Check potential senolithic on yourself

Mice in the photo are of the same age, but 50% of senescent cells were removed from the right.



This post should be considered as part of the ongoing and not yet completed process of reasoning about experiments on yourself in order to test candidates for senolithics . We are talking about substances that, as animal studies have shown, selectively destroy senescent cells to some extent. For some of them, a positive effect was demonstrated in various experiments on animals even years before the current wave of interest in senolithics, and some of the noted effects can be attributed with a certain probability to the removal of senescent cells. Some of them were tested as potential cancer aids, or painkillers , or for other purposes. Some have serious side effects, like most potential chemotherapy drugs. They are designed to destroy cells, and their selectivity is far from desired. Nevertheless, all these potential senoliths are commercially available, and therefore are available for experiments on themselves.



Experiments on a long and vivid history in the scientific community. Many well-known researchers obtained the first results of human tests experimenting on themselves, and this seems to me the most ethical approach: the researcher takes risks. Distancing for some time from the risks, the main conclusion from such stories is their senselessness without taking measurements and publishing the experiment process and the results obtained. Attempts to guess the results or use potential drugs simply in the hope that their effects in humans will be similar to those in mice are meaningless. The same can be said about the choice of indicators on the principle of ease of measurement. The objective goal of the experiment is to learn something new and report about it, which is achievable even in the conditions of one person without a control group , provided that the desired effects manifest themselves steadily and clearly, and that the experiment was carried out correctly. In such a context, experimentation on oneself can contribute to more methodologically rigorous research by groups with resources in order to more accurately determine the effects obtained, the optimal dosage, etc.

You will need the help of a doctor

First of all, you need to find a doctor who understands what you are going to do and for what purpose, and who is ready to order the appropriate tests. You will need a guide to the world of the local medical community, especially for more expensive types of tests and analyzes. Usually, accessing them is easy, since you’ll order them for a fee.

Find an intermediary laboratory

You will need an organization that would act as an intermediary in dealing with suppliers, since many of them do not accept orders for senolithic from individuals. In our time of restrictions on the circulation of medicines, the supply of medicine from abroad is simplified if it is performed between laboratories. You will need to work with a company that has a laboratory or can play a mediating role in accessing the laboratory to get the services you need. Best of all, if you cooperate with someone from the medical community through personal connections, as otherwise it will be difficult to find an organization that agrees to work with you.

Determine measurable health parameters

In the ideal case, the data set obtained from the senolithic test results includes information about (a) the extent to which senescent cells were removed (b) and the extent to which aging markers were reversed. In reality, given the current level of development of medical research, in both questions we have to compromise. After reading the literature and thinking about what indicators are likely to be affected by cell aging, based on current knowledge in this area, I chose the following analyzes. For analysis, it is important that normal rates vary greatly between the ages of 30 and 60, unless you are at a very old age. This condition is not met for a larger number of available tests than it might seem.



First of all, there are standard blood and urine tests. Comparison of their performance before and after taking the drug, most likely, will not show anything interesting, especially for people who are not yet 60, but they are inexpensive and can demonstrate that nothing terrible has happened. In addition, some blood test indicators are needed for other parts of the study. In particular, they can be used to detect signs of tumor lysis syndrome as a result of the destruction of senescent cells. The detection of the characteristic change of this indicator immediately after taking the senolithic indicates that something is happening, and this is useful information.



When considering the functioning of the liver, none of the indicators of the standard blood test seems particularly useful. Normal values ​​vary slightly with age, but they are highly dependent on conditions and lifestyle. However, the results of cholescintigraphy vary considerably with age. This is an example of nuclear medicine using a radioactive isotope as a marker, and this procedure is appropriate.



For kidney function, a desirable indicator is the Reberg-Tareev test . The result can be obtained in various ways. There is a direct and expensive method using radioactive isotopes, but there are also approximate methods based on data from a routine blood test. The difference in the two approaches is described in a large amount of literature, for example, in a PDF from the National Kidney Association . Unfortunately, the evaluation method is not entirely accurate with respect to the indicators of a healthy person. You should not use the MDRD formula, but you can try using the CKD-EPI formula.



Taking into account the available evidence in favor of the connection between cell aging and vascular calcification , scanning and assessing the level of calcium, at first glance, looks interesting. This is because the rate of calcification is very difficult to reduce; This figure increases gradually over the years and to a large extent depends on lifestyle. Scanning for the level of calcification is simply computed tomography , after which a semi-automatic analysis is performed, the result of which is an Agatson score or a specific calcification score (lesion-specific calcium score). Unfortunately, even in adulthood, a large proportion of people get zero marks , for example, more than half of 40 and 50-year-olds. If you are interested in these indicators, there is an online calculator created by one of the research groups in this field. All this makes the assessment of the level of calcification much less useful, considering also the cost of computed tomography. Perhaps it makes sense to try this technique only for people not younger than 70 and those who already know their indicator, and it is not zero.



