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Human Pilot Study Results for Senolytics Published – Article by Steve Hill

Human Pilot Study Results for Senolytics Published – Article by Steve Hill

Steve Hill


Editor’s Note: The U.S. Transhumanist Party features this article by Steve Hill, originally published by our allies at the Life Extension Advocacy Foundation (LEAF) on January 7, 2019. This article presents the results of a human pilot study that involved the consumption of two promising senolytic drugs, dasatinib and quercetin, to target idiopathic pulmonary fibrosis. The results are promising and constitute a great step forward for senolytics being tested in human clinical trials. Another promising approach is the TAME trial, which is a double-blind randomized controlled clinical trial, to test if Metformin can treat various age-related diseases. 

~Bobby Ridge, Assistant Editor, July 4, 2019

The results from a human pilot study that focused on treating idiopathic pulmonary fibrosis with senescent cell-clearing drugs has been published. The drugs target aged and damaged cells, which are thought to be a reason we age and get sick, and remove them from the body.

Senescent cells and aging

As we age, increasing numbers of our cells become dysfunctional, entering into a state known as senescence. Senescent cells no longer divide or support the tissues and organs of which they are part; instead, they secrete a range of harmful inflammatory chemical signals, which are collectively known as the senescence-associated secretory phenotype (SASP).

Dr. Judith Campisi from the Buck Institute for Research on Aging, along with her research team, identified that senescent cells secreted the various harmful chemicals that characterize the SASP in 2008, which was when interest in senescent cells really began [1]. In 2010, building on this initial research, Dr. Campisi went on to show the link between the SASP and cancer [2].The SASP increases inflammation, harms tissue repair and function, causes the immune system to malfunction, and raises the risk of developing age-related diseases such as cancer. It can also encourage other nearby healthy cells to become senescent via the so-called bystander effect. Therefore, a small number of these cells can cause a great deal of harm.

Normally, senescent cells destroy themselves by a self-destruct process known as apoptosis before being cleared away by the immune system. Unfortunately, as we age, the immune system becomes weaker, and senescent cells start to build up in the body. The accumulation of senescent cells is considered to be one of the reasons why we age and develop age-related diseases.

It has been suggested that the clearance of senescent cells might help address a number of age-related diseases at once, as senescent cells are thought to be one of the fundamental reasons that we age. Drugs that can remove these unwanted, damaged cells are known as senolytics.

Human trial results for senolytics

This new publication by researchers at the Mayo Clinic, including James Kirkland, one of the pioneers of senolytic drugs, shows the results of a pilot study that uses dasatinib and quercetin to treat idiopathic pulmonary fibrosis [3].

Pulmonary fibrosis causes scarring of the lung tissue, which leads to the progressive loss of lung function over time. When the disease’s origin is unknown, it is called idiopathic pulmonary fibrosis, or IPF. The treatment options for this disease are extremely limited with no currently known cure.

The researchers in this new study tested a combination of dasatinib and quercetin, one of the earliest senolytic drug combinations that was tested in mice and shown to have beneficial results, particularly for the cardiovascular system [4-5]. It was also shown in a previous study that clearing senescent cells using dasatinib plus quercetin was able to alleviate idiopathic pulmonary fibrosis (IPF)-related dysfunction in a mouse model of the disease.

Fourteen patients with IPF were recruited for this pilot study, and the initial results, while leaving room for improvement, are promising.

Physical function evaluated as 6-min walk distance, 4-m gait speed, and chair-stands time was significantly and clinically-meaningfully improved (p < .05). Pulmonary function, clinical chemistries, frailty index (FI-LAB), and reported health were unchanged. DQ effects on circulating SASP factors were inconclusive, but correlations were observed between change in function and change in SASP-related matrix-remodeling proteins, microRNAs, and pro-inflammatory cytokines (23/48 markers r ≥ 0.50).

It should be noted that this was only a small pilot study and that the optimal human dosage and frequency is yet to be established. Typically, the next step is to launch a larger-scale study to establish this dosage.

The researchers also note that these results warrant evaluation of dasatinib plus quercetin in larger, randomized, and controlled trials for senescence-related diseases. In other words, they would like to test senolytics in larger studies for various age-related diseases, and the results certainly support doing exactly that.

Conclusion

These initial results are positive, despite there being plenty of room for improvement. The combination of these two drugs also appears to favor particular cell and tissue types over others, much like other senolytic drugs, which were discovered after dasatinib and quercetin were originally shown to clear senescent cells. It may be that a combination of different senolytics will be needed as a “cocktail” of sorts to fully clear out all the unwanted senescent cells, as different senescent cells appear to use various survival pathways to evade apoptosis, and no single drug can target them all.

We greet these early results positively and look forward to the beginning of larger-scale studies for multiple age-related diseases. Given how senescent cells appear to be implicated in most if not all age-related diseases, there are some exciting possibilities ahead.

Literature

[1] Coppé, J. P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., … & Campisi, J. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS biology, 6(12), e301.

[2] Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathological Mechanical Disease, 5, 99-118.

