Waiting for geroprotectors
Geroprotectors: how to slow down aging with medication
We have accumulated some knowledge about the genetics of longevity. It is time to try to use them to create geroprotectors – "medicines for old age". However, we will have to find and test active molecules to affect tens of thousands of potential target proteins, and also make sure there are no side effects. In the meantime, the best remedy for aging is the daily routine, proper nutrition and periodic moderate stress. Biologist Alexey Moskalev tells about how meditation, sports and performing in front of an unfamiliar audience trigger the rejuvenation processes and what is bad for cells for complete well-being.
How aging and growth are related
As a rule, we grow, mature, and reproduce in favorable environmental conditions. With intensive growth, cells divide rapidly, double DNA, and create new proteins in large quantities. But during cell division, errors accumulate in DNA, newly synthesized proteins do not have time to adopt the correct spatial structure; they begin to aggregate before reaching their destination. As a result, the cells age rapidly.
If the body gets into stressful conditions compatible with life (for example, the ambient temperature has changed slightly, there is a short-term starvation or lack of oxygen), it goes into economy mode and redirects energy from growth to stress resistance in order to survive adverse conditions and return to the processes of growth and reproduction later. The mechanism of autophagy is triggered (translated from Greek as "self-eating"): the cell begins to digest its own structure, sacrifices part of its contents in order to obtain nutrients.
At the same time, if the stress is short-term, it does not die, but, on the contrary, rejuvenates, because everything unnecessary goes into the furnace: damaged proteins, damaged mitochondria. There is a lot of evidence that low–calorie nutrition or periodic fasting, triggering autophagy, prolongs life - for example, in unicellular eukaryotes, such as yeast. The cell not only eliminates the current damage, but also acquires greater resistance to subsequent stress – this is such a "hardening" system, and from time to time it needs to be activated.
(A person, of course, is not a yeast cell, he is more complicated, he has his own age and health restrictions. Therefore, you need to make a reservation right away: before you starve, you should consult a doctor.)
Both processes – growth and stress resistance – are very energy-consuming. Energy production systems are always running at the limit; there is not enough energy in the body for everything. And the body needs to decide: either it throws energy to slow down aging, or it grows and multiplies.
How to start the self-cleaning process
Stress triggers autophagy, so in moderation it is useful for humans. It can be both physical and emotional stress. Sauna, tempering, public speaking, traveling, vegetarian diet several times a month – all this is stressful. Even meditation is stressful, because when meditating, a person completely disconnects from the usual sources of pleasure and communication (viewing favorite social networks, for example).
Of course, there should be a recovery period after stress. If you are constantly under stress, then the reserve opportunities to eliminate errors and damage are quickly depleted, and then accelerated aging starts. It is optimal to alternate recovery and moderate stress.
How to start the self-cleaning process without stress
There are receptors on the cell surface that respond to protein hormones like insulin. The signal is transmitted inside the cell, it is amplified by kinase cascades (transfer of phosphate groups from ATP molecules to other substrates – VM), after which transcription factors are activated, which include the necessary genes in DNA. And already the products of genes – enzymes involved, among other things, in the mechanisms of growth and stress resistance – affect the cell.
It is possible to influence enzymes with the help of drugs. Substances contained in drugs either inhibit enzymes, reducing or even temporarily blocking their function, or activate them by binding to the corresponding protein.
There are proteins with such a function as transmitting a signal from an insulin-like growth factor, which is needed for cell growth and division. These proteins are associated with autophagy and its suppression. They affect aging, and they can also be regulated by medicine. That is, we can achieve the effect of geroprotection not through starvation, but by directly turning on or off some of the proteins with the help of the drug. And this opens up a huge field of possibilities for slowing down aging.
The task of the geroprotector is to hit, as a target, certain proteins that affect the rate of our aging. I repeat, proteins (genes) do not actually trigger aging, it becomes like a side effect of their main activity. The geroprotector can mute the processes that accelerate aging and activate the processes that protect against aging.
