Paradoxical effect
Intestinal bacteria of old mice forced the neurons of young ones to divide
Polina Loseva, N+1
Scientists transplanted bacteria from old mice to young ones and found that cells in their intestines and brains began to divide more actively. This refutes the existing ideas that the microbiota in the old body only aggravates aging and impaired physiological functions. The researchers assigned butyrate, a short–chain fatty acid, to be responsible for stimulating stem cells. By itself, it also caused similar effects in mice. The work was published in the journal Science Translational Medicine (Kundu et al., Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice).
With age, the body changes not only the work of its own cells, but also the composition of the intestinal microbiome. It is still not clear what caused this – perhaps a change in diet or changes in the work of the intestine – but somehow the dominant clans of bacteria are losing their positions. Opportunistic species are coming to replace them – those who could not compete with them in a young organism.
A person and his microbes spend their whole life side by side, so it is difficult to say which of them begins to age first and causes the aging of the other. To sort this out somehow, scientists are trying to transplant intestinal bacteria between animals of different ages and look at the result. In previous experiments, it has already been found out that fecal transplantation from young donors to old ones can prolong the life of the recipient. This is true at least for short-lived fish.
A group of scientists from Singapore, China, Australia and the UK, led by Sven Pettersson from the Karolinska Institute in Stockholm, conducted a reverse experiment – researchers transplanted the microbiome from elderly mice to young ones. The donors were healthy 24-month–old animals (the life span of a laboratory mouse is 2-3 years), and the recipients were 2-3 month–old non-microbial mice. As a control, bacteria from ordinary young mice were transplanted into microbial mice.
The exchange of microbes consisted of two phases: fecal transplantation and living together in cells – so that skin bacteria could also colonize young recipients. Then the scientists took samples of the microbiota and confirmed that in young mice it became similar to the old ones, that is, the transplant was successful.
It is known that with age, the reserves of stem cells in the body are depleted, and the survivors are divided less often than in youth. Therefore, the researchers tested what happens in the hippocampus of recipient mice. This is one of the few areas in the brain where neurogenesis – the division of nerve tissue cells - continues in adult mice. Scientists found that after transplanting old microbes, the multiplying cells in the brain increased by about a quarter, and this effect persisted for several months.
To confirm their observation, the authors of the work paid attention to the intestines of mice. After the transplant, more villi appeared in it, and they themselves became longer. The number of dividing cells has also increased.
Researchers have suggested that microbes somehow affect the metabolism in the body - this could explain the impact on organs as far apart as the intestines and brain. Therefore, they calculated the level of expression of different genes in the liver, the main responsible for metabolism. It turned out that under the influence of "old" microbes in liver cells, genes that are associated with the response to stress began to work more actively – despite the fact that with age, cells react to stress, as a rule, worse and worse. In addition, the expression of genes associated with longevity, such as sirtuins, has increased, and the expression of mTOR, a protein that, on the contrary, accelerates aging, has decreased.
Scientists have suggested that the influence of microbes is based on some kind of metabolite that could pass through the blood-brain barrier. When they collected the intestinal bacteria metagenome from old mice, they found that there were quite a few butyrate producers among them. It is a short-chain fatty acid that feeds intestinal cells, is absorbed into the blood and acts on various other organs, including improving the cognitive abilities of animals and promotes learning.
When scientists fed young microbial–free mice with butyrate, they found the same effects as after bacterial transplantation - the same changes in gene expression in the liver and the growth of dividing cells in the hippocampus.
The animals from which the bacteria were transplanted were elderly, but healthy. This may mean that in some way they are similar to long-lived people. At the same time, it has long been known that people who live to a certain age accumulate "useful" opportunistic bacteria in the intestines, which do not disrupt the work of the body, but help it to adjust to another regime. Probably, bacteria from the intestines of mice act in approximately the same way, and butyrate is their main tool of influence.
Until now, it was believed that only bacterial transplantation or blood transfusion from young animals can have a beneficial effect on the body, including starting cell division in the hippocampus. But in this experiment, microbial transplantation from young mice to old mice did not increase the level of butyrate in the blood and did not force the cells to divide.
Tellingly, in this experiment, scientists found that the expression of the FGF21 growth factor is growing in liver cells, and the β–klotho receptor for it is growing in hippocampal cells. Recently, we talked about how gene therapy using these genes saved mice from several age-related diseases at once.
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