[3] Nambiar, A., Justice, J., Pascual, R., Tchkonia, T., Lebrasseur, N., Kirkland, J., … & Kritchevsky, S. (2018). Targeting pro-inflammatory cells in idiopathic pulmonary fibrosis: an open-label pilot study of dasatinib and quercitin. Chest, 154(4), 395A-396A.

[4] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[5] Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging cell.[/column]

Steve Hill serves on the LEAF Board of Directors and is the Editor-in-Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ Magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Keep Me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.

 

Finally, Rejuvenation is a Thing! – Fresh Interview with Aubrey de Grey by Ariel VA Feinerman

Finally, Rejuvenation is a Thing! – Fresh Interview with Aubrey de Grey by Ariel VA Feinerman

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Ariel VA Feinerman
Aubrey de Grey


This interview was originally published here

Preface

What is ageing? We can define ageing as a process of accumulation of the damage which is just a side-effect of normal metabolism. While researchers still poorly understand how metabolic processes cause damage accumulation, and how accumulated damage causes pathology, the damage itself — the structural difference between old tissue and young tissue — is categorized and understood pretty well. By repairing damage and restoring the previous undamaged — young — state of an organism, we can really rejuvenate it! It sounds very promising, and so it is. And for some types of damage (for example, for senescent cells) it is already proved to work!

Today in our virtual studio, somewhere between cold, rainy Saint-Petersburg and warm, sunny Mountain View, we meet Aubrey de Grey, again! For those of you who are not familiar with him, here is a brief introduction.

Dr Aubrey de Grey is the biomedical gerontologist who researched the idea for and founded SENS Research Foundation. He received his BA in Computer Science and Ph.D. in Biology from the University of Cambridge in 1985 and 2000, respectively. Dr. de Grey is Editor-in-Chief of Rejuvenation Research, is a Fellow of both the Gerontological Society of America and the American Aging Association, and sits on the editorial and scientific advisory boards of numerous journals and organizations. In 2011, de Grey inherited roughly $16.5 million on the death of his mother. Of this he assigned $13 million to fund SENS research.

Note: If you have not read “Ending Aging” yet I suggest you to do it as soon as possible, and to be more comfortable with the ideas we are discussing below I highly recommend you to read short introduction to SENS research on their web page. Also if you are interested in recent news and up-to-date reviews about [anti]ageing and rejuvenation research the best place to look for is Fight Aging! blog. Finally, if you are an investor or just curious, I highly encourage you to take a look at Jim Mellon’s book “Juvenescence”.

Interview

Ariel Feinerman: Hello, Dr Aubrey de Grey!

Aubrey de Grey: Hello Ariel — thanks for the interview.

Ariel Feinerman: How do you feel 2018 year? Can you compare 2018 to 2017 or early years? What is changing?

Aubrey de Grey: 2018 was a fantastic year for rejuvenation biotechnology. The main thing that made it special was the explosive growth of the private-sector side of the field — the number of start-up companies, the number of investors, and the scale of investment. Two companies, AgeX Therapeutics and Unity Biotechnology, went public with nine-digit valuations, and a bunch of others are not far behind. Of course this has only been possible because of all the great progress that has been made in the actual science, but one can never predict when that slow, steady progress will reach “critical mass”.

Ariel Feinerman: In 2017 SENS RF have received about $7 million. What has been accomplished in 2018?

Aubrey de Grey: We received almost all of that money right around the end of 2017, in the form of four cryptocurrency donations of $1 million or more, totalling about $6.5 million. We of course realised that this was a one-off windfall, so we didn’t spend it all at once! The main things we have done are to start a major new project at Albert Einstein College of Medicine, focused on stem cell therapy for Alzheimer’s, and to broaden our education initiative to include more senior people. See our website and newsletters for details.

Ariel Feinerman: What breakthroughs of 2018 can you name as the most important by your choice?

Aubrey de Grey: On the science side, well, regarding our funded work I guess I would choose our progress in getting mitochondrial genes to work when relocated to the nucleus. We published a groundbreaking progress report at the end of 2016, but to be honest I was not at all sure that we would be able to build quickly on it. I’m delighted to say that my caution was misplaced, and that we’ve continued to make great advances. The details will be submitted for publication very soon.

Ariel Feinerman: You say that many of rejuvenating therapies will work in clinical trials within five years. Giving that many of them are already working in clinical trials or even in the clinic (like immunotherapiescell and gene therapies) do you mean the first — maybe incomplete — rejuvenation panel, when you speak of early 2020?

Aubrey de Grey: Yes, basically. SENS is a divide-and-conquer approach, so we can view it in three overlapping phases. The first phase is to get the basic concept accepted and moving. The second phase is to get the most challenging components moving. And the third phase is to combine the components. Phase 1 is pretty much done, as you say. Phase 2 is beginning, but it’s at an early stage. Phase 3 will probably not even properly begin for a few more years. That’s why I still think we only have about a 50% chance of getting to longevity escape velocity by 2035 or so.

