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Anti-Aging Gene Therapy for Dogs Coming This Fall – Article by Steve Hill

Anti-Aging Gene Therapy for Dogs Coming This Fall – Article by Steve Hill

Steve Hill


Editor’s Note: The U.S. Transhumanist Party features this article by Steve Hill of the Life Extension Advocacy Foundation (LEAF) originally published on the LEAF site on May 8th, 2019.  The article brings attention to a new program that aligns with our mission of ending age-related diseases, which the U.S. Transhumanist Party supports as part of our policy goals.

~ Brent Reitze, Director of Publication, United States Transhumanist Party, May 10th, 2019


In an article last May, we covered how Rejuvenate Bio, a startup biotech company led by Professor George Church, was planning to reverse aging in dogs as a step towards bringing these therapies to us. Those plans are now starting to move forward with news of a trial launch in the fall later this year.

Developing anti-aging therapies in dogs is the first step

Back in 2015, the Church lab at Harvard began testing a variety of therapies focused on age reversal using CRISPR, a gene editing system that was much easier and faster to use than older techniques. Since then, Professor Church and his lab have conducted a myriad of experiments and gathered lots of data with which to plan future strategies for tackling aging.

Last year, we learned that Rejuvenate Bio had already conducted some initial studies with beagles and were planning to reverse aging using CRISPR gene therapy. The goal was to move these studies forward to a larger scale as a step towards bringing similar therapies to humans to prevent age-related diseases. Professor Church was so confident that his team would find a solution, he even suggested that he may be one of the first human volunteers once therapies finally reach people.

“Dogs are a market in and of themselves,” Church said during the 2018 Radical Wellness event in Boston. “It’s not just a big organism close to humans. It’s something that people will pay for, and the FDA process is much faster. We’ll do dog trials, and that’ll be a product, and that’ll pay for scaling up in human trials.”

Choosing to develop therapies for dogs helps pave the way for therapies that address the aging processes in humans and could support their approval, which would otherwise be much more challenging. Currently, if you were to tell the FDA that you want to increase lifespan in humans by 20 years, you would need to come back in 20-30 years with the data, which just isn’t practical.

However, if Rejuvenate Bio can produce robust data in dogs showing that some processes of aging have been reversed, it lends considerable justification for human trials. The company is also taking a different tack; instead of focusing on increasing lifespan, it is instead targeting an age-related disease common in dogs, which should be cured if age reversal occurs.

This is based on the concept that in order to treat age-related diseases and cure them, you need to target the root causes of those diseases, which are the underlying aging processes themselves. If Rejuvenate Bio is successful, this would lend additional supporting evidence that directly treating aging to prevent age-related diseases could also work in humans.

Gene therapy trial for mitral valve disease

Rejuvenate Bio has now announced that it will be launching a gene therapy trial in dogs during the fall this year to combat mitral valve disease (MVD), a condition commonly encountered in the Cavalier King Charles Spaniel breed and directly caused by the aging processes. The study will initially focus on this particular breed and expand to include other dogs with MVD as time passes.

We are developing a novel cardio-protective gene therapy to stop the progression of heart failure in dogs. As a part of the technical development, we will launch a study in dogs with Mitral Valve Disease (MVD) in the fall of 2019. This study will provide valuable information that will aid our effort to address MVD.

MVD is due to the failure of the mitral valve in the heart, a one-way valve between the two chambers of the heart that prevents the backflow of blood as it is pumped around the body. As aging occurs, the mitral valve can degenerate, which allows backflow to occur, leading to left atrial chamber enlargement, congestive heart failure, and, ultimately, death.

This gene therapy is focused on adding a new piece of DNA into the cells of the dogs in order to halt the buildup of fibrotic scar tissue in the heart, which is linked to the progression of MVD and other forms of heart failure. Fibrotic tissue is the result of imperfect repair, which occurs when a more complete repair is not possible due to a lack of replacement cells or high levels of inflammation.

The researchers are keen to point out that this new piece of DNA is not passed onto the offspring of the animal and cannot transfer between dogs. This is because the therapy does not alter the DNA in the germline cells, the cells that are involved in reproduction and passing on genetics to an organism’s offspring.

If you wish to enroll your Cavalier King Charles Spaniel in the trial coming this fall, then register your interest with Rejuvenate Bio to learn more about eligibility and how to apply.

