Let us consider that all the greatest medical minds, veterinarians and scientists will all get together and receive unlimited resources to solve one problem: helping the little hamster to live as long as possible. We combine everything: the best living conditions, diet, treatment, transplantation of any damaged tissues or organs from young clone donors, the most beneficial mutations introduced even before birth, and all the conceivable achievements of scientific and technological progress.

Yet we know that aging is associated with a сomplicated set of adverse processes operating together. We would be well advised to recall it together.

1.Before the cell is divided DNA duplication occurs but simultaneously the ends of chromosomes - telomeres become shortened;
2. DNA copying should not be considered unmistakable. Mutations are accumulated, which can subsequently causes the variety of disorders, including uncontrolled cell division (cancer);
3. The DNA injuries can also occur due to other factors: reactive oxygen species, ionizing radiation, some viruses and mobile (“jumping”) genetic elements;
4. Proteins located in cells can be folded improperly or be damaged consequently accumulating in the form of a kind of garbage that interferes with normal life;
5. Although the variety of different body cell types (muscle, nervous, epithelial, and so on) have the same DNA, different genes are active in them. These differences are “programmed”, including by special markers on DNA. By the aging essential markers can disappear, and incorrect ones can be collected, disrupting cell function;
6. Accumulation of mitochondrial or other organelles damages inside cells;
7. Wear and tear of connective tissue;
8. Inflammatory processes that cause new inflammatory processes;
9. Death of difficult-to-repair cell types;
10. And much more.

To sum up, aging is a very difficult process.

We are already capable of influencing some of the mechanisms of animal aging.For example, gene therapy permits lengthening telomeres to the necessary length. Autophagy activators may promote “junk digestion.” Senolytic drugs help get rid of old cells which cause inflammation or become cancerous. There are known mutations and genes reducing oxidative stress or DNA damage.

Even if one of the mechanisms of aging is suppressed, that doesn't cancel many others. Hence, the idea is to hit different target mechanisms of aging at the same moment. Will the effect of these impacts be summarized, and even though, how? Perhaps the effect will be greater than the simple sum of the parts. How do different aging associated genes interact? Which are the most important aging factors now, and which ones would come to the fore if the organism had lived longer?

Scientists became interested in these issues within the framework of the Open Longevity project. They came up with a series of experiments, though 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 longevity-associated genes and metabolic pathways already been discovered are similar in humans and other animals, including flies. In doing so Drosophila reproduce rapidly, and they are cheap to maintain, whereas experiments on the study of factors affecting their lifespan have been conducted for more than a hundred years [1].
Several genes in Drosophila are known that switching off or an activity changing can prolong the life of the organism moreover owing to completely various mechanisms.

The chicco gene encodes an insulin receptor binding protein. Mutations in this gene can prolong the life of flies by a factor of 1.5 [2]. Insulin represents a cell signal for receiving food. The fewer insulin receptor activation is, the more likely the cell to be in a state of “preparation for adverse conditions”: the intracellular digestion of “garbage” processes are triggered, the synthesis of protecting against DNA damage proteins is activated.

Switching off or suppressing the puc (puckered) gene in fruit flies leads to a life increasing expectancy by another mechanism. It happens through the activation of a special signaling pathway protecting the cell from oxidative stress [3].
The Indy gene (stands for I'm not dead yet) encodes a protein involved in cellular metabolism. These gene mutations prolong life [4] by mimicking some of the effects of calorie restriction (the restriction works on mice, roundworms and many other animals, although not all model organisms).

Mutations in the E(z) gene affect the lifespan of flies through an epigenetic mechanism [5]. An enzyme being the product of genes labels histones, the proteins involved in the compact DNA packaging. These marks affect the operations of other gene sets. In particular, these suppress gene activity which enhances oxidative stress resistance.

