Two strikes…
Two genes saved mice from four age-related diseases
Polina Loseva, N+1
Harvard scientists have tested the method of gene therapy cocktails on mice. They injected the animals with viral constructs with three genes that are associated with longevity, and found that only two genes are enough to cure four age-related diseases: obesity, type 2 diabetes, as well as kidney and heart failure.
The study is published in the journal Proceedings of the National Academy of Sciences (Davidsohn et al., A single combination gene therapy treats multiple age-related diseases).
There are many ways to prolong the life of individual animals — with the help of diet, medications or surgery. However, genetic manipulations remain the most effective so far. The record holders for longevity — flies and worms that live several times longer than the average — are all transgenic animals that have some important gene constantly turned on or off.
Several such genes are already known, but it is not yet possible to transfer this success to humans — for this it would have to create transgenic people. As an intermediate solution, gene therapy can act — the introduction of the necessary genes into the cells of the body with the help of neutralized viruses.
A group of Harvard scientists led by George Church tested a gene therapy approach in adult mice. The researchers selected three genes that are associated with longevity and resistance to age-related diseases. The first one — fibroblast growth factor 21 (FGF21) — affects metabolism and, in particular, glucose metabolism. The second — aKlotho — provides protection from damage to the heart and kidneys. The third is transforming growth factor β1 (TGFß1) — it is connected, among other things, with the restructuring of the matrix and the work of immunity.
Scientists injected mice with gene-therapeutic constructs based on adenoviruses that contained one, two or all three target genes. First, they confirmed that the introduction of adenoviruses in itself does not cause pathologies in animals, but increases the level of expression of these target genes.
Then the authors tested how gene therapy affects the development of age-related diseases in mice. Their first target was obesity. Scientists kept mice on a high-fat diet for three months, during which time the animals gained an additional 56 percent of body weight. Then they were injected with different combinations of genes and weight changes were tracked. It turned out that FGF21 alone is enough for the weight to return to normal, regardless of whether this gene acted alone or together with others.
The second target disease was type 2 diabetes, which often develops in conditions of obesity and a high-fat diet. The researchers measured blood glucose and insulin concentrations before and after meals and found that FGF21 allowed mice on a high-fat diet to reach values comparable to the control group that ate a regular meal. The other two genes had a much weaker and statistically insignificant effect.
As the third target, the scientists chose kidney fibrosis, a disease in which normal kidney tissue is replaced by connective tissue. They assessed the percentage of preserved kidney tissue and the number of fibroblasts — connective tissue cells in the kidneys. It turned out that all three genes are effective against the destruction of the kidney, but the combination of FGF21 and TGFß1 worked best — in this case, the level of atrophy was only 6.5 percent, compared with 22.5 percent — under the action of aKlotho alone.
Finally, the role of the last age-related disease was performed by fibrosis of the heart and heart failure developing as a result of it. They were evaluated by the amount of connective tissue in the heart and the amount of blood ejected by the heart. The researchers found that the maximum effect could be achieved using a combination of TGFß1 with one of the other genes, but the combination of all three genes did not help to cope with the disease.
Thus, the pair FGF21 and TGFß1 turned out to be the best gene-therapeutic cocktail of the tested ones. Together they made it possible to mitigate the symptoms of four age-related diseases that affect different organ systems.
The authors hope that sooner or later this approach can be applied to humans. In their opinion, it should be more effective than traditional methods of treatment, which fight each disease separately, ignoring the fact that the body ages as a whole, and the work of different organs is closely related to each other.
In addition, gene therapy cocktails may be safer than conventional treatments, since they do not require the introduction of many drugs that can counteract each other and cause side effects. In this work, the researchers also faced a similar opposition — when the result from three genes turned out to be worse than from two — but the two genes remaining in the cocktail do not interfere with each other's work.
The idea of fighting aging not with individual drugs, but with mixtures or cocktails, is gradually gaining popularity among gerontologists. Recently we have already written about how some scientists extended the life of fruit flies with a cocktail of three drugs, and the other three drugs reversed epigenetic aging of humans.
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