Conclusion

This is a very exciting study and, as the company discusses on its project page, the therapy may also be useful for other heart conditions, such as dilated cardiomyopathy (DCM). If the initial results are successful, it would be highly likely that we could see more dog breeds included as well as other conditions, including DCM, added to the program.

We wish Professor Church and Rejuvenate Bio every success, as this forms the basis for potentially moving such therapies into human trials more quickly as well as potentially helping our furry friends to live longer, healthier lives as well. We love our pets, and it is only logical that we should want the same healthy and longer lives for them as we do for ourselves, and the process for them is the same for us: new medical innovations that target the aging processes directly in order to end age-related diseases.

About  Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies, Steve has provided the community with multiple educational articles, interviews and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity reporter, Psychology Today and Singularity Weblog. He is a co-author of the book “Aging Prevention for All” – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Could Filtering Our Aged Blood Keep us Young? – Article by Steve Hill and Nicola Bagalà

Could Filtering Our Aged Blood Keep us Young? – Article by Steve Hill and Nicola Bagalà

Steve Hill

Nicola Bagalà


Editor’s Note: In this article, Mr. Nicola Bagalà and Steve Hill present the interview they conducted with Dr. Irina Conboy of Berkeley University and Dr. Michael Conboy of Havard University on the topic of youthful blood.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, February 17, 2018

Due to a recently published study on the effects of young plasma on aged mice, we got in touch with Dr. Irina Conboy of Berkeley University. Dr. Conboy is an Associate Professor at the Department of Bioengineering and an expert in stem cell niche engineering, tissue repair, stem cell aging and rejuvenation. Before we dive into the main topic, let’s familiarize ourselves a little with Dr. Conboy and her work.

Dr. Conboy got her Ph.D. at Stanford University, focusing on autoimmunity. She met her partner in science—and in life—Dr. Michael Conboy at Harvard and they got married before embarking on graduate studies; they celebrated their Silver Anniversary a few years ago. During her postdoctoral studies, she began focusing on muscle stem cells, trying to figure out what directs them to make new healthy tissue and what causes them to lose their ability to regenerate the tissues they reside in as we age [1].

Together with her husband Michael, she eventually discovered that old stem cells could be reactivated and made to behave like young ones if appropriately stimulated. The Conboys’ parabiosis experiments—which consisted in hooking up the circulatory systems of aged and young mice—showed that old age is not set in stone and can be reversed in a matter of weeks [2].

The follow-up work by the Conboys uncovered that age-accumulated proteins, such as TGF-β1, inhibited stem cells’ ability to repair tissues even in young mice, and when TGF-β1 signaling is normalized to its young levels, old mice (equivalent to 80-year old people) have youthful muscle regeneration and better neurogenesis in the hippocampus (the area of the brain that is responsible for memory and learning) [3].

While young blood did appear to be beneficial to old stem cells, their evidence suggested that the real culprit of the broad loss of tissue repair with age was the negative influence of age-accumulated inhibitory proteins in aged tissues and circulation, also called the stem cell niche [4].

This conclusion is certainly compatible with the view of aging as a damage accumulation process [5]. As Irina herself pointed out in this interview, in the parabiosis experiments, the old mice had access to the more efficient young organs: lungs, liver, kidneys and immune system of the younger mice, which likely accounted for many of the benefits observed in the elderly parabiosed mice. With respect to the rejuvenation of the brain, the old mice experienced environmental enrichment by being sutured to young, more active parabionts, and this is known to improve the formation of new brain cells, learning, and memory.

An aged niche blocks the action of old and young stem cells alike very quickly; therefore, as Dr. Conboy observed in an article in the Journal of Cell Biology, we can’t treat the diseases of aging by simply transplanting more stem cells, because they will just stop working. Their niche needs to be appropriately engineered as well. Fortunately, there are potential solutions to this problem; such as the use of artificial gel niches and defined pharmacology that are designed to protect transplanted or endogenous stem cells from the deleterious environment of the old body.

This research holds the potential to significantly postpone the onset of age-related diseases and possibly reverse them one day, including frailty, muscle wasting, cognitive decline, liver adiposity and metabolic failure, but Dr. Conboy remains cautious about the possibilities until more data is in. However, she does think that longer and healthier productive lives could improve people’s attitudes towards the environment and treating each other with compassion and respect—a view that we definitely share.

We managed to catch up with Irina and Michael Conboy and talk to them about their work.

