How to rejuvenate the cells of the body?

Increase in life expectancy

Vadim Gladyshev, Post-science

Scientists have learned by genetic and pharmacological methods to increase the life expectancy of almost all model organisms: nematodes, fruit flies, mice. But for a person, there is not yet a single intervention that would definitely delay old age. We know that in order to shorten life expectancy, it is enough to start smoking, drink alcohol, not have physical activity and sleep poorly. But how to prolong life if you already lead a healthy lifestyle? 

Two ways to protect against damage 

First of all, it is necessary to determine the global processes in the body that need to be affected. Biogerontologist Aubrey de Grey believes that, since many injuries are heating up in the body, it is necessary to find a mechanism for each of them that will allow this damage to be removed. By "enabling" such protection, we thereby rejuvenate the body. But there are so many injuries and they are so diverse that it is impossible to come up with a full-fledged defense against all of them, and besides, those protective mechanisms that we will include will also be accompanied by the appearance of damage, since they themselves are biological functions. That is why such a strategy does not seem to me successful. 

There are two ways to increase a person's life expectancy: slow down aging or rejuvenate the body. The first one may be easier to implement in the near future, since this method is more understandable: already now we are increasing the lifespan of model organisms, slowing down their aging with interventions known to us. But these methods work only on model organisms, and here the question arises how to search for them for humans. 

How to slow down aging? 

You can take a large number of people and divide them into two groups: the first to give a certain intervention, the second – a placebo (while none of the participants in the experiment, including researchers, should know who received the intervention and who got the placebo). And then you will have to wait a long time for the moment when people of both groups will develop diseases and death will occur – then you can understand whether there is an effect from the intervention used. But this is not a very good method of finding interventions, as it is expensive and time-consuming.

You can compare a young and an old organism. We look at what changes in the body occur with age, and then we influence the body and determine whether these changes have reversed or not. But this method also does not seem good to me, since age-related changes can be both harmful and counteract negative processes, and if we influence the latter, we will not bring any benefit to the body. In addition, the changes can be neutral and affect the body minimally. Thus, if we just consider some age-related changes, it will be very difficult to establish a causal relationship.

Instead, we compare short-lived and long-lived states, that is, we analyze the potential to live a long time. As an example, a mouse that lives for three years and a naked digger that lives for thirty years – both are rodents of approximately the same size, but the digger lives 10 times longer. At the same time, we are not just comparing two organisms – we need to look specifically at life expectancy, and we take many mammals at once, let's say 40 species, and study their transcriptomes and metabolomes. This gives us an opportunity to understand what processes in the body were affected by nature, affecting life expectancy: mammals have approximately the same set of genes – only 100 million years ago they all had one common ancestor, and all this time, since the divergence of mammals, nature has changed something in different parts the genome of organisms and affected life expectancy. And we have to find something that can also be changed in the human genome so that he lives longer. This is the first, evolutionary way.

The second method involves comparing cell types. There are a lot of different cells inside the body. Some of them live for a very long time: for example, neurons arise in the process of embryonic development. Some cells only exist for a few days, like, say, blood cells. And there are cells that live from a year to ten years and then are replaced by new ones. You can study the diversity of cells and try to understand how they are arranged in order to influence them and make them live longer.

And the third way is to look at all the interventions we know. We already know many interventions that work on model organisms. For example, about 15 ways are known for mice to increase their life expectancy. 

When we determine whether these three methods work the same way on mice or not, we have a model consisting of different genes and metabolites that describe the potential to live longer, and we find the so-called signatures of longevity, signatures of aging. If we influence a cell so that it changes according to this signature, we assume that the organism will live longer. Let's say rapamycin was used to affect the body, and it metabolically changed so that it had the potential to live longer.

Using the signatures of life expectancy and aging, we see that there are common mechanisms for prolonging life that work for everyone, but at the same time, different long-lived mammals have unique ways to allow them to live longer, and we need to find these mechanisms. 

Among the interventions, there is a large group that acts in a similar way: for example, calorie restriction is somewhat similar to methionine restriction - both lead to prolongation of life in mice. And only recently it was possible to find out that there are interventions acting in different ways. Now the work of the laboratories is aimed at understanding which interventions can be combined into common groups. 

Duration signatures also allow you to find new interventions. Databases are used for this: suppose someone studies hypoxia in mice and enters the results into a database. We check the database based on our signatures and see that hypoxia corresponds to the signature of aging and is similar to calorie restriction. It turns out that hypoxia could potentially also increase life expectancy – this is what we discovered a few months ago. Weak hypoxia has not been tested for such an effect, but we assume that this may be a good intervention. You can also find environmental factors, including new drugs, but they also need to be checked further.

When there are effective interventions for mice and their combinations that will work perfectly on model organisms, then you can start looking at how it affects humans. We will not have to spend resources on checking each intervention – we will be able to immediately take only the best ones and check them already. This is not a question of today, but also of the not so distant future. Of course, all this requires significant investments. 

Rejuvenation of the body 

The second way to increase life expectancy is to rejuvenate the body. This is a new area that has been very little studied so far. But we know that it is possible to rejuvenate the body. In fact, this is an experiment by Shinya Yamanaki, a Nobel laureate, who realized that it is possible to take somatic cells, influence them with transcription factors and transfer some of these cells to a younger state, embryonic. How this happens is not completely clear, because when these factors affect, there is a strong heterogeneity in the cell population, and some cells rejuvenate, some, on the contrary, die, and some become differentiated, for example, similar to neurons.

Now it is possible to create a mouse in which the four Yamanaka factors begin to be expressed if you give it a certain substance. The cells are reprogrammed into a younger state. There are difficulties here: we want to rejuvenate the body, but without losing its functions, otherwise the neuron will cease to be a neuron, and the erythrocyte will cease to be a red blood cell. It is important for us that the functions are preserved, and the cell becomes younger. Therefore, partial reprogramming approaches are used. For example, a substance that expresses Yamanaki factors is given once a week and for a short period of time so that the cells become excited, rejuvenated, and then "slide" functionally into the same state they were in.

Research in this area is now in its infancy, despite the fact that a lot of laboratories have rushed into this work. Fundamentally, we don't fully understand everything yet, but we know exactly what can be rejuvenated. I hope that in the future these technologies will develop and we will be able to rejuvenate parts of the body. It is unlikely that it will be possible to rejuvenate the whole body, because some cells no longer divide and they will not be able to return to a young state. But individual organs will be young. All this will give rise to new questions: it will be unclear what age an organism has, in which half of the cells are younger than the rest, and how this will affect the aging process in general. But it's all very interesting. And we are waiting to see where this area of science will lead us.

Portal "Eternal youth" http://vechnayamolodost.ru