Progeria Pill
Cancer drug has become the first pill against premature aging
Polina Loseva, N+1
The first drug for patients with Hutchinson-Guilford progeria, an incurable congenital disease resembling premature aging, has been approved in the USA. This is a repurposed antitumor drug. According to the results of clinical trials, it can prolong the life of patients from several months to several years – depending on the age and how long it is taken.
Hutchinson-Guilford progeria is the most famous and the most severe of the diseases of premature aging. It manifests itself from birth, when children are born with a number of signs characteristic of the elderly: they have wrinkled skin, swollen joints, a disproportionately wide head and a "beak-shaped" face narrowed to the chin.
The cause of all these pathologies – as well as many others related to internal organs – is the protein lamin A. Normally, it is needed to organize the space inside the cell nucleus: it lines the shell of the nucleus from the inside and fixes DNA strands around it. To lamin And just happened to be near the nuclear envelope, it is recognized by the enzyme farnesyltransferase and hangs a hydrophobic "tail" on it. This "tail" lamin And anchors in the membrane, taking its place in the nucleus. Later, other enzymes cut off this "tail", and lamin A remains near the shell, but is not directly connected to it.
In patients with progeria in the lamin gene And there is a mutation, because of which the protein turns out to be shorter than usual. Therefore, at first everything goes according to plan: farnesyltransferase recognizes it and puts a "tail" on it, and with the "tail" the mutant protein is embedded in the membrane of the nucleus. But after that, other enzymes cannot get rid of its "tail", since the mutant lamin A is deprived of a site for which they could grab. Therefore, it remains embedded in the membrane of the nucleus, due to which the entire nucleus loses elasticity, the organization of DNA inside is disrupted, it becomes difficult for the cell to divide and copy genetic information without errors. As a result, people with such a mutation rarely survive the 15th anniversary and die from typical age-related diseases – for example, heart failure or stroke.
This is what happens in the nuclear envelope of cells with mutant lamin A (Gordon et al. / JAMA, 2018).
Since this mutation always occurs de novo and it happens quite rarely, it is usually impossible to detect the disease in the early stages. It is also not yet possible to repair the lamin A gene in all cells of a progeria patient. Therefore, the only way to prolong their life is to try to compensate for the defect of lamin A. This is how lonafarnib, the first approved progeria drug, works. This is a long-known antitumor drug.
Lonafarnib serves as a farnesyltransferase blocker. It prevents it from hanging a hydrophobic tail on lamin A, so the mutant protein, although it does not begin to work at full strength, still does not deform the membrane of the cell nucleus. This is enough to reduce mortality in patients with progeria. According to the manufacturer of lonafarnib, within two years of taking the drug, the risk of death in patients is reduced by 77 percent. Among those who took lonafarnib for more than 11 years during long-term trials, the average life expectancy increased by 2.5 years compared to the placebo group.
The probability of survival for 2.5 years in patients with progeria increases when taking lonafarnib (blue line). On the right is a photo of cell nuclei in a healthy cell, a cell with progeria and a cell under the action of lonafarnib, respectively (picture from the website eigerbio.com ).
Thus, a medicine has finally appeared in the world that at least partially solves the problem of premature aging. However, it has nothing to do with medicines for aging "ordinary", timely. Although the processes that lead progeria patients to early death are in many ways similar to the natural mechanisms of aging, their cause is completely different. Therefore, lonafarnib will not help people without a corresponding mutation and with a normal structure of the cell nucleus to cope with aging.
With drugs for "normal" aging, the situation is much more complicated. However, some time ago, scientists still managed to "unscrew" the age of a person backwards – if measured using an epigenetic clock. To do this, they needed a cure for diabetes and a couple of hormones. In addition, recently people have learned "grow out" telomeres with oxygen – however, the data of this experiment are still in doubt, and it is not known whether this result is related to rejuvenation.
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