Q: Give me a quick overview of your experiment? What is going to happen with this mouse?
Daniel Wuttke: We have aged mice (females and males) of the C57Bl/6 strain which will undergo a treatment of a combination of drugs that were shown to robustly extend the lifespan. One group of mice will receive placebo, while the other group will undergo the combined drug treatment. During the time of the experiment we will take measures of biomarkers of aging to assess the effect of the drugs. We hope that the drugs will slow down the aging process in this mice effectively and extend their lifespan… and healthspan!
Iryna Pishel: The increase in life expectancy in developed countries, which we observe currently, made it necessary to extend the period of healthy aging. We know that our body is subject to the emergence of various diseases with age, most of which are complex. There are already developed a number of drugs that are acting on some of the functional systems of the body, and can improve the health and prolong the life of the experiment. But often it is necessary to use a combination therapy. This approach can lead to increased cumulative effect it action of several drugs, but needs verification. This project suggests conducting a full-scale research on the effects of combination therapy on life expectancy of mice.
Q: Your experiment addresses metoprolol, everolimus, Metformin, Simvastatin, Ramipril, and aspirin. Can you say a bit about each of these substances?
Dmitri Shytikov, Edouard Debonneuil: We shall use a number of chosen drugs, that proved to be the most prospective geroprotectors. Here is a short description of each drug (without mentioning adverse effects):
– Aspirin is one of the most widely used medicines. Its action depends on the inhibition of cyclooxigenase I and at to lesser extent of cyclooxigenase II types: those play a central role in the production of prostaglandins and thromboxanes. Thus aspirin has anti-inflammatory, analgesic and antipyretic actions. Further, aspirin has also cardioprotective and geroprotective activities. Aspirin was shown to increase the lifespan of mice .
– Metformin has been even more used than aspirin, because it is the most standard treatment when diabetes type II is diagnosed. It is an antihyperglycemic drug: one of its actions is the inhibition of gluconeogenesis in the liver through activation of PKA, and the activation of glucose capture by cells. Its geroprotective and anticancer effects were described by V. Anisimov in multiple studies since 1986. Recently its positive effect on mouse lifespan was observed by Ryazantsev in 2006 and confirmed, along with improved healthspan, by Stephen Spindler and his team in 2013.
– Metoprolol is a cardioselective b1-adrenoblocker. The positive geroprotective effect has been observed in studies on mice and fruit flies by Stephen Spindler. Its most known action is to prevent heart fibrillation.
– Ramipril inhibits the angiotensin-converting enzyme (ACE). Thus it is used to correct of high blood pressure and for the complex treatment of heart diseases. Given with simvastatin, it increases the lifespan of mice (communication from S. Spindler at a congress, not published yet).
– Simvastatin belongs to the family of statins. Statins are medicines used to lower plasma lipid levels and thus used for complex treatment and prophylaxis of cardiovascular diseases. Given with simvastatin, it increases the lifespan of mice (communication from S. Spindler at a congress, not published yet).
– Everolimus is a derivative of rapamycin. Its action is based on inhibition of mTOR, a key regulator of metabolism. Rapamycin (the commercial name is sirolimus) used to be given to avoid rejection of grafts, as it modulates the immune system down. However is was found to robustly increasethe lifespan of mice (rapamycin was the Intervention Testing Program and everolimus by Stephen Spindler) and is now one of the most given human drugs in case of cancer. Multiple studies showed geroprotective qualities of rapamycin for multiple model organisms including yeast, worms, fruit flies, mice and cells of progeria children.
Q: Can you please say a few words about experimental design? How much can we learn from this experiment actually?
Daniel Wuttke: We are testing a combination treatment versus placebo. It will test whether a combination of treatments is effective in extending the lifespan. The continuous measurement of the aging biomarkers will provide us detailed information about the actual effects of the drugs in addition to the actual maximum lifespan values.
Dmitri: Well, we have 100 mice divided into 2 groups. All groups have equal representation of both sexes. One will receive a combination of drugs mentioned above with their food, while another one will not. During experiment we shall assess a lifespan and state of health of mice. I mean, we shall examine behavioral tests, biomarkers of immune system aging in blood (e.g. CD4/CD8 ratio), some biochemical markers in plasma, and make posthumous investigations to analyze presence of changes or tumors in organs. All this should give full picture of mice` health. Final version of protocol can undergo some changes, but they wouldn`t be principial.
All drugs, used in this experiments, proved to have positive effect on the state of health and lifespan of test animals while used alone. The main aim of this experiment is to test effect of their combination. And from this experiment we can see if this combination is effective.
Q: Some of our readers are DIY self experimenters and citizen science enthusiasts. Can you provide any advice or warnings about these substances?
Iryna: We plan to make public reports about the conduct of the study an online, to publish the design of the experiment, the choice of optimal methods of research that can help citizens better understand how conduct research in this area.
