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Boosting Bone Healing Using a Key Protein – Article by Steve Hill

Boosting Bone Healing Using a Key Protein – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill highlights research on selective bone regeneration using a protein called Jagged-1. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, March 7, 2018

Today, we would like to highlight a recent study in which researchers show a way to selectively accelerate bone regeneration. They have achieved this by delivering Jagged-1 to injuries instead of the bone morphogenetic proteins (BMPs) that have been traditionally used.

What is Jagged-1?

Jagged-1 is an osteoinductive protein that activates the Notch signaling pathway, which regulates bone healing at the site of injury. Osteoinduction is the process by which osteogenesis is induced.

Osteoinduction involves recruiting immature cells and stimulating them to change into preosteoblasts. In a bone healing situation, such as during a fracture, the majority of bone healing depends on osteoinduction.

The new technique avoids the issues of inappropriate or excessive bone growth because, unlike BMPs, it targets osteoinductive mechanisms that are more directly associated with the regenerative process.

Testing their hypothesis

The researchers led by Kurt Hankenson, D.V.M., Ph.D., a professor of orthopedic surgery at Michigan Medicine, hypothesized for some years that by binding Jagged-1 to a biomaterial structure and delivering it to the site of injury, it could improve healing of the bone.

The published study results confirm this to be the case [1]. Mice and rats that were given Jagged-1, applied using a wet collagen sponge, saw improvements to both femoral and skull injuries. In contrast, the rodents treated with BMPs benefited but also experienced problematic bone hypertrophy, which is also observed in humans using BMPs.

The findings of this study suggest that the use of Jagged-1 for location-specific bone injury could potentially be developed into a therapy to help people recover from fractures and broken bones.

Conclusion

The use of signal molecules rather than drugs to encourage tissue regeneration is likely to increase in popularity in the coming years as the process becomes increasingly refined. This study is yet another example of how researchers are exploring the use of signalling molecules produced naturally in the body as an alternative to drug approaches, which can often have unwanted side effects. It should prove interesting to see how this approach develops in the next few years.

Literature

[1] Youngstrom, D. W., Senos, R., Zondervan, R. L., Brodeur, J. D., Lints, A. R., Young, D. R., … & Loomes, K. M. (2017). Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects. NPJ Regenerative medicine, 2(1), 32.

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.

Dentists May Soon Regenerate Teeth Using GSK3 Antagonists – Article by Steve Hill

Dentists May Soon Regenerate Teeth Using GSK3 Antagonists – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill explains a teeth-regeneration technique that works by activating the stem cells that reside in the dental pulp of teeth. The technique has the potential to translate to other tissues to help encourage regeneration. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, March 6, 2018

What if I told you that we could regenerate our teeth? Well, that may soon be a possibility thanks to new research showing that teeth can be encouraged to regrow. Rather than drilling holes into teeth and plugging them with artificial fillers, dentists in the near future may be able to rebuild your teeth with a new technique.

Stimulating stem cells

Professor Paul Sharpe, a scientist based at King’s College in London, and his team have found a way to do just this in mice. They published a study last year that described this new approach [1].

The researchers wanted to increase the natural ability of teeth to repair themselves by activating the stem cells that reside in the dental pulp of teeth. They knew that previous research showed that the wnt signaling pathway is a key pathway for stem cell activity in many parts of the body, and they wanted to see if it works the same way in teeth.

The researchers believed by that using drugs to stimulate the wnt pathway, they could increase stem cell activity in teeth and boost their regenerative potential significantly. Normally, this level of regeneration is only seen in animals like starfish and salamanders, but the researchers wanted to see if we can benefit from the same regenerative capacity.

To see if this would work, the team drilled holes into the molar teeth of mice to simulate dental cavities. Next, they exposed collagen sponges (the same protein found in the dentin in teeth) to a variety of drugs known to stimulate the wnt pathway. Then, they placed these sponges into the cavities and sealed them in for between 4 to 6 weeks.

After this time, the researchers saw that the teeth exposed to these sponges had created a lot more dentin than the control mice and mice given typical dental fillers. The researchers observed that this was essentially a full repair and, in most cases, the teeth of the mice were as good as new.

The next step towards clinical trials

Since then, the researchers have tested the technique on rats, which have considerably larger teeth than mice, making them the logical next step. The research team report that the therapy worked equally well on the rats as it did in the mice in the original study; however, the data is yet to be published.

The researchers are now screening their drug candidates to identify the most effective of the wnt-stimulating drugs. They are also adapting the technique to work with modern dental practices by injecting a gel containing the drug into a dental cavity and hardening it using a UV light to seal it in. This is similar to how dentists currently seal and repair teeth, so this technique would be easy to incorporate into dental practice.

Literature

It will be several years before this enters human clinical trials, but the results so far are promising, and the process may be quicker than normal because a number of the candidate drugs are already approved for human use. The arrival of this technique will revolutionize dentistry and is a great step forward for regenerative medicine in general.

Such techniques have the potential to translate to other tissues to help encourage regeneration, so it is also relevant to aging research. We look forward to more developments from this team in the future.

References

[1] Neves, V. C., Babb, R., Chandrasekaran, D., & Sharpe, P. T. (2017). Promotion of natural tooth repair by small molecule GSK3 antagonists. Scientific reports, 7, 39654.

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.