Theoretically, the geroprotector should extend the life span to the maximum life span of the species or exceed it, protecting against one or another aging mechanism. However, in practice, we are talking about increasing the service life by several percent, at best by 20%, and then in animals in the laboratory. (Therefore, it is more correct to talk about gerosuppressors, and not about geroprotectors.) The potential benefits of using a geroprotector in humans can manifest themselves after a long period of time, so it would be good if geroprotectors first improved some health-related quality of life parameters: physical, mental, emotional or social functioning of a person. This can serve as a basis for their chronic use. For example, to help with depression or insomnia, to serve as a cure for any chronic disease.
Why there are still no "medicines for aging"
For each protein "target" associated with the mechanisms of aging, you need to make your own medicine. This is happening now, and it has already reached clinical trials in some places, that is, human trials. So far, many things don't work.
We have about 30 thousand genes and even more proteins, because one gene can encode up to ten different isoforms of a protein. In addition, these proteins are still undergoing posttranslational modifications. When we launch a small molecule into a target protein, along the way it can collide with other proteins and cause an effect that we did not plan to achieve. In addition, many enzymes affect several functions in the cell and the body at once, only part of which is related to the rate of aging. Therefore, there is a high probability of side effects, especially against the background of prolonged use or overdose.
About ten geroprotection mechanisms are now known. But all of them need to be studied, investigated, including taking into account the likely side effects.
What substances are considered as potential geroprotectors
At the moment, there are no geroprotective drugs that have a proven effect on humans. We can talk about potential geroprotectors, many of which are more rational to get from food rather than take in the form of medicines.
It is known that there are substances that affect such an aging mechanism as chronic inflammation – these are glucosamine, taurine, carnosine, melatonin, magnesium citrate. Some vitamins (K2, D3, B12) affect such aspects of healthy longevity as vascular condition, immunity, osteoporosis, cognitive functions. Several substances affect the operation of the energy stations of the cell – mitochondria, for example, PQQ, NMN. Polyphenols (found in berries, fruits, tea, coffee, herbs and vegetables) improve the functioning of blood vessels. Trace elements like zinc or lithium also increase the level of protection of the body, but it is important not to overdose them, that is, monitor their level. Currently, clinical studies are underway of such potential geroprotectors as berberine (found, for example, in barberry), urolitin A (in pomegranate) or spermidine (in wheat seedlings, mushrooms, legumes and other types of food), as well as senolytics (causing the removal of aged cells).
What to do before geroprotectors are invented
Monitor the mode. In the body, many functions are subordinated to circadian rhythms. It is important to eat at the same time, go to bed at the same time. Let it be late, but at the same time, because our internal clock is also aging, and they affect both the hormonal background and the regeneration process. Regeneration depends on the circadian rhythms: if the internal clock is knocked down, then regeneration is disrupted, and the risk of tumor growth increases. By synchronizing the internal clock from the outside, we slow down its age-related desynchronization.
The circadian clock of a cell is a transcriptional-translational autonomous feedback loop that generates circadian rhythms of gene expression and, as a consequence, periodic fluctuations in physiological parameters and the behavior of the organism as a whole. Regulatory proteins of circadian rhythms, in the case of deregulation, make a significant contribution to the aging process by activating with their products, known as transcription factors, many signaling cascades associated with aging. The internal clock of the body can be synchronized or desynchronized from the outside through the mode of lighting, sleeping or eating.
Another mechanism of protection against aging is nutrition. Food contains substances, some of which accelerate aging, while others slow it down. By regulating the amount and frequency of intake of certain substances into the body (amino acids, glucose, fats, vitamins, minerals, dietary fiber and others), eating more of one food and less of another, we can have a geroprotective effect on the body. But I repeat: regarding proper nutrition, it is worth consulting with a specialist nutritionist.
At the same time, it is important to periodically create moderate stress. Let's say skipping one of the meals three times a week is stressful. This way you activate the defense mechanisms that will begin to better cope with the errors that have already accumulated in the cells, and at the same time do not violate the principle of regularity.
About the author:
Alexey Moskalev – Doctor of Biological Sciences, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Geroprotective and Radioprotective Technologies of the Institute of Biology of the Komi National Research Center Ural Branch of the Russian Academy of Sciences, Head of the Department of Ecology of Syktyvkar State University.
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