An Interview With The Major Mouse Testing Program: We Talk Longevity Advocacy And Fast Tracking Progress

Innovative new project the MMTP aims to fast forward translation from lab to clinic with rapid, parallel mice testing. We caught up with Steve Hill and Elena Milova from the MMTP team to discuss the program and why being pro-actively involved with longevity advocacy is so important.

What’s the gap in the market you’re aiming to fill and the major motivation behind the MMTP?

Steve – The bridge between basic research and taking it to clinical trials. People like The SENS Foundation are spinning a lot of plates doing the high risk, nitty gritty research that isn’t profitable, but crowdfunding can get that done. We want to create a solid gold standard testing platform without the restrictions of government, where any team can come to us for parallel testing and halve development time. The problem with animal testing is there’s this disconnect; it’s not sexy science basically. A common response is let me know when it’s available in humans, but it’s not going to be! No animal data means no human testing, organizations like the FDA, NHS and EMA all insist on a battery of animal testing before human trials.  Period. It’s not sexy, it’s not available in humans next week, but if MMTP or other projects don’t get things done on mice for example, it’s never going to get done. It doesn’t matter if one theory turns out to be wrong, let’s get stuck in and find out! 

Elena - It’s not just about the science, too many people claim to support longevity but don’t actually do anything to contribute or get things moving. Right now we’re pushing to promote ideas among decision makers at a wide range of levels - at the international level like the last World Health Organization Conference in Geneva and at the local level trying to stimulate the same process in multiple countries. There is a big problem with funding today, but if there’s even the smallest chance to stimulate movement and make a bigger research impact, we’ve got to do it. That’s why the MMTP formed. 

"No animal data means no human testing"


Tell me about the upcoming fundraiser?

Steve - We’ve tentatively earmarked a fundraiser for April this year, but it’s unwise to set an arbitrary date and launch no matter what. If we launch before we’re ready it would be a mistake. Lifespan.io is probably the most logical choice, but in the future with other therapies we could explore Indiegogo or Experiment.com, especially if the therapies we are testing have wider appeal outside of regenerative medicine, e.g. AGE breakers could help diabetes too, so there is a wider scope for support beyond the immediate longevity research enthusiasts. 

Elena – For now we have our goal, several stretch goals and we’re going to train ourselves to do crowdfunding projects. Last year, I helped to organize a crowdfunding campaign for an experiment in Russia, we were testing a set of geroprotectors in mice. But the cost was relatively small, most of it was provided by one generous donor. The MMTP first stage testing is a bit bigger, so we’re exploring different strategies. The more money we get, the more experiments we’ll be able to do. Everything rides on that initial response, and it’s not just money - we need to galvanise people too. I tell people every time you buy a drink, that money can support one or two mice in the entire experiment. It’s a small amount of money we’re asking for, but it could have a big impact on your future life.


What is the funding situation? Why crowdfunding?

Steve - We can’t rely on a traditional model of funding like the FDA, EMA and other government organizations. They may fund some ventures, but it’s never going to be the avalanche of support we need to get things done in a timely manner. The pace of progress is glacial in that model. We can’t afford to just preach to the choir unfortunately, we need to make bigger waves. AGE breakers for example is one treatment we’d like to explore, and AGEs are closely implicated with diabetes and atherosclerosis, which means we could potentially draw on mainstream and charity support if the data is there to support it. We’ve got to cast a wide net ultimately or we’re not going to go anywhere near fast enough; it’s’ that simple. 

Sugar molecules form pesky bonds with proteins and fats across the body leading to something called advanced glycation end products (AGEs).  These accumulate with aging and cause a number of problems. Molecules that break these bonds, AGE breakers, are another potential avenue of treatment 

We’re back to the problem of the mindset here, too many people have this idea that aging isn't amenable to intervention and yet they’re quite happy to fund disease research for age-related diseases like Alzheimer's. The money is out there, but we need to be more tactical in how we pursue it. The 1st phase of testing using senolytics is quite a difficult concept to sell, but the more we learn and the more robust results we get, the more we can capture hearts and minds. No-one is taking any wages either, which it’s why it’s so cheap and we can achieve a lot more.