Exosome Therapy Repairs Stroke-Damaged Brain Tissue – Article by Steve Hill

Exosome Therapy Repairs Stroke-Damaged Brain Tissue – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill explains a new therapy that uses exosomes to repair damaged brain cells. The human trials are intended to begin in the year 2019. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, March 5, 2018

Today, we wanted to highlight more progress in a rapidly advancing area of medicine and talk about a new study that uses an exosomes-based approach for stroke treatment that repairs brain tissue.

A stem cell-based approach to treating stroke

Professor Steven Stice from the University of Georgia (UGA) and Nasrul Hoda of Augusta University led the team that developed AB126, a treatment that uses a type of extracellular vesicle known as an exosome [1]. Exosomes are small fluid-filled structures that are created by stem cells and, in the case of AB126, are produced by human neural stem cells.

Essentially, the researchers are isolating the beneficial signals given out by stem cells and using them rather than the stem cells as a therapy. This makes sense, as other cells react to these signals and change their behavior accordingly. We have talked about the therapeutic potential of extracellular vesicles, particularly exosomes, in a previous article.

An exosome can remain hidden in the bloodstream, carry multiple doses, and store and administer treatment, and its small size allows it to cross barriers that cells cannot. This is ideal for delivering therapies to the brain, as it crosses the blood-brain barrier and other checkpoints in the body.

After the administration of AB126,  the researchers used MRI scans to assess brain atrophy rates in an animal model of stroke. The scans showed around 35 percent decrease in the size of injury and a 50 percent reduction in brain tissue loss. These results were also replicated by Franklin West, associate professor of animal and dairy science at UGA, in a pig model of stroke.

Within days, the researchers observed improved mobility, better balance, and measurable behavioral benefits in treated animal models of stroke.

Based on the successful results of these preclinical tests, the next step is to take this therapy to human clinical trials by 2019 via ArunA Biomedical, a UGA startup company. The company plans to expand its scope beyond stroke, and preclinical studies in epilepsy, traumatic brain, and spinal cord injuries begin later this year.

Conclusion

This is another example of the recent interest in using extracellular vesicles, such as exosomes, as therapies rather than stem cells themselves. Multiple research groups are now developing these therapies to treat various age-related diseases, so we can almost certainly expect to hear more in the near future.

The use of extracellular vesicles also holds the promise of being more cost-effective from the point of view of storage, logistics, manufacture, and delivery. With the first clinical trials now in the cards for the near future, it will be interesting to see how this develops in the next few years.

References

[1] Webb, R. L., Kaiser, E. E., Scoville, S. L., Thompson, T. A., Fatima, S., Pandya, C., … & Baban, B. (2017). Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model. Translational stroke research, 1-10.

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.

Gene Cocktail Helps Hearts to Regenerate – Article by Steve Hill

Gene Cocktail Helps Hearts to Regenerate – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Steve Hill explains a technique that enables significant human tissue regeneration, so that it becomes possible to repair damaged human hearts. This technique can also be potentially applied to other body organs.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, March 4, 2018

The human heart is an organ whose cells rarely divide, making tissue repair and regeneration a huge problem following a heart attack. Many animals, such as zebrafish and salamanders, are different; they can regenerate damaged hearts easily.

As humans, we also once had the same regenerative capacity during our early development, but after we were born, we lost this ability. This is also true for many other organs, including the brain, spinal cord, and pancreas. The cells in these tissues divide very rarely if at all, and this is a big problem. But, what if we could get that regenerative ability back and repair damage to our hearts the way these amazing animals do?

Researchers have been trying for decades to find out how we can enjoy the same tissue regeneration, but they have met with limited success—until now.

Unlocking cell division in cardiomyocytes

A research team led by Dr. Deepak Srivastava, president of the Gladstone Institutes, has finally achieved this long sought-after goal in a study published in the journal Cell [1]. The researchers have developed an efficient and reliable way of making non-dividing adult cardiomyocytes divide so that they can repair damaged hearts.

They identified four genes that regulate cell division in adult cardiomyocytes. When all four of them are combined together, they cause the cardiomyocytes to re-enter the cell cycle and start dividing quickly. They also demonstrated that following heart failure, these combined genes improve cardiac function significantly.

The researchers tested the technique in animal models using cardiomyocytes derived from human stem cells. They stained newly divided cells with a special dye in order to track them; they found that between 15 to 20 percent of the cells divided and remained alive thanks to the four-gene combo. This is a vast improvement on previous studies, which have only managed around 1 percent cell division in adult cardiomyocytes.

The team also made the technique simpler by identifying drugs that could replace two of the four genes involved in the combination. This still produced the same result as using all four genes and is significantly easier, logistically speaking.

Could be used in multiple tissues

As mentioned, the heart is not the only tissue that has cells that either do not divide or do so very slowly. The researchers believe that their technique could also potentially be applied to encourage other tissues and organs to regenerate. This is because the four genes are not unique to the heart and are found in other cells around the body.

If science can unlock the same regeneration in nerve cells, pancreatic cells, and retinal cells, this could be the basis of therapies for heart failure, brain damage, diabetes, blindness, and many other conditions. The good news is these four genes encourage cell division the same way in mice, rats, and human cells.

Conclusion

Manipulating non-dividing cells and returning them to the cell cycle to boost regeneration in organs and tissues holds great potential. Scientists have been working for decades to achieve this in the heart, and now it has been achieved. The next big step is to translate this approach to humans, and we wish them the very best in their future research.

