Here is an article that could hang on the banner of immortalists along with, say, SENS:
https://pubmed.ncbi.nlm.nih.gov/23805382/ (2013, 625 citations).
The authors tell how to beat cancer.
What's the problem now? modern detection methods detect cancer when it has ~10^8 cells and 64mm3 volume (well, that's what they say).
Their mathematical model shows that in such a large volume of cells there should be cells whose individual mutations make them resistant to several therapies at once. After treatment, they survive, multiply, and the tumor becomes resistant to the therapy.

They have two conclusions on how to avoid this.
1) fig.3 - the extreme importance of progress in the early detection of cancer. If you reduce the detection threshold from 5mm to 1mm, even modern methods can cure. If there are fewer cells, then most likely there will not be among them resistant to several types of therapy at once. (well, these are approximate arguments on a specific mathematical model, but in general something like this)
2) increase the number (and quality) of therapies in combination so that there are no cells resistant to all of them.

Both conclusions are not just quite mainstream, but probably the main directions in NIH / etc research in general, and receive a lot of funding.

Maybe one of the hottest topics of discussion among immortalists should be how to detect tumors with a diameter of 1mm?
By the way, Batin has a post about defeating cancer - defeating aging https://www.facebook.com/MikhailBatin/posts/4971748182845046 (December 2021).

P.S. it is clear that their model is simplified, and there are all sorts of other theories out there, for example, cancer stem cells, but still, in my opinion, it is more than worthy of being on the banner. Or maybe there are newer interesting works on this topic.

Vladimir Shakirov

💬 Misha Batin

Such strange things with aging

1/3

The problems start from the very beginning. There is no definition for human aging. The most common definition is that aging is something that increases the likelihood of death. It is also incorrect, since it does not say anything about what actually happens to a person.

Intuitively, aging is what makes a young person old. But what?

Some scientists will name the reason - by-products of metabolic reactions. Such a definition does not explain the enormous difference in life expectancy between species. Actually, the theory of aging should explain the difference in life expectancy between species.

It would be nice like this: you load the data of the DNA sequencing of an animal into a computer, at the output the neural network says what is the average duration of the species. Also not a theory yet, but it will become easier to look for a cure for old age.

Here we are faced with the problem of the minimum sufficient information to create a life extension technology. How much more do we need to learn? Is one global transcriptome analysis sufficient?

Any omics research is limited. The transcriptome does not tell us about the functionality of proteins. The proteome does not speak of the compartmentalization of proteins.

Of the dozens of types of post-translational modifications, we have studied in detail the effects of only phosphorylation and acetylation. Ubiquitination, carbonylation, sumonylation, nitrosylation, methylation, butyration, and many others have been studied only on the example of individual proteins.

Let's add microRNAs here, each of which binds and degrades the transcripts of dozens of genes. Thousands, perhaps tens of thousands, of these miRNAs have already been discovered. Finally, there are thousands of genes whose proteins we do not know. We can predict their primary structure, but we have never looked at their function in experiments.

Having finished with proteins, we move on to lipidoma. This is a huge area and also directly related to aging. There is even a lipid theory of aging. Further, the ocean of uncertainty is the metabolome.

That is, now it is completely unpredictable for us: is it enough for us to know about some three effects on mice with a 50% increase in lifespan (for example, a safe epio-rollback) or do we need a metabolic model to create a cure for old age. There are a million intermediate options between these statements.

The difficulty with the aging of living things is that organisms can repair themselves. Aging just consists in second-order errors - repair mechanisms break down. Or they don’t even break, and they have a predetermined expiration date.

That's not all the complexity. The genome itself is immortal. Every cell in our body carries the information of how to be young, can be reprogrammed and create a new organism.

In general, it is a mystery: how can two old organisms create a very young one? This happens for two billion years in a row, and errors do not accumulate.

If the theory of the accumulation of errors were comprehensive, life would cease to exist on earth.

There is no agreement among experts on the relationship between major (age-related) diseases and aging. Is disease a continuation of aging or a separate process? It is logical to think that the continuation. At first we imperceptibly deteriorate, and when it becomes noticeable, we call it a disease.

The question then becomes, why are the R&D departments of pharmaceutical giants looking at different targets than aging researchers? The best specialists are involved in the company, they do not eat their bread for nothing.

That is, most scientists, in fact, believe that aging is a separate process and acts as a risk factor in relation to diseases (I emphasize that we are talking about 18 major diseases of age).

