genes daf–2 (analog of human IGF-1) and rsks-1 (which stimulates protein synthesis under the action of the TOR analog) were simultaneously turned off. Each of these mutations individually can prolong the life of the worm, but only by 30-100 percent. The double mutant was able to live 5 times longer than usual. This allowed scientists to assume that the two mutations do not act in ways independent of each other, but synergistically, that is, they enhance each other's action.
In the new work, Chen and his colleagues went in search of mechanisms that could combine these two signaling pathways: the path of protein synthesis and the path of energy absorption and waste. To do this, the researchers sequenced RNAs that are bound to ribosomes (that is, they are in the process of protein synthesis) in the cells of double mutants and ordinary nematodes. Comparing these two sets, scientists have identified 115 proteins, the synthesis of which is suppressed in long-lived mutants. They suggested that one of them plays an important role in limiting the length of life (and suppressing its production, on the contrary, lengthens the life of nematodes).
To find the key protein among these 115, the researchers used the method of RNA interference: they blocked their production singly in different individuals. It turned out that in 39 cases out of 115 nematodes stopped developing at the larval stage, that is, these 39 proteins were necessary for the growth and development of worms. This observation fits into the framework of the theory of antagonistic pleiotropy. According to her, aging is the result of a double action of genes: at the beginning of life they stimulate the growth and development of an individual, and then have a side effect, accelerating its aging and bringing death closer. Thus, the authors of the work found a pleiotropic effect in these 39 proteins: their blocking stopped development at an early age, but they did not work in adult long-lived worms.
The suppression of the cyc-2.1 protein extended the life of adult worms the most – almost twice. Therefore, the researchers assumed that this is the intermediary between the two signaling pathways that they are interested in. This protein, cytochrome C, is one of the elements of the mitochondrial respiratory chain: it transports electrons during cellular respiration, that is, obtaining energy from food. To check whether he really works as an intermediary, the researchers bred triple mutants: daf-2 rsks-1 cyc-2.1. However, they lived as long as the doubles, from which scientists concluded that cyc-2.1 does not introduce new changes in the life of nematodes, but only mediates the action of other genes.
Thus, the key to the synergy of the two signaling pathways turned out to be inside the mitochondria. Apparently, the final picture looks like this. Protein synthesis, including cyc-2.1 protein, is suppressed in rsks-1 mutants, that is, less of it enters the mitochondria. If these mutants are also deprived of daf-2, then there are few substrates for obtaining energy in the mitochondria. In conditions of energy deficiency and low activity, mitochondria secrete signaling substances – mitokines (they are known not only in worms, but also in other animals, including humans), which, in turn, give an "alarm signal" to surrounding cells and enhance their response to stress. Therefore, such animals are better able to tolerate both external and internal stresses (for example, oxidative stress, which occurs during breathing and inflammation) and live longer.
Recently, there have been many papers in which scientists are investigating the synergy of several mechanisms in prolonging life. Thus, for example, they made a "cocktail" of three drugs to prolong the life of flies, cured four age-related diseases in mice with the help of two genes, and even reduced the epigenetic age of a person with three drugs.
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