Literature

[1] Mohamed, T. M., Ang, Y. S., Radzinsky, E., Zhou, P., Huang, Y., Elfenbein, A., … & Srivastava, D. (2017). Regulation of Cell Cycle to Stimulate Adult Cardiomyocyte Proliferation and Cardiac Regeneration.

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.

Is Aging Natural, a Disease That We Can Treat, or Both? – Article by Steve Hill

Is Aging Natural, a Disease That We Can Treat, or Both? – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill explains that aging can be described as both natural and pathological without contradiction. This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, February 16, 2018

Aging is something that we all share, rich or poor; it is something that happens to us all, and we are taught from a young age that it is inevitable. However, some scientists believe that aging is amenable to medical intervention and that such interventions could be the solution to preventing or reversing age-related diseases.

Academics are currently debating whether aging is natural or a pathological disease that we can treat.

In fact, there is now pressure from many academics to classify aging itself as a disease; indeed, doing so could potentially improve funding for aging research and help to speed up progress in finding solutions to age-related diseases. [1] The debate continues, but does it really matter if aging is classified as a disease, or is it largely a matter of semantics?

Fighting a losing battle

Current medical practice sees us trying to treat age-related diseases in the same way we do other diseases; this is the “infectious disease model”, and when it comes to treating age-related diseases, it is a losing battle.

The current approach works like this: as soon as a disease appears, the doctor attacks the disease using everything in the medical armory, and the patient can then continue with life until the next disease happens; this process is repeated until failure. This is an excellent way to deal with infectious diseases, and it has helped to increase life expectancy greatly in the last century; however, there are signs are that this approach is starting to run out of steam. [2-4]

Unfortunately, this “whack-a-mole” approach is a poor choice when it comes to treating the chronic diseases of old age. This is because the damage that the aging processes cause still continues to take its toll; therefore, treating the symptoms will ultimately achieve very little and certainly not cure the disease.

So, given that the aging processes lead to the diseases of aging, it is understandable that scientists are starting to consider aging itself to be a disease. While we do not yet fully understand all the intricacies of aging, we already know a great deal about the individual processes.[5] Certainly, we now know enough about aging to begin developing and testing interventions that directly target the underlying processes in order to prevent or treat pathology.

Treating the underlying processes and repairing their damage, which leads to the familiar diseases of old age, is the basis for the medical approach known as rejuvenation biotechnology, a multidisciplinary field that aims to prevent and treat age-related diseases by targeting the aging processes directly.

Aging is the foundation of age-related diseases

Even if aging is not a disease itself, the individual processes do lead to pathology and age-related diseases, such as cancer, heart disease, Parkinson’s, and Alzheimer’s. So, knowing that these processes create the conditions for diseases to develop, it makes sense to target the processes themselves in order to potentially prevent or treat a slew of age-related diseases at once.

The changes that aging brings vary from one person to another, but the common processes of aging are at work in all of us, albeit with some small variances between individuals. For example, we all suffer wear and tear in our joints due to the loss of cartilage, and we all experience the loss of skin elasticity due to the degradation of elastin and the failure of connective tissues. We all encounter other age-related changes, such as the accumulation of non-dividing senescent cells that cause chronic inflammation and disrupt tissue repair, and we also suffer from the accumulation of metabolic waste products that collect in our bodies over time.

As these changes progress, they eventually lead to the familiar diseases of aging. For example, lipids are critical for the function of our metabolism and are essential as part of our diet; however, over time, these processed lipids begin to accumulate in the blood vessel walls. Macrophages arrive to clear the toxic fatty waste away, but they become immobilized and die. This causes inflammation, attracting more macrophages and continuing the cycle. Ultimately, this debris forms plaques that harden the blood vessels and cause them to narrow; this causes blood pressure to rise and can eventually result in a heart attack or stroke.

This demonstrates that the normal metabolic processes that keep us alive ultimately lead to disease. Importantly, in this case, the early age-related changes that set the scene for disease progression, such as high cholesterol, have no symptoms. Nevertheless, such changes are the precursors of deadly diseases and are considered suitable targets for treatment. The same can be said for the other, more subtle, changes and damages that the aging processes cause.

Age-related conditions, such as arthritis, diabetes, osteoporosis, Alzheimer’s, Parkinson’s and many cancers, all follow this dynamic. Simply put, given the sufficient passage of time, the aging processes will cause us to suffer from multiple diseases. Therefore, we should consider these diseases to be the clinical manifestation of these age-related changes. In fact, medicine has been fighting against age-related changes for a long time, even if it was not obvious. For example, a doctor recommending that his patient should reduce his fat and carbohydrate intake to delay heart disease is already fighting those age-related changes. The diabetic who modifies her diet to better manage blood sugar levels is also doing the same thing.

Some people might contest this point of view, stating that the aging process is “natural” and therefore cannot be a disease. The argument that natural things are always good, the appeal to nature, is a logical fallacy. Such people may see natural and pathological as being mutually exclusive. Thus, what is natural must always be good, and what is pathological is bad, and so it cannot also be natural. This is, of course, false when you consider the meaning of each word. Natural simply means something that follows the normal, established course of events, and pathological means something that is harmful.

Conclusion

So, is aging natural or pathological? Well, by the dictionary definitions, aging can be described as both natural and pathological without contradiction.

