We take a trip down Lifespan.io’s Rejuvenation Roadmap – and it’s a journey towards Longevity progress.

Lifespan.io is a US-based non-profit organisation that seeks to raise public awareness of research on aging and rejuvenation. Sound familiar?
Longevity.Technology: intrigued by their Rejuvenation Roadmap, a curated database of “the most promising therapies and technologies in development” which charts progress and allows the user to keep tabs on the latest Longevity news for the nine hallmarks of aging, we caught up with Lifespan.io’s Steve Hill and Elena Milova.

Steve is Lifespan.io’s Editor-in-Chief and serves on Life Extension Advocacy Foundation’s Board of Directors. Elena is Board Director and outreach officer.  She is also a Longevity activist and advocate organises educational events to make new evidence-based methods of healthy life extension more popular.

Longevity.Technology: The Roadmap is a great tool for seeing what progress is being made in each of the nine hallmarks. Can you tell us what are the general principles behind the roadmap?
Elena Milova: Our primary goal is to accelerate the development of evidence-based therapies targeting various types of damage associated with age. In medicine, evidence is a very important thing, as you would want the treatment to have reproducible results, such as health benefits and better outcomes.

It might not be obvious, but the system of clinical trials allows us to gradually increase the level of evidence until we can definitively say that yes, it works, and it is good for you. A new therapy is first tested in cell culture and then in animals. This is weak evidence, which is why we can never extrapolate data from cell culture and animal data to people and start taking drugs just because they helped mice live longer.

Next, a therapy is proven non-toxic in humans in Phase 1, and it is taken into Phase 2 to determine if it produces a beneficial effect and what dosage provides the best results. Then, a larger study confirms the best dosage and proves that the treatment works for most of the patients. Only after that can we conclude that it is a good treatment that can be registered and introduced into clinical practice.

The Roadmap is a database reflecting how a therapy gains evidence for its effectiveness as it moves through clinical trials. Its main value is in telling you when you can start considering a longevity therapy to be safe and reliable.

Longevity.Technology: If we could judge therapies by universally accepted biomarkers, would that allow a more accurate comparison, or would we be boxing ourselves into a corner?
Elena Milova: It depends on what exactly you want to know about those treatments. If you want to compare their general ability to reduce biological age, then you would probably want some complex biomarker or set of biomarkers that can assess and predict the development of age-related diseases.

If you want to assess how soon a therapy will be registered and become accessible, then you would probably benefit from learning the results of Phase 2 clinical trials and the financial status of the company developing it, as the ability to quickly conduct Phase 3 clinical trials pretty much depends on available funding.

If you want to understand the current level of evidence behind a therapy, then you should look at the clinical trial stage of that therapy on our Roadmap.

Which therapy has the most potential is actually a very good question. It is presumed that therapies that address the primary causes of aging might have a larger effect on health and longevity compared to therapies that address downstream causes, but we don’t know that for sure because it is extremely hard to create such treatments in the first place. This is why there is an advantage in using clinical trial phases as a way to determine progress. They are consistent and offer a clear picture of how close a therapy is to being available.

Steve Hill: Also, the issue with biomarkers is which ones to use, what combination of biomarkers would form the ideal panel for monitoring biological age, and any changes to it. In my view, researchers are some considerable way from reaching a consensus on what biomarkers are best combined to be used in clinical trials and such.

Epigenetic clocks are an increasingly popular biomarker, but there are also now dozens of different ones to choose from, and it is still far from clear what exactly many of them are measuring. That said, epigenetic clocks are becoming increasingly refined and accurate as predictors of biological age. I think that they are likely to become a part of an aging biomarker panel for clinical trials in the near future.

Longevity.Technology: On your roadmap, the hallmarks Loss of Proteostasis and Cellular Senescence have a healthy range of therapies under research, but Epigenetic Alterations and Deregulated Nutrient Sensing only have a couple each; what are the reasons for this, do you think, and how can this be improved?
Steve Hill: Some compounds, such as NR and NMN, also address deregulated nutrient sensing as well as the DNA repair element, and in such cases where a therapy may address more than one hallmark, the higher-priority hallmark is chosen. DNA damage occurs higher up in the hierarchy of hallmarks, and repairing DNA damage is a greater technical challenge than adjusting metabolism, as is the case with deregulated nutrient sensing, so this is the reason for prioritizing the listings in this way.

In the case of epigenetic alteration, partial cellular reprogramming is a relatively new area of research. It is yet to shift into high gear as animal studies are still ongoing. There are still a number of unanswered questions and refinements needed to ensure that it is as safe as possible.

That said, Iduna Therapeutics, which we recently added to the roadmap in the category of epigenetic alterations, is preparing for human trials in the near future and has some serious researchers behind it, including David Sinclair, Steve Horvath, Juan Carlos Izpisua Belmonte and Manuel Serrano. Iduna is part of the growing collection of companies working on the individual hallmarks of aging under the banner of Life Biosciences.

Longevity.Technology: People might raise eyebrows at the inclusion of treatments for animals being included on your Roadmap. How much overlap for human potential should there be, or does the research stand on its own merits?
Steve Hill: Animal testing is the initial requirement for human trials to begin, and this is the reason why we include therapies that are aimed at eventual translation to humans but that are currently in the animal testing phase. While many drugs do not translate, of course, it is still useful to include promising therapies at the animal stage for the interest of readers and to give the bigger picture.