Anton Kulaga, Edouard Debonneuil: Do It Yourself biology is great! When it is done right it strengthens connections between professional researchers and citizen scientists where all parts benefit a lot. So we support DIY movement, we even organize DIY workshops in Kiev and provide biology training as one of the perks. The main advice here is to keep contacts with professional scientists in the field of your citizen science research. Clearly, not all labs are friendly to DIY activists, but the world is huge and you can find labs that will be eager to help you with your research, and vice versa find ways for you to help them.
In ageing research and in lifespan tests in particular there are several groups trying to do something. One of them is coordinated by the LongeCity forum, a quite active forum but many of its activists do experiments with… a huge room for improvement in scientific quality. We have to warn that lifespan experiments are not as easy as they may look like, many details count and it is not just buying mice and feeding them with some drugs. For example, lab lifespan tests usually involve many animals in both control and test groups and the strains are important. A first step is to look at current interventions databases and look at interventions done on mice (or animal of your interest); one of such databases is created and maintained by Denigma project ( http://www.denigma.de/lifespan/interventions/ ).
The easiest thing is to reproduce experiments of others, as dosages and protocols are already designed there. Even to reproduce experiments it is desirable to write to the researchers that performed them as many details, some of them potentially important, are not in papers.
To get fast and reliable experiments it is useful to buy aged animals from a specific strain, but depending on countries such animals might be restrained to animal research facilities with very restrictive agreements. DIY activists cannot afford having many animals so you should cooperate: fund labs to conduct lifespan tests for you, create joint vivariums or distribute your tests among many people (but be aware that distributed lifespan tests might not be well trusted and therefore be hard to publish). You have to make sure that treated and control mice are treated identically, so double-blinded tests are highly desirable.
Q: How do you plan to use the fundraising proceeds?
All: The funds will invested in buying the drugs and the assessment of the aging biomarkers as well as in enhancing the vivarium to optimize it for scaling up lifespan experiments.
Q: How will this experiment lead to human life extension?
Daniel: Many individuals take already a combination of several drugs that are expected to have geroprotective effects. If we want to effectively intervene with the aging process it is very likely that a combination therapy is necessary. Our experiment will assess whether such an combination therapy is effective in already aged organisms which is applicable to also already aged humans. We can not know for sure that results found in mice are applicable to humans but, due to the immediate potentiality of transfer to humans, results in mice are likely to immediately lead to prospective or retrospective studies in humans.
Q: Tell me something about the researchers and their qualifications, affiliations, etc.
All: The study will be conducted by an international team
Daniel: I dedicated my life to aging research already as child. I graduated as biochemist, specialist into molecular medicine (oncology, immunology, gene therapy, and stem cell research). I did my PhD on the genomics of aging and its modulation by diet.
Dmitri, Iryna: All experimental studies of this project will be conducted in the laboratory of Pathophysiology and Immunology D. F. State Institute of Gerontology NAMS of Ukraine. Gerontology Institute was established in 1958 and was the first and only institution that dealt with problems of gerontology in the Soviet Union. Several words about Ukrainian branch of team. Dmitri Shytikov is PhD student in immunology. He graduated as a molecular biologist and since his entrance in State Institute of Gerontology he took part in several immunological researches. He is highly interested in solving aging. He thinks that finding and controlling mechanism of aging is absolutely exciting and interesting task. This task is the only one worth of involvement.
Iryna Pishel is PhD in immunology and M.D. in physiology. She is highly motivated researcher. For decades she carried immunological researches. She started her work in early 1980th in the team of Gennadij Butenko, and she had made multiple experiments.
Edouard: I did some biology of aging research at UCLA, at the Pasteur Institute and at Inserm. I performed some lifespan tests in mice and helped several research teams perform other lifespan tests in rats and mice. I believe that rodent lifespan tests are a needed step to discover new facts for longer healthy lives, and a crucially needed step as pharmacology and medicine have so far mostly focused on short term health effects, whereas the most important human health needs now concern long term health.
Q: How will the results of this experiment be published and shared? Is this an open science project?
Anton Kulaga: Yes it is an open science project. We strongly believe that the science must be open, so the paper will be in open access. We even designed an online protocol of experiment, so supporters will be able to see experiment live, even before it was published.
Q: Anything you want to add to this? Is there something more i should know about this project?
Daniel Wuttke: Yes, the mouse lifespan experiment is a part of an overall roadmap to lifespan extension which includes an alliance of pro-longevity organizations (including ILA, the International Longevity Alliance; http://longevityalliance.org/), and information technology (Denigma, the Digital Decipher Machine; http://denigma.de/). The Mouse lifespan tests are one the three important components: experimentation.
UPDATE: Initial Funding Goal Reached!!!!
Watch this video to learn more about how you can help achieve the stretch goal!