Additionally, as it is currently classified, aging could be considered a syndrome, specifically a co-morbid syndrome. This really does describe aging perfectly; it is a group of symptoms that consistently occur together and a condition characterized by a set of associated symptoms. Ultimately, aging is an umbrella term describing a range of pathological changes; it may struggle to be accepted as a disease, but it already qualifies as a syndrome.

However, the question of aging being a disease or not is essentially semantic in nature. What rejuvenation biotechnology seeks to achieve is nothing more than preventing age-related diseases by treating the early stages of pathology, which are considered a natural process. While these early age-related changes have not been given a disease name, they are instrumental in the development of diseases, and surely, when it comes to medical treatment, that is all that matters.

References

[1] Bulterijs, S., Hull, R. S., Björk, V. C., & Roy, A. G. (2015). It is time to classify biological aging as a disease. Frontiers in genetics, 6.

[2] Crimmins, E. M. (2015). Lifespan and healthspan: Past, present, and promise. The Gerontologist, 55(6), 901-911.

[3] Olshansky, S. J., Passaro, D. J., Hershow, R. C., Layden, J., Carnes, B. A., Brody, J., … & Ludwig, D. S. (2005). A potential decline in life expectancy in the United States in the 21st century. New England Journal of Medicine, 352(11), 1138-1145.

[4] Reither, E. N., Olshansky, S. J., & Yang, Y. (2011). New forecasting methodology indicates more disease and earlier mortality ahead for today’s younger Americans. Health Affairs, 10-1377.

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

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.

Alzheimer’s Drug Turns Back the Clock in Mitochondria – Article by Steve Hill

Alzheimer’s Drug Turns Back the Clock in Mitochondria – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Mr. Steve Hill discusses an experimental drug, J147, for treating Alzheimer’s disease and also how Alzheimer’s disease is closely linked to aging.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, January 26, 2018

J147 is an experimental drug that has been shown to treat Alzheimer’s disease, and it also appears to reverse some aspects of aging. It is also poised to enter human clinical trials in the near future, although how it works has been somewhat of a puzzle.

A new study  published in the journal Aging Cell has changed all that, and the results are quite intriguing [1]. Researchers at the Salk Institute have solved the mystery of how J147 works and why it makes old flies, mice, and cells more youthful.

Rejuvenating mitochondria

The drug apparently works because it binds to a protein found in mitochondria, the powerhouses of cells; this, in turn, causes cells to function in a more youthful manner. Mitochondrial dysfunction is one of the hallmarks of aging and is thought to be a key reason why we age and develop age-related diseases [2]. This drug appears, at least partially, to address some of that dysfunction.

Finding the target of J147 was the key to revealing the link between Alzheimer’s disease and the aging process. It was the critical information the researchers needed and was holding the drug back from clinical trials.

Dave Schubert, head of Salk’s Cellular Neurobiology Laboratory, and his team originally developed the J147 drug in 2011. The team screened numerous plant-sourced compounds with the potential to reverse the cellular and molecular signs of aging in the brain. The drug was developed as a modified version of a molecule found in the spice curcumin, a common ingredient in Asian foods such as curry.

Since then, the researchers have shown that J147 can reverse memory deficits, increases the production of brain cells, and slows the progression of Alzheimer’s in mice [3]. However, at that point, they did not understand how J147 worked.

Finding the target

During the new study lead by Dave Schubert and Salk Research Associate Josh Goldberg, the researchers used a number of approaches to find out how J147 worked. They eventually identified that the target of J147 was the mitochondrial protein known as ATP synthase, specifically ATP5A, a subunit of that protein. ATP synthase is involved in the mitochondrial generation of ATP, which cells use for energy.

The researchers demonstrated that by reducing the activity of ATP synthase, they were able to protect neuronal cells from a number of toxicities associated with the aging of the brain. One reason for this neuroprotective effect is thought to be the role of excitotoxicity in neuronal cell damage.

Excitotoxicity is the pathological process by which neurons are damaged and killed by the overactivation of receptors for the excitatory neurotransmitter glutamate. Think of it being a bit like a light switch being turned on and off so rapidly that it ends up causing the light bulb to blow.

Recently, the role of ATP synthase inhibition for neuroprotection against excitotoxic damage was demonstrated in a mouse study [4]. The second study showed that mouse models expressing the human form of mutant ATPase inhibitory factor 1 (hIF1), which causes a sustained inhibition of ATP synthase, were more resilient to neuronal death after excitotoxic damage. This data is consistent with this new J147 study, in which an increase in IF1 in the mice reduced the activity of ATP synthase (specifically ATP5A) and was neuroprotective.

ATP synthase is implicated in aging

ATP synthase has previously been shown to influence aging in C. elegans worms and flies. Given that aging is the greatest risk factor for developing Alzheimer’s disease, it is no surprise that the target of the drug is also involved in the aging process.

The team also revealed that by modulating the activity of ATP synthase, they could influence the levels of ATP and other molecules and were able to encourage healthier, more stable mitochondria during aging. Mice given the compound showed profound changes, appearing to look younger at a cellular and molecular level.

The researchers believe that these results are not only encouraging for the treatment of Alzheimer’s, they suggest that J147 may also be useful in treating other age-related diseases.

“People have always thought that you need separate drugs for Alzheimer’s, Parkinson’s and stroke,” said Dave Schubert. “But it may be that by targeting aging we can treat or slow down many pathological conditions that are old-age-associated.”