Regarding therapies specifically aimed at companion animals such as dogs being included, our four-legged friends share considerably more in common with us than mice, so, in general, the translation potential of therapies that work in dogs could be higher than in rodents.

I also consider it quite likely that companion animal anti-aging therapies could arrive before human ones are widely available and that they serve as a good indication of the likely future direction that anti-aging will take. We are already seeing evidence of this in the form of the so-called longevity dog foods being developed, which contain things such as rapamycin, as well as the ongoing Dog Aging Project led by Dr Matt Kaeberlein.

Longevity.Technology: Which therapy has surprised you the most with its progress?
Steve Hill: Senolytics. Until a few years ago, the idea of removing senescent cells had only been mentioned by people such as Dr Aubrey de Grey. It wasn’t really until Barker et al. first demonstrated that removing them is a viable concept that things really started to take off.

In the last 3-4 years, we have seen a huge explosion of interest in the area of senescent cells and senolytics, and where there were only a few companies developing senolytics, such as SIWA, there are now dozens engaged in this space.

It is my view based on the meteoric rise of interest in this area, that senolytics and the periodic purging of problematic senescent cells is likely going to be the first truly regenerative therapy, as part of a repair-based approach to aging, to arrive.

Longevity.Technology: In which hallmark do you think the next longevity game-changer will happen?
Steve Hill: To be fair, there has been no game-changer in any hallmark in humans yet; therefore, in my view, senolytics that address cellular senescence is poised to be the first real game-changer, as it has such a broad applicability to many age-related diseases and conditions.

Senolytics are already in human trials, and they are exciting because they represent a true therapy in the repair-based approach to aging, which has been proposed by researchers such as Dr Aubrey de Grey and his SENS model of aging.

Finally, another reason why I think senolytics will be the first game-changer is because they have a potentially wide application. Not only could they possibly treat a wide range of age-related diseases, they may also mitigate the negative effects of chemotherapy by removing the healthy cells that it damages and reducing the chance of relapse. This means that senolytics have an even greater likelihood of reaching mainstream adoption quickly compared to other therapies.

Now, there, are of course, other promising avenues of research that may deliver in the near future, though nothing is as far ahead as senolytics currently. One approach, the next-gen plasmapheresis based on the research of Drs Irina and Michael Conboy, filters the pro-aging inflammatory factors out of aged blood. This has spurred rejuvenation in mice and, in my view, has an excellent chance of translating to humans once human trials begin in the near future.

There has also been great progress in stem cell research, particularly the related area of exosomes, which uses the secreted signals from stem cells as its own form of therapy. There are still a number of challenges to get stem cell therapy working consistently well, such as reliable engraftment, but they are also a contender for the next game-changer once things are ironed out.

Elena Milova: There is a direction of research that I personally find exciting. It is the application of mesenchymal stem cells for regeneration of various tissues. Longeveron LLC has recently announced the approval of its clinical trial of Longeveron’s Mesenchymal Stem Cells (LMSCs) for treatment of aging frailty in Japan.

I should note that frailty is not a synonym of weakness: it is a condition that implies deterioration of many physiological and cognitive functions. If the researchers managed to reverse frailty, it would be indicative of considerable health improvement and reduction of risks of developing age-related diseases. I am very much looking forward to seeing the results of this trial.

But there is more than that. Mesenchymal stem cells have been successfully used for helping patients with severe and moderate COVID-19 by regulating their immune function and rescuing pulmonary function. Taking into account that the application of those cells shows the ability of reversing lung fibrosis in animals, I think we are yet to discover their full potential for dealing with age-related changes.

Longevity.Technology: As advocates for life extension, how are you using the Roadmap to drive your agenda?
Elena Milova: The hardest part of advocacy activities right now is that the percentage of people who know about the revolution in geroscience is really low. Quite often, we deal with people who know almost nothing about it. Not only do you have to share the idea that aging can be modified, you also need to make it look believable, and the best way to do that is to put new concepts in a familiar context. Most people know that new drugs for various diseases are undergoing some sort of trials before being approved and entering clinical practice. When we show them that drugs for aging are undergoing animal and human trials, it rings a bell.

We created this roadmap not only to understand where we are in the process of creating longevity therapies but also to help active people in our community illustrate the plausibility of anti-aging therapies to newcomers by sharing just one link.

Steve Hill: In a more active way, we use the roadmap during our various talks at conferences and events, again to showcase a fair and scientifically accurate assessment of the field. The roadmap is designed in a visually accessible format with understandable categories and stages so that a person seeing it can have an instant grasp of how things are moving along.

Longevity.Technology: Any honourable mentions that didn’t make the final cut but we should know about?
Steve Hill: In a rapidly changing field such as this, there are frequently new companies and approaches appearing, and we are constantly watching and evaluating their progress. The roadmap will be frequently updated as an ongoing process, so do keep an eye on it as things change.

For those interested in the latest progress in the field, I would like to mention that on August 20-21, we are holding Ending Age-Related Diseases 2020, our third annual scientific conference. This will be two action-packed days filled with talks, panels, interviews, and more from the leading experts in the field.

This year, the event will be online so everyone can join us, and as a special thank you to Longevity.Technology readers, we are offering a 10% discount with the code LT2020, which you can redeem during ticket registration. We hope to see you there, and thank you to Longevity.Technology for taking the time to interview us today.

Images courtesy of Lifespan.io