And some researchers say that this is a quasi-process. That is, there is no general aging in itself, but there is aging of organs, and together we see it as aging.

Somewhere in the mid-10s, scientists gave up on the definition of aging, well, they study what they see. It's pretty clear what it's about.

A paradoxical situation has arisen. At any conference on aging, there are 50 reports on various topics, and not a single one, how exactly all processes are connected.

2/3

More precisely, this work was undertaken by Hallmarks of Aging, but in a general way.

It is necessary to connect all studied molecules with each other by intersecting databases.

The fundamental problem of aging is how to digitize it. In particular, how to calculate how much a person has left to live?

If there were a reliable clock, on the one hand, it would be possible to quickly evaluate drugs for old age, and on the other hand, the mechanism of this clock, perhaps, would tell where to intervene.

Most scientists believe that we cannot cure aging. The problem here is that everything in the body is connected to each other. We can act on many targets in the body, but the genetic network has its own trajectory of change and is stable.

However, most researchers agree with the theory of antagonistic pleiotropy. This is when some genes are useful in the first half of life and harmful in the second. Here it would be logical to identify them and drown them out. In my opinion, this is a slightly misinterpretation. Harm creates a state of the genetic network, that is, a small contribution from a change in the work of "each" gene (not quite each).

The task of the science of aging is to cluster the network and learn how to influence it.

We are supporters of the idea to influence the network with another network, integrating it into the old one. For example, with the help of their own young cells. But integration factors are also important.

The influence of the microbiome increases the problem by 10 times. The influence of viruses and mobile genetic elements also increases the problem by 10 times. The presence of glycans in the structure of proteins again increases the problem by 10 times. The "independent" life of mitochondria once again increases the problem by 10 times.

The aging of a particular organ is not simpler than the aging of the whole organism. Therefore, neither diabetes nor Alzheimer can be cured yet. We have not learned how to break down the impact on aging into subtasks.

However, life extension science faces a number of big questions.

Is there a combination of known drugs that can prolong a person's life?

On the one hand, the answer is obvious: naturally, there is. A huge number of drugs prolong the remaining period of life. The same statins or metformin.

A paradoxical situation is emerging. On the one hand, there is a global disbelief in the possibility of life extension, on the other hand, you can buy medicines at a pharmacy and live longer. It is simply believed that they do not act on aging. Medications prolong life not for every person, but according to indications.

The question remains whether these drugs in some combination can bring a positive off-label effect.

Moreover, it is not necessary to appeal specifically to well-known drugs. Medicines can be created and new ones.

Here the global question is: are the known mechanisms of aging (targets of aging) enough for us to prolong human life by acting on them?

The answer “yes” seems more plausible, if only because there is sport, and this is a complex effect, the work of 2000 genes changes, and sport makes life.

Even in this case, this means that some physical activity will prolong more, and some less. It is necessary to study what are the main targets here. We at Open Longevity can show you 3 of the most intriguing.

The main stumbling blocks in trying to slow down aging are cancer and drug side effects.

Otherwise, it would be possible to give all the growth factors, including the nerve growth factor, and everything in the body would be renewed.

The most surprising situation: the life of animals is often prolonged by opposite influences.

You and I are in favor of using this phenomenon blindly: to carry out a series of interventions with opposite molecular effects. Expecting that in this way we will strengthen the constancy of homeostasis.

Another difficulty is that each drug has many effects, and we often do not know which mechanism was acted upon when we extended the life of animals.

3/3

This is exactly why antibody therapy is more accurate and has a greater chance of passing clinical trials. A small molecule clings to everything.

Here is the hope of science for artificial intelligence trained on data from quantum chemistry. To take into account the polytarget effect of small molecules on the whole organism.

Many disorders in the body are associated with exposure to free forms of oxygen. Why antioxidants do not prolong life is completely incomprehensible. The explanation that free oxygen species have a useful signaling function does not seem satisfactory to us.

In addition, damage to macromolecules does not explain the million-fold difference in lifespan between species. Something controls this rate of damage, and it is in the genome.

In general, there are hypotheses that the worst happens outside the control of genes. The same lipid peroxidation or non-enzymatic glycation of proteins. We believe that such processes do not actually exist, and the genes “consciously” stop monitoring the situation. Otherwise, evolution solves every problem. She not only repeatedly solved the problem of the non-aging of an individual, but also ensured the immortality of species in the case of unlimited resources.

It's amazing, but every species (not a single individual) on earth is immortal in the case of unlimited resources. All species are ready to change in case of trouble (some more quickly). It shocks me that practical immortality has been invented for species.