With J147 having just completed the FDA required toxicology testing in animals, the next step is phase 1 human clinical trials, and the road to approval begins.

Conclusion

It is very heartening to hear important researchers suggesting that in order to treat age-related diseases, one needs to treat the aging processes themselves. This is the exactly what Dr. Aubrey de Grey and others have been saying for many years. It is good to hear more voices joining the call to tackle age-related diseases at their root: the hallmarks and damages where they all begin.

The process of age-related disease begins long before the familiar signs and diagnoses are made; by targeting the early processes that are not given specific disease names, we might yet defeat horrific diseases, such as Alzheimer’s, which rob us of who we are.

Literature

[1] Joshua Goldberg et al. The mitochondrial ATP synthase is a shared drug target for aging and dementia. Aging Cell, 2018 DOI: 10.1111/acel.12715
[2] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
[3] Prior, M., Dargusch, R., Ehren, J. L., Chiruta, C., & Schubert, D. (2013). The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer’s disease mice. Alzheimer’s research & therapy, 5(3), 25.
[4] Formentini, L., Pereira, M. P., Sánchez‐Cenizo, L., Santacatterina, F., Lucas, J. J., Navarro, C., … & Cuezva, J. M. (2014). In vivo inhibition of the mitochondrial H+‐ATP synthase in neurons promotes metabolic preconditioning. The EMBO journal, 33(7), 762-778.

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.

The Link Between Cellular Senescence and Cellular Reprogramming – Article by Steve Hill

The Link Between Cellular Senescence and Cellular Reprogramming – Article by Steve Hill

Steve Hill


Editor’s Note: In this article, Steve Hill discusses the link between Cellular Senescence and Cellular Reprogramming.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

            ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, January 8, 2018

The reprogramming of cells is a well-established technique in medicine and has been for over a decade now. It allows the en masse creation of patient-matched cells and is the basis for multiple current therapies.

Cellular Senescence and Cellular Reprogramming share mechanisms

Induced pluripotent stem cells (also known as iPS cells or iPSCs) can be created directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka, who demonstrated in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells[1]. These factors are Oct4, Sox2, Klf4, and c-Myc (OSKM), or as many call them, the Yamanaka factors.

Today, we have a new paper that discusses how induced pluripotency and cellular senescence, two of several possible cellular states, share similarities[2]. It is likely no surprise that the two states are closely related and that some of the mechanisms for one process are shared by the other. It appears that certain key signaling molecules are important in determining both cell fate and senescence.

Controlling cell behavior in living animals

As our understanding of guiding cell fate grows rapidly by the passing year, it has huge implications for therapies that seek to control cellular activities and encourage certain types of cells to be created. Research is now starting to move beyond the petri dish and to where cells are being programmed in situ in living animals.

In 2013, the Hallmarks of Aging proposed that epigenetic changes are a primary reason we age, but, at the time, the evidence in living animals was lacking[3]. All this changed in late 2015 when researchers induced pluripotency in living animals using the OSKM reprogramming factors, in much the same way as iPSC technology creates on-demand cell types outside the body. In this case, they only very briefly induced OSKM so that the aging markers in cells were reset but not long enough to cause the cells to revert to a developmental state.

The results of this first attempt to reprogram cells in living animals resulted in the cells of the mice becoming functionally younger in many ways and increased their healthy lifespan[4]. These results lend yet more support for the hypothesis that epigenetic alterations are one of the reasons we age and that reversing those changes is a path to maintaining health and tissue function as we age. A number of research teams are now exploring cellular reprogramming in living animals with a view to translating this to humans. We discussed the findings of this paper during our monthly Journal Club here.

Conclusion

This paper may be of interest to those wishing to delve deeper into the world of cell fate and understand the connection between cellular senescence and induced pluripotency. This builds on the knowledge we already have, and it is not difficult to imagine a time in the near future when we will have a very high level of control over our cells via reprogramming techniques.

If the hypothesis of epigenetic alterations being one of the causes of aging turns out to be correct, then that would be a real game changer. We are likely not too far off from determining if this is the case or not, and we may have the answer in the next few years, given the current pace of progress.

Literature

[1] Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. cell, 126(4), 663-676.

[2] Mosteiro, L., Pantoja, C., Martino, A., & Serrano, M. (2017). Senescence promotes in vivo reprogramming through p16INK4a and IL‐6. Aging cell.

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

[4] Ocampo, A., Reddy, P., Martinez-Redondo, P., Platero-Luengo, A., Hatanaka, F., Hishida, T., … & Araoka, T. (2016). In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 167(7), 1719-1733.

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.

The Best of the SENS AMA – Article by Steve Hill and Aubrey de Grey

The Best of the SENS AMA – Article by Steve Hill and Aubrey de Grey

Steve Hill

Dr. Aubrey de Grey


Editor’s Note: In this article, Steve Hill highlights the Ask Me Anything on Reddit held on December 7th by Dr. Aubrey de Grey.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, December 13, 2017

 

Dr. Aubrey de Grey from the SENS Research Foundation (SRF) did an Ask Me Anything on Reddit on December 7th, and there were many great questions and answers; we thought it would be a great time to summarize some of the best ones and offer a little commentary.

What do you think were the biggest wins of the last couple of years in SENS-relevant advocacy, research, and development? What has moved the needle?