For the sake of those new to the topic, what is it in young blood and aged blood that affects aging?

Irina: Numerous changes in the levels of proteins that together regulate cell and tissue metabolism throughout the body.

Mike: We wondered why almost every tissue and organ in the body age together and at a similar rate, and from the parabiosis and blood exchange work now think that young blood has several positive factors, and old blood accumulates several negative, “pro-aging” factors.

A lot of media attention and funding is currently being directed to youthful blood transfusions; how can we move beyond this to potentially more promising approaches, such as filtering and calibration of aged blood?

Irina: People need to understand not just the titles, abstracts and popular highlights of research papers, but the results and whether they support (or not) the promise of rejuvenation by young blood. In contrast to vampire stories, we have no strong experimental evidence that this is true, and there is a lot of evidence that infusing your body with someone else’s blood has severe side effects (even if it is cell-free).

Mike: Translational research!

Some evidence suggests dilution is the most likely reason that young blood has some beneficial effects; what are your thoughts on this recent study [6] in rats that shows improved hepatic function partially via the restoration of autophagy?

Irina: There are certainly “young” blood factors that are beneficial, not just a dilution of the old blood, and this benefit differs from organ to organ. We have published on improved liver regeneration, reduced fibrosis and adiposity by transfusion of old mice with young blood, but these are genetically matched animals, and in people, we do not have our own identical but much younger twins [7].

If dilution is also playing a role here, then can we expect similar or better results from calibrating aged blood?

Irina: Yes, and our work in progress supports the idea.

In your 2015 paper, you identified that TGF-β1 can be either pro-youthful or pro-aging in nature, depending on its level [8]. In the study, you periodically used an Alk-5 inhibitor to reduce TGF-β1 levels and promote regeneration in various tissues. In the study, you showed that TGF-β1 was important in myogenesis and neurogenesis; is there reason to believe that this mechanism might be ubiquitous in all tissues?

Irina: Yes, because TGF-β1 receptors are present in most cells and tissues.

Also, TGF-β1 is only one of a number of factors that need to be carefully balanced in order to create a pro-youthful signalling environment. How many factors do you believe we will need to calibrate?

Irina: There will be a certain benefit from calibrating just TGF-beta 1, but also additional benefits from more than one or just TGF-beta.

How do you propose to balance this cocktail of factors in aged blood to promote a youthful tissue environment?

Irina: We are working on the NextGen blood apheresis devices to accomplish this.

So, you are adapting the plasmapheresis process to effectively “scrub” aged blood clean and then return it to the patient. This would remove the need to transfuse blood from young people, as your own blood could be filtered and returned to you, and no immune reaction either, right?

Irina: Accurate.

This plasmapheresis technique is already approved by the FDA, we believe, so this should help you to develop your project faster, right?

Irina: Exactly.

Do you think a small molecule approach is a viable and, more importantly, a logistically practical approach to calibrate all these factors compared to filtering aged blood?

Irina: Yes, it is a very feasible alternative to the NextGen apheresis that we are working and publishing on.

It is thought that altered signaling is caused by other aging hallmarks higher up in the chain of events; even if we can “scrub” aged blood clean, is it likely to have a long-lasting effect, or would the factors reach pro-aging levels fairly quickly again if nothing is done about the other hallmarks antagonizing them?

Irina: That needs to be established experimentally, but due to the many feedback loops at the levels of proteins, genes and epigenetics, the acquired youthful state might persist.

Ultimately, could a wearable or an implanted device that constantly filters the blood be the solution to these quickly accumulating factors?

Irina: Maybe, but the first step of a day at a NextGen apheresis clinic once every few months might be more realistic.

Filtering seems to be a far more practical solution, so how are you progressing on the road to clinical trials?

Irina: We are collaborating with Dr. Dobri Kiprov, who is a practicing blood apheresis physician with 35 years of experience, and he is interested in repositioning this treatment for alleviating age-related illnesses.

Senolytics and removing senescent cells and the resulting inflammation they cause during the aging process has become a hot topic in the last year or so. What are your thoughts on senolytics as a potential co-therapy with a blood filtering approach?

Irina: Might be good, but we should be careful, as p16 is a normal, good gene that is needed for many productive activities by many cells.

What do you think it will take for the government to fully support the push to develop rejuvenation biotechnology?

Irina: Clear understanding of the current progress and separating the real science from snake oil is very important for guiding funding toward realistic clinical translation and away from the myth and hype.