"We need to proclaim far and wide: Guys we have a problem to solve, it’s time"


What is your opinion on current state of the longevity movement, and how important is advocacy in the field? 

Elena - One of the major limitations we face is that aging isn’t recognised as a disease. If it was we would probably have far less problems attracting money. It’s a question of public perception, and we hope that aging will be introduced as a disease in the new ICD11 in 2018. There’s now a wave of articles claiming we must recognise aging as a disease, but official recognition would lead to a wider perception change among many different kinds of people. We need to proclaim far and wide : ‘Guys we have a problem to solve, it’s time’.

Steve - Another problem in society is too many people are waiting and trusting their governments to tackle this issue, but the finances and will just isn’t there. Science isn’t well funded. That’s a major myth we’ve got to dispel, and we want to be a part of a wider effort to galvanise people to be more proactive. Pessimism is a big drain in the community, and I can guarantee if we don’t do anything the worst will happen, but if we try who knows? It might work sooner rather than later, and that means more lives saved. There is a great need to communicate to people the link between basic research and somebody in bed getting a pill because the response is usually let us know when it’s available in people. It never will be with that attitude! 

The media also dash hopes by vastly over exaggerating any news. We need to stop being sensationalist and talking about ‘the elixir of life’. Longevity research can be very complicated, but we have to appeal to everybody including those with less time on their hands. MMTP is strictly about avoiding hype, we want to be realistic, scientific but also engaging and interesting. You need to educate people without blinding them with science. That’s a difficult balance, but we don’t want to lie to get the numbers. We’ve got to be honest and well rounded, taking the good news from each test and expanding on it. There are some incredible technologies being developed around the world, so let’s test, test, test. 

"When it comes down to it, aging is truly something for everybody, let’s face it"

 

Elena –  You really can’t understate how important the advocacy end is. Other organizations in the field like the ILA and Heales all do a good job at this. We’ve got to educate people! They can’t make informed decisions if they don’t know enough, so that’s why we put up a good list of frequently asked questions and links to evidence on the MMTP site. We’ve also been working and talking with several like-minded groups like the Global Healthspan Policy Institute, Heales, the Foundation of Science for Life Extension, and we support the upcoming TAME metformin trial for the FDA. Step by step you educate people and they start to perceive the situation as normal. It just takes time. We also need to reach more young people confident they’ll have access to these breakthroughs later on, because therapies don’t magically appear by themselves and not everyone has the luxury of time. 

Courtesy of increased advocacy and understanding, the FDA has given the initial green light for the first official 'anti-aging' trial in history with diabetes drug metformin, set to begin in 2016

Do you have anything to add for people who are interested?

Steve -  Anyone passionate can learn, and every little bit helps! Take ownership of your health and educate yourself, and we want to help encourage that process. That’s equally as important as funding the research itself, it’s about personal empowerment. Crowdfunding and knowledge sharing is a massive factor in whether we succeed or not. It’s no exaggeration, some days the actual science is the easy bit! If anyone’s interested in getting involved in a grassroots project that’s going to do something useful, we’d love to hear from you. We also have a variety of multimedia outlets to check out: a youtube channel, linkedin, reddit…we’re everywhere. We don’t mind using that as a megaphone to help other groups out either, the more interest the better. 


So you’re making your data open to the public?

Steve – We insist that all data will be open and all costs are 100% transparent. Everything we do will be available. Science should be open and free, we don’t believe in paywalls and we’re not interested in patents. Anyone will be able to check out our data and get in touch. Hopefully we can promote a lovely warm, fuzzy feeling and get people working together. 