Ariel Feinerman: Even now many investors are fearful of real regenerative medicine approaches. For example pharmacological companies which use small molecules, like Unity Biotechnology, received more than $300 million, in much more favour than real bioengineering companies like Oisin Biotechnologies, received less than $4 million, even though the biological approach is much more powerful, cheap, effective and safe! Why is this so in your opinion, and when can we see the shift?

Aubrey de Grey: I don’t see a problem there. The big change in mindset that was needed has already occurred: rejuvenation is a thing. It’s natural that small-molecule approaches to rejuvenation will lead the way, because that’s what pharma already knows how to do. Often, that approach will in due course be overtaken by more sophisticated approaches. Sometimes the small molecules will actually work well! It’s all good.

Ariel Feinerman: Do you agree that the small-molecule approach is generally the wrong way in the future rejuvenation therapies? Because they have many flaws — especially their main mechanism via interference with human metabolism. Unlike them SENS bioengineering therapies are designed to be metabolically inert — because they just eliminate the key damage, they do not need to interfere with metabolism, so it is much easier than usual to avoid side effects and interactions with other therapies. They just eliminate the key damage, which means they are easier to develop and test — and much safer.

Aubrey de Grey: Ah, no, that’s too simplistic. It’s not true that small molecules always just “mess with metabolism” whereas genetic and enzymatic approaches eliminate damage. Small molecules that selectively kill senescent cells are absolutely an example of SENS-esque damage repair; the only thing against them is that it may be more difficult to eliminate side-effects, but that’s not because of their mode of action, it’s because of an additional action.

Ariel Feinerman: In recent years many countries gave the green light for regenerative medicine. Fast-track approval in Japan, for example, allows for emerging treatments to be used so long as they have been proven safe. The similar approach works in Russia. What about the EU or USA?

Aubrey de Grey: There’s definitely a long way to go, but the regulatory situation in the West is moving in the right direction. The TAME trial has led the way in articulating an approvable endpoint for clinical trials that is ageing in all but name, and the WHO has found a very well-judged way to incorporate ageing into its classification.

Ariel Feinerman: Do you think of working with USA Army? As far as we know they conduct research on regeneration and are very interested in keeping soldiers healthier for longer. And they have much money!

Aubrey de Grey: The Department of Defense in the USA has certainly funded a lot of high-impact regenerative medicine research for many years. I’m sure they will continue to do so.

Ariel Feinerman: Is any progress in the OncoSENS programme? Have you found any ALT genes? Is any ongoing research in WILT?

Aubrey de Grey: No — in the end that program was not successful enough to continue with, so we stopped it. There is now more interest in ALT in other labs than there was, though, so I’m hopeful that progress will be made. But also, one reason why I felt that it was OK to stop was that cancer immunotherapy is doing so well now. I think there is a significant chance that we won’t need WILT after all, because we will really truly defeat cancer using the immune system.

Ariel Feinerman: Spiegel Lab has recently published an abstract where they say they have found 3 enzymes capable of breaking glucosepane. Very exiting info! When can we hear more on their research? Revel LLC is a very secretive company.

Aubrey de Grey: They aren’t really being secretive, they are just setting up.

Ariel Feinerman: When can we see the first clinical trial of glucosepane breaker therapy?

Aubrey de Grey: I think two years is a reasonable estimate, but that’s a guess.

Ariel Feinerman: What do you think of the Open Source approach in rejuvenation biotechnology? The computer revolution in the early 2000s has taken place only because Open Source caused an explosion in software engineering!

We have many examples when Big Pharma buys a small company which has patents on technology and then cancels all research. In the Open Source approach you cannot “close” any technology, while everyone can contribute, making protocol better and everyone can use that without any licence fee! Anyway, there are countries where you cannot protect your patents. Maybe it will be better to make technology open from the beginning?

Famous biohacker Josiah Zayner said: “In the gene therapy world most treatments are easy to replicate or pirate because you can reverse engineer the DNA from scientific papers or patents. Same exact treatment, same purity and quality I could give to someone rejected from the clinical trial. The cost? Hundreds or a few thousand dollars at most. Same deal with immunotherapy.”

Aubrey de Grey: I think you’ve pretty much answered your own question with that quote. The technologies that will drive rejuvenation are not so easy to suppress.

Ariel Feinerman: Is the SENS RF going to begin new research programmes in 2019?

Aubrey de Grey: Sure! But we are still deciding which ones. We expect that our conference in Berlin (Undoing Aging, March 28–30) will bring some new opportunities to our attention.

Ariel Feinerman: What are your plans for 2019?

Aubrey de Grey: I’d like to say less travelling, but that doesn’t seem very likely at this point. Really my goal is just to keep on keeping on — to do all I can to maintain the growth of the field and the emerging industry.

Ariel Feinerman: Thank you very much for your answers, hope to see you again!

Aubrey de Grey: My pleasure!

Ariel VA Feinerman is a researcher, author, and photographer, who believes that people should not die from diseases and ageing, and whose main goal is to improve human health and achieve immortality. If you like Ariel’s work, any help would be appreciated via PayPal: arielfeinerman@gmail.com.