The field is making amazing progress, but, sadly, it is plagued by snake oil. As much as an “anti-aging free market” encourages innovation, it also encourages hucksters. How can a member of the public tell the difference between credible science and snake oil?

Irina: I was thinking for some time about starting a popularized journal club webpage where ordinary people can see what we typically critically point out in the lab setting about published papers and clinical trials.

How can our readers learn more about your work and support your research?

Irina: The new Conboy lab website is coming up; meanwhile, contact me and Dr. Mike at iconboy@berkeley.edu and conboymj@berkeley.edu

Conclusion

We would like to thank Irina and Michael for taking the time to answer our questions and for providing the readers with a fascinating insight into their work.

Literature

[1] Conboy, I. M., Conboy, M. J., Smythe, G. M., & Rando, T. A. (2003). Notch-mediated restoration of regenerative potential to aged muscle. Science, 302(5650), 1575-1577.

[2] Conboy, I. M., Conboy, M. J., Wagers, A. J., Girma, E. R., Weissman, I. L., & Rando, T. A. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433(7027), 760-764.

[3] Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L., Paliwal, P., … & Schaffer, D. (2015). Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget, 6(14), 11959.

[4] Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature communications, 7.

[5] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[6] Liu, A., Guo, E., Yang, J., Yang, Y., Liu, S., Jiang, X., … & Gewirtz, D. A. (2017). Young plasma reverses age‐dependent alterations in hepatic function through the restoration of autophagy. Aging cell.

[7] Rebo, J., Mehdipour, M., Gathwala, R., Causey, K., Liu, Y., Conboy, M. J., & Conboy, I. M. (2016). A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nature communications, 7.

[8] Yousef, H., Conboy, M. J., Morgenthaler, A., Schlesinger, C., Bugaj, L., Paliwal, P., … & Schaffer, D. (2015). Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal. Oncotarget, 6(14), 11959.

 

About Steve Hill

As a scientific writer and a devoted advocate of healthy longevity technologies Steve has provided the community with multiple educational articles, interviews and podcasts, helping the general public to better understand aging and the means to modify its dynamics. His materials can be found at H+ Magazine, Longevity reporter, Psychology Today and Singularity Weblog. He is a co-author of the book “Aging Prevention for All” – a guide for the general public exploring evidence-based means to extend healthy life (in press).

About Nicola Bagalà

Nicola Bagalà has been an enthusiastic supporter and advocate of rejuvenation science since 2011. Although his preferred approach to treating age related diseases is Aubrey de Grey’s suggested SENS platform, he is very interested in any other potential approach as well. In 2015, he launched the blog Rejuvenaction to advocate for rejuvenation and to answer common concerns that generally come with the prospect of vastly extended healthy lifespans. Originally a mathematician graduated from Helsinki University, his scientific interests range from cosmology to AI, from drawing and writing to music, and he always complains he doesn’t have enough time to dedicate to all of them which is one of the reasons he’s into life extension. He’s also a computer programmer and web developer. All the years spent learning about the science of rejuvenation have sparked his interest in biology, in which he’s planning to get a university degree.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.

Why Rejuvenation Biotechnology Could Benefit You – Article by Nicola Bagalà

Why Rejuvenation Biotechnology Could Benefit You – Article by Nicola Bagalà

Nicola Bagalà


Editor’s Note: In this article, Mr. Nicola Bagalà discusses the benefits of Rejuvenation Biotechnology (age-reversing technology).  This article was originally published by the Life Extension Advocacy Foundation (LEAF) .

~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, October 25, 2017

The benefits are many; some are obvious, and some are less so. The ones I’ll discuss in this article are the ones I see as obvious, tangible, immediate benefits for the people undergoing rejuvenation.

Health

We’ve kind of made a rather big deal of this one, haven’t we? Rejuvenation, we have said time and again, is pretty much all about health. The causal link between biological aging and pathologies is well established, and even when we account for the few elderly who are exceptionally healthy for their age, we’re left with the obvious fact that the older you are, the sicker you are, and even the aforementioned exceptions aren’t in the best of shape.

To the best of my knowledge, the number of people who actively wish to be sick at some point tends to be fairly small; so, when you think that a truly comprehensive rejuvenation platform would allow people to maintain youthful health irrespective of their age, the health benefits of rejuvenation become crystal clear. To be honest, this benefit alone would be enough for me, and I wouldn’t even need to look into the other ones.

