In Douglas Adams’ The Hitchhiker’s Guide to the Galaxy, the answer to “The Ultimate Question of Life, the Universe, and Everything” was supposed to solve all the problems of the universe. This answer was eagerly awaited by all sentient races. It was obtained as a result of seven and a half million years of continuous calculations on a specially created computer – the Thinker. According to the computer, the answer has been checked several times for correctness, but it can upset everyone. It turned out that the answer to the question is “42”.

Yes, scientists at Open Longevity have unraveled the meaning of the number 42.

In our Open Genes database , you can find 166 human genes, the impact on the orthologs of which prolongs the life of various animals: mice, rats, fish, fruit flies, and nematodes.

That is, each of the 166 genes is present in both a person and an animal, and turning it on / off, the remoteness of a particular fish or fly to prolong life.

In fact, this is the basis of our optimism: animals have managed to extend their lives many times over by acting on genes or their products.

(We are aware of the limitations of our knowledge and maybe every experiment is not about the exact gene we think it is, and maybe the result is not always accurate. However, there are thousands of life extension experiments, so there are hope).

How to extend this experience to a person? Which genes should we influence to work in order to increase our lifespan?

In fact, the correct question sounds like this: what genes, in what cells, at what points in time and in what way should we influence to work in order to increase the lifespan of a person? Even so, the question does not sound complete enough. It should be added: and how can the effect of therapy be assessed without waiting for the death of a person?

This raises our next question: can we, based on known research, find a combination of therapies that works in humans.

We want to act not on one molecular pathway involved in aging, but on several at once.

What else do we know?

We have data on human polymorphisms associated with longevity. We can say that these are experiments set on people by nature itself.

There are many functionally significant regions in the human genome, in which there is diversity among people. Each specific genetic variant has its own frequency – a measure of its prevalence among people. If some genetic variant makes its carrier more viable than other people, its frequency will be higher than average. And if some genetic variant increases life expectancy, then its frequency will be higher among centenarians.

Differences in the DNA sequence in the genome between representatives of the same species are called polymorphisms (Single nucleotide polymorphism, SNP, pronounced as snip). We have data on 323 genes that have polymorphisms that are supposedly associated with longevity or better human survival (not all of them are listed on the Open Genes website yet, but you will be able to see them soon).

For example, genetic studies of Ashkenazi Jews are known, in which a number of such genetic variants associated with longevity were found. In particular, in the TERT gene .

By the way, Elizabeth Parrish, a man of great courage, introduced herself a genetic vector with the TERT gene .

Here it would be appropriate to make a small digression. There are many myths in everyday consciousness. Including, and about the genetics of aging. For example, it is customary to say that longevity genes do not exist, and a person’s life expectancy depends mainly on lifestyle. So, such reasoning is a half-truth, which, as you know, is worse than a 100% lie.

Longevity genes don’t really exist. That is, there is no such gene that would be enough to turn it on or off, and you would be guaranteed to live 120 years.

How fast we age, and how long we live, depends in general on a huge number of genes. There can be a lot of differences in such genes between different biological species, so different species age at very different rates.

A mouse lives for two or three years, while a person lives on average for more than seventy. Because they have different genes.

Within the same species, genetic differences are minimal, and individuals live more or less the same way.

Lifespan is very clearly defined by our genetic network. But longevity is an intraspecific fluctuation, also set by genes, and depending on the external environment. That is, it is not sports or alcohol in itself that affect life expectancy, but they influence indirectly, through gene products, the network begins to somehow react, and as a result, we see a change in life expectancy.

In addition, it has been established that longevity is partially inherited. The exact mechanism is still unknown.

As we have already said, our database contains 323 genes with polymorphisms, for which an association with human lifespan has been shown. That’s quite a lot. But are all these genes actually linked to human aging? Here you need to be careful.

A genetic variant associated with longevity in humans does not necessarily slow down aging. Here, much depends on the specifics of the environment and the ability of genes to respond effectively to it. For example, there are predators around, and then more sensitive sleep or hearing will lead to an increase in life expectancy. With the same genes of the mind, it is natural to sleep on the grass and listen to how the beast sneaks.

We need to somehow choose from 323 genes exactly those that are most likely associated with aging.

But what if we cross two sets of genes? 323 genes associated with longevity in humans and 166 human genes whose orthologues in animals affect their lifespan. Will we find a match? We have carried out such an analysis.

It turned out 42. Forty-two common genes! Solemn music sounds. Here is Kashchei’s needle in a haystack.

Of these, 25 increased the lifespan of mammals.

It’s great to have one of our favorites, VEGFA , among the supergenes . Its amplification prolongs the life of mice by almost one and a half times. And, most importantly, a gene drug based on the VEGFA gene , neovasculgen, is one of the few clinically approved gene drugs that currently exist.

Let’s look at what kind of genes we found, and think about what we can do with them in experiments.

All 42 genes can be roughly divided into functional clusters. We’re breaking down genes by function, because that’s the easiest way to put together a combination gene therapy: target different functions.

To be continued.