"We’re not focused on profit, our job is to tackle the non-profitable, high risk stuff and pass it on to another company for clinical trials"

 

What makes the MMTP unique?

Steve - We’re breaking the mould a little bit, traditionally you’d have large groups that produce pretty curves in lifespan studies, but we want to move beyond that; experiments providing meaningful, robust data without getting lost in the noise. We won’t just test 40 mice on the same dosage, one group could take a 3 week course and then nothing for another 6 months, one on high infrequent dosage, one frequent low. We all know what happens with the set dosage from The Scripps senolytics study, there’s no point repeating it. 

We also have a sneaky trick up our sleeve, with access to already old mice aged 16-18, the equivalent of about 60 in humans. We can test them without having to wait and house them for a couple of years - cutting costs and focusing on results. We have 60 mice which is a decent cohort, plus a positive caloric restriction cohort, and a normal control. Quality control is important so we don’t waste crucial data.  We’re all about high information yield and narrowing down optimum dosages, we wouldn’t gain anything from copying another study. We’re not focused on profit, our job is to tackle the non-profitable, high risk stuff and pass it on to another company for clinical trials. We’re not about getting it to clinical, we can’t do that, but we can speed up the bridge between the two. 

Who else is involved?

Steve – Our senior researcher Dr. Alexandra Stolzing is a keen advocate of longevity research and highly skilled in stem cell work. We also benefit from good relationships with breeders and a number of researchers. Dr Josh Mitteldorf is also involved and has designed a computational testing method for us. He has some great ideas too. We’ve also consulted with many other experts who aren’t directly co-operating at this point. We’re not a huge group yet,  but we’ll get there. 


Let's talk a little bit about your first project senolytics using the drugs Dasatinib and Quercetin

Steve – Lots of research now supports the validity of senolytics. We know it’s not the holy grail, and it might not extend life much but it’s looking like it could help healthspan. These treatments aren’t supposed to be a cure-all, we need combination therapies to tackle the variety of problems. One of our big selling points is combination testing, which very few people have done. Daily low dose quercetin has actually been linked with reduced lifespan, and the evidence with senolytics suggests infrequent, high doses are more effective. You need enough of a dose to kill off these old cells but constant dosing might actually harm you. If we get to run these experiments, these are exactly the kind of questions we’ll answer by testing multiple dosage regimens.

(If you're a bit confused about what senolytics are, read about previous work on senescent cells here and here)

Removal of senescent cells has shown promising results in precious experiments and can prolong health and lifespan in mice. You can see the contrast here in mice of the same age, the mouse on the right has had its senescent cells removed. Credit: Jan van Deursen and Darren Baker

If the first stage goes well, can you talk about the synergy approach?

Steve - In the long term as we collaborate and obtain more potential therapeutics we’ll test them in combination to ascertain if there is synergy. We’ve been talking to Ichor Therapeutics, Oisin biotechnology and David Spiegel’s lab in yale, working on either lipofuscin removal, senolytics, and glucosepane cleaving respectively. The first out of the stable will effectively go on our bench after we’ve done some manouevering. We have our resident stem cell expert too Dr. Stolzing, so we could attempt some really interesting stem cell work if things go to plan. We’re not just about drugs, we want to test other exciting therapies like targeted liposomes too. Maybe then we can convince people the science is a little bit sexy, who knows? 


If you succeed in getting extra funds, what will that enable you to do?

Elena – With additional funding we’ll put more resources into metrics and post-mortem analysis to get even more data from each group. Post-mortem analysis is extremely important because it reveals any unseen effects like cancer. If we can see the number of tumours has increased for example, then we know a substance might extend life but increase cancer risk. We really need to observe what’s happening in the bodies of the deceased mice to get a sense of what’s really going on.

How much do you feel the situation has changed in recent years?