There have been lots. On the research, I would highlight our paper in Science two years ago, which shows how to synthesize glucosepane, and our paper in Nucleic Acids Research one year ago, which shows simultaneous allotopic expression of two of the 13 mitochondrial genes. Both of those projects have been greatly accelerated in the meantime as a result of those key enabling breakthroughs; watch this space.

On advocacy, I think the main win has been the arrival of private capital; I would especially highlight Jim Mellon and his Juvenescence initiative because he is not only a successful, energetic and visionary investor, he is also a highly vocal giver of investment advice.

We are pleased to have been involved with the second project mentioned here, as we hosted the MitoSENS project at Lifespan.io, where it raised 153% of its initial fundraising goal. Less than a year later, after raising this money, it went on to publish the groundbreaking study showing that backup copies of mitochondrial genes could indeed be created in the nucleus. Dr. de Grey originally proposed the idea over a decade ago amid much scepticism; it is really good to see that years later he has been vindicated. This is the power of crowdfunding and how we as a community can make big changes in science by working together.

How do you feel about the impact of groups like LEAF advocating and reporting on rejuvenation biotech? Has the advocacy and reporting of these groups made your life any easier?

Massively! A huge thing that I say all the time is that advocacy absolutely relies upon the diversity of its messengers. Different people listen to different forms of words, different styles of messaging, etc. The more, the better.

It’s good to know that our work is appreciated and helping. Working together as a community is essential for progress, so it was nice to see this question and response from someone we respect a great deal.

We have said many times before effective advocacy efforts are just as important as the research itself. Professional advocacy has the potential to increase public support and funding, paving the way for the arrival of rejuvenation biotechnology. In the past decade or so, advocacy has mostly been left to volunteers and people such as Dr. de Grey.

Popular causes attract celebrities, public support, funding and investment; if we want a revolution in medicine and how we treat aging, then we must popularize the movement. There has been a serious shortage of full-time and organized advocacy; therefore, we decided to create LEAF to support groups like the SRF, advocate to popularize the cause, and help to raise much-needed funds for research efforts. We are only able to do this thanks to the support of the community, and we are extremely grateful to our Lifespan Heroes for helping us to do the work we do.

Aside from funding, what do you consider to be a burden or delay for your type of research?

Nothing. Seriously, nothing at all. We have the plan, and we have the people. It’s all about enabling those people by giving them the resources to get on with the job.

Indeed, funding for research is one of the four major bottlenecks slowing down the development of therapies that address the aging processes. The more funding the field gets, the more projects can be launched, the sooner breakthroughs can potentially happen, and the greater the benefits will likely be for all of us.

Is there anything new you are able to say about the breaking of cross-links in the extracellular matrix?

Absolutely. Short story, we now have a bunch of glucosepane-breaking enzymes, and we are within a few months of spinning the work out into a startup.

A suspected cause of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products (AGEs). These are wastes that are, in some cases, hard for our metabolism to break down fast enough or even at all. Some types, such as glucosepane, can form cross-links, gumming together important proteins such as those making up the supporting extracellular matrix scaffold.

The properties of elastic tissues (skin and the blood vessel walls) derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. AGEs’ presence contributes to blood vessel stiffening with age, and it is implicated in hypertension and diabetes.

That SRF now has candidate enzymes is very significant because it means that there are now potential ways to remove these crosslinks from our tissues. There are many types of crosslinks, and we already know of compounds and drugs that can break other kind of crosslinks; the major problem is glucosepane, as it lasts a very long time, and, so far, nothing is known to remove it. Given that other types of crosslinks can be removed, Dr. de Grey rightly thought that there must be ways to remove (cleave) glucosepane from tissues; now, it seems that we are a step closer to that potentially becoming a reality.

If the SRF is successful in finding ways to break glucosepane crosslinks, this has huge implications for diabetes, hypertension and aging. It is great to hear that the organization is now reaching the point at which it is almost time to develop this as a therapy by creating a startup company.

It seems likely that artificial intelligence will be a necessary tool in order to reach longevity escape velocity. I was wondering how much of a role does artificial intelligence play in your research? Is this something you devote many resources to?

We don’t, but that is because other major players in this field (and good friends of mine), such as Alex Zhavoronkov and Kristen Fortney, are doing it so well already (with Insilico Med and BioAge, respectively). Check out the BioData West conference that will occur in SF a couple of days before our Undoing Aging conference in Berlin; I will be chairing a session on this.

We believe that the application of AI and, in particular, machine learning will prove to be a very valuable tool for research in the coming years. Such systems are ideally suited for high-throughput, laborious tasks that also require high attention to detail and would take humans a long time to do. Drug discovery, image analysis and many more tasks in the lab could potentially be automated, saving time and freeing up researchers to work on other critical tasks.

We are proud to have hosted the MouseAge project this year, which is an AI-based visual aging biomarker application that helps researchers determine the age of mice without the use of harmful tests. In a few months, researchers will be able to use the MouseAge application in the lab to help speed research progress up. This is just one example of how AI can be used in aging research and how the community helped to make it happen.

Given current funding, how far away from robust mouse rejuvenation do you think you are?

