Imagine that all the world’s greatest doctors, veterinarians and scientists got together and were given unlimited resources to solve one problem: help a little hamster live as long as possible. We combine everything: the best living conditions, diet, medicines, transplantation of any damaged tissues or organs from young clone donors, the most beneficial mutations introduced before birth, every conceivable achievement of scientific and technological progress.
How long would such a hamster live? Alas, we do not have an answer to this question. Although we know that individual mutations, diets and gene therapies can extend the life of rodents by tens of percent. But to combine different methods of combating aging and death is an interesting idea, but technically complex and costly.
Yet we know that aging is associated with a wide range of adverse processes acting together. Let’s remember them together?
In general, aging is very difficult. We already know how to influence some of the mechanisms of animal aging. For example, gene therapy allows you to build telomeres to the desired length.
Autophagy activators may promote “junk digestion”. Senolytic drugs help to get rid of old cells that can cause inflammation or become cancerous. Mutations and genes are known to reduce oxidative stress or DNA damage. But even if one of the mechanisms of aging is suppressed, this does not cancel all the others.
Will the effect of such impacts be cumulative, and if so, how? Perhaps the effect will be greater than the simple sum of the terms? How do different genes associated with aging interact? Which aging factors are the most important now, and which ones would come to the fore if the body lived longer?
Scientists became interested in these issues within the framework of the Open Longevity project. They came up with a series of experiments, however, not on rodents, but on flies, in which it is supposed to combine different mutations associated with longevity. Drosophila is a convenient and informative model object for studying aging. Many of the genes and metabolic pathways already discovered that are associated with longevity are similar in humans and other animals, including flies. At the same time, fruit flies multiply rapidly, they are cheap to maintain, and experiments on studying the factors affecting their life expectancy have been going on for more than a hundred years1.
Indeed, in Drosophila, a number of genes are known, the switching off or a change in the activity of which can prolong the life of the organism, and thanks to completely different mechanisms.
The chico gene encodes a protein that binds to insulin receptors. Mutations in this gene can extend the life of flies by 1.5 times2. Insulin is a signal for cells to receive food. The lower the activation of insulin receptors, the more likely the cell is to be in a state of “preparation for adverse conditions”: the processes of intracellular digestion of “garbage” are launched, the synthesis of proteins that protect against DNA damage is activated, and not only.
Switching off or suppression of the puc (puckered) gene in Drosophila leads to an increase in lifespan through a different mechanism. Through the activation of a special signaling pathway that protects the cell from oxidative stress3.
The Indy gene (stands for I’m not dead yet ) codes for a protein involved in cell metabolism. Mutations in this gene prolong life4 by mimicking some of the effects of calorie restriction (restriction itself works in mice, roundworms, and many other animals, although not in all model organisms).
Mutations in the E(z) gene affect the lifespan of flies through an epigenetic mechanism5. The product of a gene is an enzyme that labels histones, proteins involved in the compact packaging of DNA. These marks affect the operation of a number of other genes. In particular, they suppress the activity of a gene that enhances cell resistance to oxidative stress.
I have listed examples of genes whose downregulation leads to longer lifespans in flies. But there are also many genes, the activity of which, on the contrary, should be spurred on. Probably the most interesting of these is the dFOXO gene6. The importance of this gene can be better demonstrated using the Hydra as an example. These coelenterates do not age, that is, with age, the likelihood of their death does not increase7. But it is worth turning off their FOXO gene (related to the fly) – and this rule is canceled8. Related analogues of this gene are involved in aging in a variety of animals, from roundworms to humans. Our species has a mutation in the FOXO3a gene that is much more common in ultra-centenarians than in the general population9.
At one time, the FOXO gene made such an impression on me that I mentioned it in my fantasy novel, The Harvard Necromancer. In the book, scientists try to extend the lives of mice by inserting a human version of the FOXO3a gene from super-centenarians. But in the end, they accidentally discover the magical properties of the sacrificed “humanized” (humanized by our genes) animals.
The genes of the FOXO family are genes for transcription factors, proteins that bind DNA and regulate the work of other genes. In a number of organisms, FOXOs are activated in response to starvation and, in turn, increase the synthesis of proteins that protect DNA from damage. Therefore, it is so interesting to see how the activation of this gene interacts with other mechanisms that affect longevity.
To turn off a gene, it is enough to remove it or break it with a mutation. But how to increase the activity of a particular gene? Today, experts have learned to do this very pointwise and massively.
There is a protein called Cas9 – these are specific molecular scissors that can cut DNA with a strictly defined nucleotide sequence (letters ATGC). The sequence for recognition is given by a special “guiding” molecule, which can be designed in an arbitrary way. It turns out something similar to “search with replacement” in modern text editors, but only for genes and other parts of DNA.
Scissors cut, but with the help of a separate mutation in the gene that encodes the Cas9 protein, they can be “blunted”. The resulting defective dCas9 protein still recognizes and binds the desired DNA region, but it can no longer cut. From a tool for cutting DNA, it has become a tool for sticking to DNA.
Other proteins are attached to such a dCas9 protein that can activate (or vice versa, suppress) the work of the target gene10. For example, the dFOXO gene in Drosophila cells. Moreover, the dCas9 protein can be given not one, but several “guiding” molecules in order to target it to several genes at once. Even more than that: it is possible to make sure that the activation of the dCas9 protein, and after it the target genes, occurs under certain conditions that are convenient for scientists.
By combining different mutations and variations in the activity of genes associated with longevity, we can finally study their synergistic effect. And this is very important, because in order to slow down aging, it is desirable to affect not one, but all the main mechanisms by which it occurs. This is exactly what specialists are trying to do within the framework of the project with Open Longevity.
Well, I will watch the scientists with interest, and then I will tell you about the results of their work.