The old people were rejuvenated

Genetic intervention has prolonged the life of very old worms

Polina Loseva, N+1

Researchers of aging in an experiment with nematodes managed to extend their life span twice. This is not a record value in itself, but it is important that scientists acted on the worms at the very end of their life, when a significant part of the population has already died. The method they used cannot yet be transferred to humans, but the very fact of their success means that life extension technologies can also be effective in old organisms.

Article by Venz et al. End-of-life targeted auxin-mediated degradation of DAF-2 Insulin/IGF-1 receptor promotes longevity free from growth-related pathologies published in the journal eLife.

The nematode C.elegans is one of the most studied animals from the point of view of gerontology (and not only). The daf-2 gene is one of the most studied in the genome of C.elegans, because mutations in it double the lifespan of worms. This gene (more precisely, its homologues) is also present in humans: in our body, the genes of insulin and the receptor for insulin-like growth factor-1 originated from daf-2. And today it is known that mutations in these genes affect the life of mammals: mice with mutant IGF-1 live longer than normal, and long-lived people also sometimes find variants of this gene.

Based on these data, one could hope that a recipe for prolonging life has been found: it is enough to turn off the work of some of these genes or other proteins from the same signaling pathway. However, experiments on the same nematodes show that there is a problem with this. If the mutation seriously disrupts the work of daf-2, some animals stop at the early stages of larval development (go into the state of the so-called Dower larva) and do not grow into adult worms. Less severe mutations also affect the quality of life of nematodes: even those individuals that have passed through the larval stages turn out to be smaller and less fertile than usual.

There is an explanation for this: the signaling pathways associated with daf-2 react to the intake of energy into the body and trigger the processes of growth and development. At the cellular level, this is protein synthesis and division, at the level of the body – the development of sexual organs and puberty. If these processes are slowed down, then the nematode (and, probably, the person too) can really live longer – since reproduction will not take over the resources of the body – but the quality of this life and fertility will inevitably suffer.

Therefore, a group of researchers led by Collin Ewald from the Institute of Translational Medicine in Zurich is looking for a way to interfere with the work of these signaling pathways after the individual has formed and managed to reproduce. The only question is whether it is possible to influence the life span of the body if you start doing it so late.

Previously, scientists tried to get close to daf-2 using RNA interference - this method destroys the RNA that is built from the gene. However, this approach turned out to be not reliable: it did not prolong life in the same way as mutations in the gene, and it did not work in adults yet. This time, the researchers tried a new method. They built into the daf-2 gene a sequence encoding a degron, a label borrowed from the proteins of the arabidopsis plant, which signals to intracellular enzymes that this protein needs to be destroyed. But it works only in the presence of the plant hormone auxin.

Thus, by introducing auxin into the body of the nematode, scientists were able to turn off the work of the DAF-2 protein – it became about 40 percent less in cells. This corresponds to the effect of not the strongest mutation, which does not completely destroy the work of the gene. Auxin had a similar effect on the physiology of nematodes: they stopped developing and all passed into the state of Dower larvae – but only in stressful conditions for worms, at a temperature of 25 degrees. Weak mutations also act in the same way, but the complete blockade of the gene ends with the formation of Dower larvae already at 15 degrees.

The researchers then tested what happens if auxin is applied to adult nematodes that have already completed their development. It turned out that their life is really getting longer – by 70-135 percent.

The survival curve of adult nematodes. Black, red and blue – control, yellow, red, green and pink – daf-2 mutants with and without auxin, blue – nematodes with built-in degron and auxin. Drawings from an article in eLife.

To get this effect, it turned out to be enough to act on some key tissues. When the authors of the work introduced the auxin regulation system selectively into the nervous tissue or intestines, they found that the prolongation of the life of these tissues also affects the lifespan of the organism – nematodes lasted on average up to 50 days against the usual 30.

The survival curve of nematodes depends on which tissues the auxin-degron system works in. Red – all over the body, pink – in the intestines, blue – in the muscles, the rest of the curves – different types of controls.

Finally, the scientists tested their method on elderly worms – those who have already ended the breeding period (older than 8 days). When auxin was added to the nutrient medium of 10- and 12-day-old nematodes, their life lengthened by 48-72 and 49-57 percent, respectively. But even in an experiment with very old animals, aged 21 and 25 days – up to this point, three quarters of the population no longer survives even in laboratory conditions – feeding auxin allowed nematodes to live another 43 days.

Prolonging the life of nematodes in old age. Black is the control curve, red is the auxin added on the 20th day of life, blue is on the 25th.

Thus, the authors of the work demonstrated that interference with the daf-2 signaling pathway can prolong the life of an organism even at its very end. And although it is unlikely to be possible to project this method directly on a person – it would require its genetic modification – this means that interventions in the work of the insulin pathway can be very effective even in old age.

However, the researchers did not set out to rejuvenate the nematodes – only to extend their life span. And about how gerontologists are going to achieve exactly the rejuvenation of a person, read the article "Plans for old age".

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