My estimate is 5-7 years, but that’s not quite “given current funding”. My overoptimism in saying “10 years” 13 years ago consisted entirely of overoptimism about funding – the science itself has not thrown up any nasty surprises whatsoever – but, nonetheless, I am quite optimistic as of now about funding, simply because the progress we have made has led to a whole new world of startups (including spinoffs from the SENS Research Foundation) and investors, so it’s not only philanthropy anymore. Plus, the increase in overall credibility of the approach is also helping to nurture the philanthropic side. We are still struggling, that’s for sure, but I’m feeling a lot surer that the funding drought’s days are numbered than I felt even two or three years ago.

Robust mouse rejuvenation (RMR) has long been a goal for the SENS Research Foundation, going back to when the SENS approach was initially proposed. RMR was originally outlined as being able to demonstrate and replicate SENS to double the remaining life expectancy of an already aged mouse. This would not mean the first RMR would be a total implementation of all the SENS approaches or that rejuvenation would need to be absolute; it would be a first pass to demonstrate the viability of multiple SENS approaches combined to produce robust results.

Being able to achieve a first-pass RMR could do much to convince academia that the repair approach to aging is plausible and attract more funding and interest in the approach. While RMR working in mice may not sound that exciting, it has huge implications for the field and potentially the rate of funding and progress.

How confident are you still in your previous prediction that humans will be able to control aging by 2029?

I think we’ve slipped a few years, entirely because of lack of funding. The tipping point will be when results in mice convince a critical mass of my curmudgeonly, reputation-protecting expert colleagues that rejuvenation will eventually work, such that they start to feel able to say so publicly. I think that’s on the order of five years away.

We think that the tipping point could well be if senolytics have the same result in humans as they have in mice. Enhanced tissue repair and regeneration in older people would be a very strong case for the repair approach to aging and almost certain to convince the academics sitting on the fence.

Certainly, if AGE breakers could be demonstrated to work in humans, this would also go a long way towards not only convincing academia but also grabbing public interest. Removing AGEs from the skin may potentially reverse wrinkles, for example, and restore skin elasticity, offering a very visual demonstration of repair being plausible.

There is almost certainly going to be a tipping point at which the bulk of academic and public support swings in favour of a repair approach to aging; the only question is when? Well, the sooner the basic science can be done and moved to translational research, the sooner we can all potentially benefit from these technologies. This makes supporting both the research and advocacy of rejuvenation biotechnology very important for progress.

 

About Dr. Aubrey de Grey

Dr. Aubrey de Grey is a biomedical gerontologist based in Cambridge, UK and Mountain View, California, USA, and is the Chief Science Officer of SENS Research Foundation, a California-based 501(c)(3) charity dedicated to combating the aging process. He is also Editor-in-Chief of Rejuvenation Research, the world’s highest-impact peer-reviewed journal focused on intervention in aging. He received his BA and Ph.D. from the University of Cambridge in 1985 and 2000 respectively. His original field was computer science, and he did research in the private sector for six years in the area of software verification before switching to biogerontology in the mid-1990s. His research interests encompass the characterisation of all the accumulating and eventually pathogenic molecular and cellular side-effects of metabolism (“damage”) that constitute mammalian aging and the design of interventions to repair and/or obviate that damage. He has developed a possibly comprehensive plan for such repair, termed Strategies for Engineered Negligible Senescence (SENS), which breaks aging down into seven major classes of damage and identifies detailed approaches to addressing each one. A key aspect of SENS is that it can potentially extend healthy lifespan without limit, even though these repair processes will probably never be perfect, as the repair only needs to approach perfection rapidly enough to keep the overall level of damage below pathogenic levels. Dr. de Grey has termed this required rate of improvement of repair therapies “longevity escape velocity”. Dr. de Grey 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 organisations.

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.

SENS: Progress in the Fight Against Age-Related Diseases – Article by Nicola Bagalà and Steve Hill

SENS: Progress in the Fight Against Age-Related Diseases – Article by Nicola Bagalà and Steve Hill

Nicola Bagalà

Steve Hill


Editor’s Note: In this article, Mr. Nicola Bagalà and Steve Hill discuss the progress that the SENS Research Foundation has made in tackling the aging processes. Below is a brief summary of some of the highlights of their research efforts.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, December 8, 2017

 

 

Today, there are many drugs and therapies that we take for granted. However, we should not forget that what is common and easily accessible today didn’t just magically appear out of thin air; rather, at some point, it used to be an unclear subject of study on which “more research was needed”, and even earlier, it was just a conjecture in some researcher’s head.

Hopefully, one day not too far into the future, rejuvenation biotechnologies will be as normal and widespread as aspirin is today, but right now, we’re in the R&D phase, so we should be patient and remind ourselves that the fact that we can’t rejuvenate people today doesn’t mean that nothing is being done or has been achieved to that end. On the contrary, we are witnessing exciting progress in basic research—the fundamental building blocks without which rejuvenation, or any new technology at all, would stay a conjecture.

In particular, SENS Research Foundation (SRF), a pioneering organization of the field, is sometimes unjustly accused by skeptics for failing to produce results. But produce results it has, and many at that. Skeptics either decide to ignore them or do not have access to reliable sources. For the benefit of the latter, we’ll discuss below what has been achieved by SRF over the past few years, in relation to the infamous “seven deadly things”, the seven categories of damage that aging causes as described in the SENS repair approach.