Independence

Frailty, failing senses, weakness, and diseases aren’t good friends of independence, but they are good friends of old age. That’s why nursing homes exist in the first place to take care of elderly people who are no longer independent. Again, even the few exceptional cases who manage on their own until death don’t have it easy. Having people doing things for you can be nice in small doses, but having to have people doing things for you, not so much. Rejuvenation would eliminate the health issues that make the elderly dependent on others, which is a rather evident benefit.

Longevity

As odd as it may sound, longevity is really just a ‘side effect’ of health, because you can’t be healthy and dead. The longer you’re healthy enough to be alive, the longer you’ll live. Since rejuvenation would keep you in a state of youthful health, the obvious consequence is that you’d live longer. How much longer exactly is hard to say, but as long as you’re healthy enough to enjoy life, it’s safe to say that longevity would be a benefit; you’d have more time and energy to dedicate to what you love doing, and you could keep learning and growing as a person for an indefinitely long time.

You would not have to worry about the right age to change your job, get married, or start practicing a new sport, because your health wouldn’t depend on your age, and the time at your disposal would not have a definite upper limit. If the first few decades of your life weren’t as good as they could have been for one reason or another, you would still have time ahead and a chance of a better future, which sounds more appealing than ten years in a hospice with deteriorating health to me. (Let’s face it: If your life isn’t very good to begin with, a disease is hardly going to make it better.)

Additionally, a longer life would allow you to see what the future has in store for humanity. I wouldn’t be too quick to think the future will be all doom and gloom.

Today’s world is more peaceful and prosperous than it was in the past, and while there’s no certainty it will be at least this good in the future, there’s no certainty that it won’t be worth living in either. I would argue it’s best not to cross our bridges before we get there, and we shouldn’t opt out of life before we actually reach a point when we don’t care for it anymore, if ever.

I don’t think I will ever have a reason to give up on life or get bored with it, but I accept that somebody might think otherwise. Even so, I think being able to choose how long you want to live, and always living in the prime of health, is a much better deal than the current situation of having a more-or-less fixed lifespan with poor health near the end.

Choice

Ultimately, all of these perks can be summarised into one: choice. If we had fully working rejuvenation therapies available and were thus able to keep ourselves always perfectly healthy, regardless of our age, we could choose whether we wanted to use these therapies or not. Those who wish a longer, healthier life could avail themselves of the opportunity and escape aging for as long as they wanted; those who prefer to age and bow out the traditional way could just as easily not use the therapies.

Rejuvenation would give us an extra option we currently don’t have; everyone is forced to face the burden of aging and eventually die of it, for the moment. Being able to choose what we wish for ourselves is one of the most fundamental human rights and an obvious, unquestionable benefit.

About Nicola Bagalà

Nicola Bagalà has been an enthusiastic supporter and advocate of rejuvenation science since 2011. Although his preferred approach to treating age related diseases is Aubrey de Grey’s suggested SENS platform, he is very interested in any other potential approach as well. In 2015, he launched the blog Rejuvenaction to advocate for rejuvenation and to answer common concerns that generally come with the prospect of vastly extended healthy lifespans. Originally a mathematician graduated from Helsinki University, his scientific interests range from cosmology to AI, from drawing and writing to music, and he always complains he doesn’t have enough time to dedicate to all of them which is one of the reasons he’s into life extension. He’s also a computer programmer and web developer. All the years spent learning about the science of rejuvenation have sparked his interest in biology, in which he’s planning to get a university degree.

About LIFE EXTENSION ADVOCACY FOUNDATION (LEAF)

In 2014, the Life Extension Advocacy Foundation was established as a 501(c)(3) non-profit organization dedicated to promoting increased healthy human lifespan through fiscally sponsoring longevity research projects and raising awareness regarding the societal benefits of life extension. In 2015 they launched Lifespan.io, the first nonprofit crowdfunding platform focused on the biomedical research of aging.

They believe that this will enable the general public to influence the pace of research directly. To date they have successfully supported four research projects aimed at investigating different processes of aging and developing therapies to treat age-related diseases.

The LEAF team organizes educational events, takes part in different public and scientific conferences, and actively engages with the public on social media in order to help disseminate this crucial information. They initiate public dialogue aimed at regulatory improvement in the fields related to rejuvenation biotechnology.