Lung tissue tests suggest that removal of senescent cells may in some way reverse the loss of tissue elasticity . It is worth looking at ways to measure skin elasticity. The indicator can be obtained using kutometers or ballistic meters sold on the market, while in scientific papers there are comments on the reliability of the results obtained. You may have to go not to a regular dermatological clinic, but to a plastic surgeon or one of the questionable rejuvenation clinics. Perhaps more useful is the indirect method of measuring the elasticity of blood vessels based on the speed of the pulse wave , which is simple to measure and the result of which varies significantly in adulthood. The question here, as in the case of the other cardiovascular parameters, is the extent to which normal indicators change due to the primary factors of aging (including accumulation of senescent cells) or secondary (weight gain, sedentary lifestyle). The use of this metric also tests the testing methodology itself, along with the testing of the senolithic. For this reason, one cannot simply limit one type of analysis.



Another indicator of the cardiovascular system with suitable characteristics of age-related changes is the variability of the heart rhythm . It is simple to measure. Note that the founders of the Palo Alto Prize chose heart rate variability as an indicator of biological age for interventions developed by competing teams.



Aging biomarkers based on DNA methylation are now becoming available research tools, although there is still no consensus on how to use them. However, Osiris Green offers a biological age estimate based on DNA methylation at reasonable prices. Price gives reason to consider a similar method, although it requires no less checks than senolitiki.



If it is possible to use personalized laboratory tests, you should pay attention to existing cell aging tests or skin sample analysis , and both types of tests require a biopsy. In the first case, there are special kits for analysis and tests taken by the scientific community, but with uncertainty about the effect of biopsy on the aging of wound cells, which can make the results unreliable. In the latter case, the scientific article describes quite fully the methodology for its reproduction, but it remains to be seen how useful it will be in practice. This is another case where the calibration of the research methodology is no less necessary than the performance analysis of the senolithic themselves.

Selection of substances - candidates for senolitics

First of all, let's exclude from the list of candidates Dasanitib , Navitoclax and similar substances aimed at the Bcl-2 protein family. This means of chemotherapy is a relatively indiscriminate effect, and almost all other substances, defined by the scientific community as potential senolitics, are better, judging by the results of experiments on animals, either have less side effects, or are more effective, or both. Of the remaining substances, it makes sense to try the combination, since some studies argue in favor of having some synergistic effect between candidates and the performance of different senolithic against different types of senescent cells. In addition, scientific and corporate research in the initial stages rarely check combinations of substances. Therefore, their use increases the chances of new interesting results.



Substances worthy of closer attention fall into two categories. The first - easy to obtain, similar to dietary supplements and relatively cheap preparations for oral administration, which are considered safe. Fisetin and Quercetin fall into this category, although there are doubts that the latter has any senolysis properties. The second is the senolithic, discovered later, they are more difficult to obtain and use, and for them there is almost no data on applications in humans and safety, but seemingly promising from the results of recent studies. This category includes Piperlongumine and FOXO4-DRI . In any case, you will need to familiarize yourself with the pharmacological data, with studies where the drug was used, current ideas about its work, and decide whether you are ready to risk taking it. You will have to read scientific articles and assess your willingness to take an attendant risk. Do not blindly follow someone else's advice, decide for yourself.

Determination of dose and regimen

Determining the dose for human testing requires reading a large amount of literature on animal research to determine the most appropriate dose used in each case, which is often expressed in mg / kg, and multiplying it by weight. You will soon find that for most senoliticists it is not easy to determine the dose, and you will have to make such decisions yourself. For example, Piperlongumine has so far been tested only on cell cultures for its effect on senescent cells. The literature describes its use as an anesthetic with a dosage of 1-250 mg / kg, and for the suppression of cancer - 2.5-5 mg / kg, to increase the sensitivity of cancer cells to other drugs - 1 mg / kg and the direct removal of cancer cells - 2.5 mg / kg. In some cases, the assessment was carried out after a single application, in others the application lasted several weeks.



Likewise, for Fisetin, there are no published animal studies on the effects on senescent cells. For other purposes in recent years there is information on the pharmacokinetics for dosages of 10-250 mg / kg, in one study - 10-45 mg / kg twice a day and another one for cancer suppression - 5 mg / kg twice within 2 weeks.