Steve - When people first started talking about this they were dismissed at crackpots, but respected scientists like Harvard’s George Church was in the news recently and Elizabeth Blackburn who spoke at the Davos conference recently saying this can be done. It’s not a career ender anymore and increasingly respected scientists are stepping forward and saying that aging is something that is amenable to intervention, the data supports this.The latest IQ squared debate with Aubrey de Grey was really entertaining, and we won! Hopefully debates like that will get more people involved. That’s why on our website we go into detail about some common objections to regenerative medicine like overpopulation and unemployment.

Elena – Representatives of our community often don’t talk to people much because of resistance and negative reactions. It’s not easy to say what you really think, but on the other hand if you’re not saying what you want, what’s right, what has to be done, then some people just don’t understand. People don’t always have time to think about these issues, but once you bring it to their attention they’re on board.

The Black 6 mouse is a mainstay in life extension studies (find out more about the little guys here) Credit: The Jackson Laboratory

Why is animal research so important?

Elena – Improved computer models and a good battery of biomarkers could be a huge help in the future, but right now we have to foster research in animals if we want to get anywhere.

Steve – Analogs are just not suitable. Most researchers would prefer to use analogs like Athena and organs on chips wherever possible but lifespan studies need a living system to understand the effects. There is no alternative until aging biomarkers are sophisticated enough. We’re getting there slowly, Steve Horvath’s methylation system is a gold standard for aging biomarkers and with a few more like that we’re on a home run. Right now it’s mice, guess work and deduction. 
It would be great if AI came along and did everything for us. We could relax then, but until that point we can’t.

Elena – Even then we can’t relax! There are too many other existential risks! We won’t have time to get bored even if we live for 150 years.

"It’s not in our interest to stress these animals at all, we’d prefer they had a good time with little interference"


Do you have anything to add about mice and ethics for people cautious about animal research?

Steve –  It’s imperative that we look after the animals, and we’re providing regularly cleaned, very high quality cages in Leipzig university. They live a lot longer in those spaces than their wild cousins do and in a nice kind of way, our experimental success hinges on them living as long and as healthily as possible. The procedures we’ve chosen are also minimally invasive, but unfortunately at the same time we’ve got to be realistic and test things. There isn’t a real alternative today to mice experiments, so you’ve got to do the best you can do. Lots of vivisectionists paint animal research as black and white, but it’s just not like that. We’re not cosmetics research. Nothing is black and white, and we’ll make the experiments as ethical as we possibly can. We talk about some of the ethics on the website to show we’ve thought about it, and maybe someone on the fence will be reassured.

Elena – You have to remember if you do any work on mice in the countries we’ll work in, you need a specific license. We have a lot of paperwork to fill in regarding animal ethics and welfare. It’s very strict and costs money, but it does ensure that quality practice is followed and living conditions are acceptable. We’re not just complying with the law, we all care about the animals too.

How do you foresee the future?

Elena – Caring for older people in poor health is actually more expensive than fixing most of these problems, even if the initial cost is substantial. That makes these treatments affordable, and we have to emphasise that to authorities and national governments. 

"It’s a learning curve, one pill doesn’t have to accomplish everything"

 

Steve – There are no magic bullets, eventually we’ll hit something that triggers the domino effect, but until then we'll work from multiple angles and see what happens. Cutting edge things now will be commonplace eventually and people will take it for granted, just like antibiotics and vaccines. Taking a pill for a headache is normal, but a while ago someone might have accused you of devilry! In the past people protested about these things with almost exactly the same arguments we see now, but we adapted. They became normal and so too will these new technologies.

Want to find out more about the project, prospective treatments and read plenty of informative articles? Check out the MMTP website at majormouse.org, and keep an eye out for the fundraiser coming soon!

 

Based near London in the UK, Steve Hill is the project lead for the MMTP as well as being an advocate of regenerative medicine and scientific research

 

 

 

Elena Milova is a head of an NGO Optimum Health and a Honorary member of the International Longevity Alliance, promoting life extension technologies development in Russia via educational and advocacy activities