Strictly speaking, prolonging life and slowing down aging are not the same thing. You can even not study aging and prolong life. Confirmation - organ transplant.

In theory, even brain tissue can be transplanted. This is the top trend in modern lifespan research.

A person runs out of hematopoietic cells, and this is one of the mechanisms for approaching death. Most likely, it is this problem that scientists will solve primarily as part of the creation of rejuvenation technologies.

Rejuvenation is a word with different meanings. Strictly speaking, to rejuvenate means to make immortal. It seems that immortality sounds like a utopia. And rejuvenation of the body for 1 month? Sounds realistic, but it's the same.

Our rejuvenation mechanisms are already built in: repair, regeneration, autophagy, proteolysis.

They operate with an efficiency of 99% (conditionally). We only need to increase their efficiency by 0.5% in order to live 200 years.

The main hopes now lie with molecules that can reprogram cells individually. Here the task is to do it already in the body without causing cancer. There are successes.

Also, scientists to a certain extent have established that the body changes with age, but have not established causal relationships. It is not even known whether this aging causes cancer or the threat of cancer causes aging?

A map of changes in cell phenotypes has not yet been made. There are effects when removing senescent cells, but most likely there are a large number of different types of senescent cells with different functions, and it makes sense to remove only a certain one.

Ignorance of cause-and-effect relationships in aging leads to the problem that we, seeing changes in function, do not understand: is this aging or aging compensation? Should these changes be increased or reduced?

This is precisely why the doctrine of the lack of vitamins and microelements in the body does not work. Why was there enough vitamins for 20 years, and then not enough? Perhaps the body no longer needs it.

We don't even know if the decline in protein synthesis is aging itself or a response to aging, such as lack of energy due to mitochondrial damage.

In general, the ideas of complex therapy are between the idea of ​​resisting some basic mechanism of aging by attacking it in several places, or influencing the most different ways.

4/4

In short, all this requires a 100-fold increase in funding, and we must act on society. Society is an immortal biological system that does not really think about us. Here, too, a combination of interventions is needed. To make it happen, join us at Open Longevity.

Thanks for the advice in preparing the material Alexey Rzheshevsky, Stanislav Yankauskas, Timofey Glinin

Vladimir Shakirov:

It's probably a bad idea to talk about some kind of uniform aging.
I would suggest talking about multiple ages:
(1) aging of the blood composition. This is just the closest thing to a certain uniform aging. Because this is the only thing that connects the different organs of the body. Inflammatory cytokines, changes in the concentrations of hormones, minerals, impaired immunity, etc. And here you can specifically talk about how to influence the composition of the blood (maybe drugs or antibodies to cytokines?) And what composition of the blood is optimal for whom.

And separately already (2), (3), (4), ... (99) the processes of aging (deterioration of the state) of specific organs, leading to their breakdowns. Depending on each other almost exclusively only through (1). The aging processes of each organ are very specific. It is one thing to treat atherosclerosis, and another thing is COPD or Alzheimer's. A unified theory of aging of different organs, in addition to (1), is more about interdisciplinary interaction, they say that in the treatment of atherosclerosis they have achieved something by acting on the hallmark of stem cell exhaustion (I wonder how), can they do something similar in COPD? True, interdisciplinary interaction is wider - it is about reprogramming T-cells, and about general methods. There is a big important article in the theory of aging about hallmarks of aging - but this is essentially just a listing of what negative processes are. Cool review, but specialists in a particular disease already know all this well, as well as their relative contribution to the disease they study.

And cancer - all the more so separately for each organ, there are a lot of specific features, and again, specialists in cancer of a particular organ know all the contributions of aging of an organ and blood to cancer. It is unlikely that aging of the composition of the blood or an organ causes cancer - rather, probably the opposite (which is reflected in the other half of the question - "or does the threat of cancer cause aging?").

Have anyone noticed that a year ago average amount of DAILY deaths were 115,000, now its 166,000 that’s 31% increase.

Most of them due to diseases!

https://worldpopulationreview.com/countries/deaths-per-day

2 days ago Professor Vladimir Skulchev known for his studies on the anti aging pill dies

http://www.rexresearch.com/Skulachev/skulachev.htm

A clip published today with Dr Gordon Lithgow, Professor at the Buck Institute for Research on Aging and Adjunct Professor of Gerontology, presenting 3 "hit compounds" through chemical scan that show extend healthspan and lifespan in preclinical studies in mice.
https://youtu.be/RiHUXSuPOZw