I have listed examples of genes whose downregulation leads to lifespan extension in flies. But there are also many genes, the activity of which, on the contrary, should be spurred on. Probably the most interesting of them is the dFOXO gene [6]. The importance of this gene can be better demonstrated using Hydra as an example. These coelenterates do not age, in other words, the possibility of their death does not increase with age [7]. But if their FOXO gene turns off (related to the flies’s) - this rule is canceled [8]. These gene-related analogs are involved in the aging of a wide variety of animals, from roundworms to humans. Our species has a mutation in the FOXO3a gene, which is much more common in ultra-centenarians than in the general population [9].
At one time, the FOXO gene made such an impression on me that I mentioned it in my “The Harvard Necromancer” fantasy novel. Scientists try to extend the lives of mice by inserting a human version of the FOXO3a gene from supercentenarians in this book. But, they accidentally discover the magical properties of the sacrificed “humanized” (humanized by our genes) animals in the end.

The genes of the FOXO family being genes transcription factors are the proteins that bind DNA and regulate the other genes working. In response to starvation, FOXOs become activated inducing increasing the synthesis protecting against DNA damage proteins In several organisms. Therefore, it is so interesting to see how the activation of this gene interacts with other mechanisms that affect longevity.

Removing and destroying with mutations is enough to turn off the gene. But how is it possible to increase the activity of a particular gene? Today, the 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 recognition sequence is given by a special “guiding” molecule, which can be designed in an arbitrary way. It seems to be something similar to “search with replacement” like in high-tech text editors, but for genes and other DNA sections.
"Scissors" cut molecules, but with the help of one gene mutation, encoding Cas9 protein they can be “blunted”. These produced defective dCas9 proteins still can recognize and bind the desired DNA region, but they can’t cut more. From a tool for cutting DNA, it has become a tool for sticking to DNA.

This dCas9 protein is attached by other proteins that can activate (or vice versa, suppress) the target gene, for example, the dFOXO gene in Drosophila cells [10]. 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 the activation of the dCas9 protein, including the target gene's activation, occur 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 highly important because it is desirable to affect not one, but all of the main mechanisms by which it occurs to slow down aging.This is exactly what specialists are trying to do within the framework of the project with Open Longevity. Well, I will be watching the scientists progress with huge interest, and then I will tell you about the results of their work.

[1] Piper MDW, Partridge L. Drosophila as a model for ageing. Biochim Biophys Acta Mol Basis Dis. 2018 Sep;1864(9 Pt A):2707-2717.
[2] Clancy DJ, Gems D, Harshman LG, Oldham S, Stocker H, Hafen E, Leevers SJ, Partridge L. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science. 2001 Apr 6;292(5514):104-6
[3] Wang MC, Bohmann D, Jasper H. JNK signaling confers tolerance to oxidative stress and extends lifespan in Drosophila. Dev Cell. 2003 Nov;5(5):811-6
[4] Rogina B, Reenan RA, Nilsen SP, Helfand SL. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science. 2000 Dec 15;290(5499):2137-40
[5] Siebold AP, Banerjee R, Tie F, Kiss DL, Moskowitz J, Harte PJ. Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance. Proc Natl Acad Sci U S A. 2010 Jan 5;107(1):169-74
[6] Hwangbo DS, Gershman B, Tu MP, Palmer M, Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature. 2004 Jun 3;429(6991):562-6
[7] Schaible R, Scheuerlein A, Dańko MJ, Gampe J, Martínez DE, Vaupel JW. Constant mortality and fertility over age in Hydra. Proc Natl Acad Sci U S A. 2015 Dec 22;112(51):15701-6
[8] Boehm AM, Rosenstiel P, Bosch TC. Stem cells and aging from a quasi-immortal point of view. Bioessays. 2013 Nov;35(11):994-1003
[9] Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92
[10] Shakirova KM, Ovchinnikova VY, Dashinimaev EB. Cell Reprogramming With CRISPR/Cas9 Based Transcriptional Regulation Systems. Front Bioeng Biotechnol. 2020;8:882. Published 2020 Jul 28. doi:10.3389/fbioe.2020.00882