For Quercetin, you can see its original research as a senolithic, where researchers used a single dose of 50 mg / kg. There is very little data for FOXO4-DRI, with the exception of one recent article on its effects and another equally recent article on cancer. Access to both articles is paid and, unfortunately, dosage data are not included in the main text of the original article, but are indicated in additional materials that I have not yet received. But in time I will get them.



You need to understand that at the beginning you should try a very small dosage and gradually increase it up to the target. This is a reasonable precaution for many reasons. In some cases, senolithics are not sufficiently tested in humans. Secondly, how much can you be sure that the suppliers did everything correctly, and that the testing of substances has passed correctly? Moreover, when testing anywhere not described combinations, one may encounter unforeseen effects of interference. Finally, if the substance works, and you have many senescent cells that collapse at the same time, there is the danger of tumor lysis syndrome . All this is a very good reason to increase the dosage gradually.



Of course, the mentioned drugs have different dangers, from Quercetin (sold in stores, and produced by many companies over the years) to FOXO4-DRI (relatively new, little produced, delivered only on pre-order, with no data on human exposure and only a couple of articles on exposure on animals). When choosing a poison for yourself, be aware of the entire level of risk to which you expose yourself.

Think about how to use

Quercetin and Fisetin are preparations that can be put in a jar, put on a shelf and stored for months. These are tablets intended for ingestion, which makes their use quite simple. Piperlongumine requires low storage temperatures and, possibly, pulverization or inclusion in the mixture for ingestion. FOXO4-DRI is a short-lived protein that should be stored at low temperatures, and then restored and injected - an abdominal for mice, but probably intravenous is most suitable for people. If you are familiar with how diabetics organize medication, the situation is very similar.



Injections - this is what is desirable to enlist the help of the laboratory and the doctor, and not what you need to do on their own. Note that given the current ridiculous war on drugs, which has lasted for more than three decades, caution should be exercised in obtaining syringes for injections. This is another reason to organize everything in collaboration with a friendly laboratory and a doctor.

Determination of suppliers and products

The search for suppliers has different complexity for different senolithic. For Quercetin, you can go across the street, take a couple of packages in the nearest store and, subject to the brand's reliability, calmly skip the self-testing step. You can also find an overview of the supplier’s products online. Fisetin can also be ordered in the form of packages, but here the quantity and quality of suppliers is less known, so testing of the substance obtained should be considered.



For Piperlongumine, you’ll have to order a drug from a supplier and pay a substantial amount - hundreds of dollars per dose, given the dosages from animal studies. For FOXO4-DRI, perhaps the best solution, given the small number of suppliers, is to order a synthesis of the drug from a company specializing in protein synthesis. It is expensive, and laboratory assistance will be needed here. In both cases, the suppliers are reluctant to deliver the drug to someone who, in their opinion, will use it for human testing outside of official research organizations.

Substance check

You will also need the help of a friendly lab to check the quality of your preparations. Such a quality check is not so simple and may require the use of special services that are better obtained through a company operating in this area than trying to order them yourself. It is important to make sure that you get what you pay for, both in order to avoid wasting money and time on independent experiments, and in terms of security. Even under optimal conditions, individual batches of substances that are not mass produced can be of poor quality.

Conducting an experiment

The first stage is the conduct of all analyzes to determine the initial indicators. For many of them, such as a standard blood test, it makes sense to perform tests twice, possibly with an interval of several weeks, because the results may vary depending on external conditions. This is followed by taking the drug according to the scheme. Then there are two more stages of analysis, one after a few days after the end of the intake and one after a few months, and precisely because many indicators depend on lifestyle, it is important not to change the amount of exercise, diet and other conditions during this period.



After the deed is done, it remains only to present the entire study and publish it on the Internet for universal access.

The choice of simple and complex ways

From this text it becomes clear that the choice of a candidate for senolithic depends on the difficulty of conducting a successful experiment on yourself. The level of risk assumed is also of great importance. I chose the senolithics in part to demonstrate this circumstance. In the simplest and safest experiment, you can use Fisetin and Quercetin and for the most part do without the services of specialized laboratories, relying only on the help of a doctor for blood tests, cardiovascular system and other medical tests. In this case, you can be fairly confident that the risk of negative developments is lower than for other drugs. Alas, these drugs are less likely to show good results compared to other candidates; there seems to be no obvious optimal option for this.



Translation done Pattern, SENS Volunteers group