Two genes of "senile memory"
Worms and mammals found two genes-the enemy of healthy aging
Polina Loseva, N+1
Chinese scientists have found two genes in roundworms that turn on in old age and inhibit their cognitive functions. Relatives of these genes were also found in mammals. It turned out that blocking these genes somewhat prolongs the life of mice, but more importantly, slows down their cognitive aging. The work was published in the journal Nature (Yuan et al., Two conserved epigenetic regulators prevent healthy aging).
The modern science of aging faces two tasks: to figure out how to increase life expectancy, and to make this extended life healthy. The second does not always follow the first: even among super-long-livers, there are not so many healthy people. Therefore, many researchers of aging focus on individual age-related changes in the body and try to find a way to target them.
Jie Yuan from The University of the Chinese Academy of Sciences together with colleagues worked on C.elegans nematodes. As a target in the fight against aging, they used the BAS-1 protein, which in roundworms is involved in the synthesis of serotonin and dopamine. With age, its concentration in tissues decreases, and after it the number of neurotransmitters decreases. This leads to the fact that in old nematodes, both motor functions (for example, the activity of swallowing food) and behavioral skills (for example, finding a partner or reacting to food) deteriorate. In this sense, the aging of worms resembles the aging of humans: with age–related neurodegeneration, the concentration of neurotransmitters in the brain can also decrease, for example, dopamine - in Parkinson's disease.
Scientists have derived a line of nematodes in which BAS-1 was expressed together with a green fluorescent protein. Thus, by the intensity of the glow, it was possible to conclude whether its concentration decreases with age or not. To find the genes responsible for the drop in concentration, the researchers used RNA interference. This is a method in which RNA, complementary RNA of the gene under study, is introduced into the body, then they form a duplex, and intracellular interference mechanisms destroy it, stopping the work of the gene. The researchers tested 80 percent of all nematode genes: they derived many bacterial lines, each of which produced RNA to interfere with one of the nematode genes. The worms were then fed these bacteria and the intensity of BAS-1 fluorescence in old age was compared.
At the initial stage, 16250 bacterial lines participated in the experiment – that is, scientists tested 16250 genes. After three rounds of selection, 59 genes remained, the blocking of which best allowed maintaining the concentration of BAS-1. The researchers built a hypothetical network of their interaction and identified several central genes. For them, scientists managed to find orthologs (that is, genes with a common origin and function) in the human genome.
As a result, two genes were the most influential and associated with aging not only in nematodes, but also in humans. One of them, SET-6, encodes a methyltransferase– a protein that attaches an epigenetic (methyl) label to histone proteins on which DNA is wound in the nucleus. This is necessary for certain sections of DNA strands to fold or unfold, "closing" or "opening" the information recorded in them. The second important gene, BAZ–2, encodes a protein that recognizes these epigenetic labels. The authors found both of these proteins in the nuclei of nerve cells throughout the body of nematodes, and their concentration increased 1.5-2 times with age.
Scientists blocked the work of these two genes in worms and found that, both together and singly, their blocking increases the concentration of BAS-1, serotonin and dopamine in the tissues of nematodes – however, only in old age, and not in young. At the same time, the mutant worms also partially recovered the functions of the nervous system - for example, they performed swallowing movements about a third more often than ordinary old nematodes. In addition, the life expectancy of the mutants increased slightly but significantly (p<0.001) compared to the control group.
Since mutations in BAZ-2, SET-6 and both genes had the same effect at once, the researchers assumed that both proteins encoded by them were part of the same aging mechanism. Following this, they found out that both proteins bind to regulatory regions of the same genes – and found 2,383 such genes in nematode cells. Among these genes, there were especially many that are associated with mitochondria, ribosomes and protein synthesis. This is consistent with the data of previous studies, in which it has been repeatedly shown that active protein production accelerates cell aging – probably, BAZ-2 and SET-6 can trigger this process in nematode neurons as well.
Then the scientists switched to mammals and found that the concentration of homologous proteins BAZ-2 and SET-6 also increases in the brains of mice with age (in mice it is BAZ2B and EHMT1). Their functions, apparently, in mammals are also about the same as in nematodes – they also bind to the regulatory regions of genes and also suppress the production of mitochondrial proteins. Many neurodegenerative diseases are associated with mitochondrial dysfunction today, so the researchers checked what happens to cognitive functions in mice mutated by these two genes. It turned out that mice with Baz2b turned off live several tens of days longer than ordinary animals, and are better trained and oriented in space (p=0.012).
This study is a clear example of how working with model organisms that are far from humans can bring practical results. Nematodes allow you to quickly check thousands of genes and isolate key ones from them, and you can confirm their specific functions during aging already in mice. At the next stage of the work, scientists will have to check what happens in humans with the orthologs of these genes, and whether it is possible to somehow use their blocking in order to make aging healthier.
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