Mitochondrial mutations

In a nutshell, a mitochondrion is a cell component that is in charge of converting food nutrients into ATP (adenosine triphosphate), a chemical that powers cellular function. Your DNA is contained within the nucleus of each of your cells, but this isn’t the only DNA in your body; mitochondria have their own DNA (known as mtDNA), likely because, at the dawn of life, they were independent organisms that eventually entered a symbiotic relationship with eukaryotic cells, such as those found in our bodies.

Unfortunately, as mitochondria produce ATP, they also produce so-called free radicals as a byproduct—atoms with unpaired electrons that seek to “pair up” with other electrons, and to do so, they’ll gladly snatch them from other molecules nearby, damaging them. As free radicals are created by mitochondria, they’re very close to mtDNA, which is thus very susceptible to being damaged and undergoing mutations.

Mitochondria with damaged DNA may become unable to produce ATP or even produce large amounts of waste that cells cannot get rid of. To add insult to injury, mutant mitochondria have a tendency to outlive normal ones and take over the cells in which they reside, turning them into waste production facilities that increase oxidative stress—one of the driving factors of aging.

MitoSENS: How to solve this problem, and how far we’ve got

Cell nuclei are far less exposed to free-radical bombardment than mitochondria, which makes nuclear DNA less susceptible to mutations. For this reason, the cell nucleus would be a much better place for mitochondrial genes, and in fact, evolution has driven around 1000 of them there. Through a technique called allotopic expression, we could migrate the remaining genes to the nucleus and solve the problem of mitochondrial mutations.

Human-made allotopic expression was a mere theory until late 2016, when, thanks to the successful MitoSENS crowdfunding campaign on Lifespan.io, a proof of concept was finally completed. Dr. Matthew O’Connor and his team managed to achieve stable allotopic expression of two mitochondrial genes in cell culture, as reported in the open-access paper[1] they published in the journal Nucleic Acids Research. As Aubrey de Grey himself explains in this video, of the 13 genes SRF is focusing on, it’s now managed to migrate almost four. This had never been done before and is a huge step towards addressing this aspect of aging in humans. In the past few months, the MitoSENS team has presented its results around the world and worked on some problems encountered in the project.

A list of SRF-funded papers on the topic of mitochondrial mutations can be found here. A more detailed description of its intramural MitoSENS research can be found here.

Lysosomal dysfunction

Lysosomes are digestive organelles within cells that dispose of intracellular garbage—harmful byproducts that would otherwise harm cells. Enzymes within lysosomes can dispose of most of the waste that normally accumulates within cells, but some types of waste, collectively known as lipofuscin, turn out to be impossible to break down. As a result, this waste accumulates within the lysosomes, eventually making it harder for them to degrade even other types of waste; in a worst-case scenario, overloaded lysosomes can burst open and spread their toxic contents around.

This eventuality is especially problematic for cells that replicate little or not at all, such as heart and nerve cells—they’ve got all the time in the world to become swamped in waste, which eventually leads to age-related pathologies, such as heart disease and age-related macular degeneration.

LysoSENS: How to solve this problem, and how far we’ve got

As normal lysosomal enzymes cannot break down lipofuscin, a possible therapy could equip lysosomes with better enzymes that can do the job. The approach suggested by SRF originates with ERT—enzyme replacement therapy—for lysosomal storage diseases. This involves identifying enzymes capable of breaking down different types of intracellular junk, identifying genes that encode for these enzymes, and finally delivering the enzymes in different ways, depending on the tissues and cell types involved.

SRF funded a preliminary research project on lipofuscin clearance therapeutics at Rice University[2] and another project relating to atherosclerosis and the clearance of 7-ketocholesterol[3] (a lipofuscin subtype), which eventually spun into Human Rejuvenation Biotechnologies, an early-stage private startup funded by Jason Hope.

A LysoSENS-based approach is currently being pursued by Dr. Kelsey Moody, who used to work at SRF. Dr. Moody has been working on an ERT treatment for age-related macular degeneration. The treatment consists in providing cells of the macula (a region of the eye’s retina) with an enzyme capable of breaking down a type of intracellular waste known as A2E. The treatment, called LYSOCLEAR, is being worked on by Moody’s company Ichor Therapeutics, which earlier this year has announced a series A offering to start Phase I clinical trials of its product.

If LYSOCLEAR proves successful, it could pave the way for future LysoSENS-based therapies to treat lysosomal dysfunction in different tissues.

A list of SRF-funded papers on the topic can be found here.

Cellular senescence

As cells divide, their telomeres—the end-parts of chromosomes protecting them from damage—shorten. Once a critical length has been reached, cells stop dividing altogether and enter a state known as senescence. Senescent cells are known to secrete a cocktail of chemicals called SASP (Senescence Associated Secretory Phenotype), which promotes inflammation and is associated with several age-related conditions.

However, senescent cells are a bit of a double-edged sword; as explained by Professor Judy Campisi during RB2016, as long as they’re not too numerous, senescent cells carry out an anti-cancer function and may promote wound healing; however, too many of them have the opposite effect, and on top of that, they induce neighboring cells to undergo senescence themselves, starting a dangerous spiral.

Normally, senescent cells destroy themselves via programmed cell death, known as apoptosis, and are then disposed of by the immune system, but some of them manage to escape destruction, and as the immune system declines with age, this gets worse.

The result is that late in life, senescent cells have accumulated to unhealthy amounts and significantly contribute to the development of age-related diseases. Osteoarthritis, cardiovascular diseases, cancer, metabolic disorders such as diabetes, and obesity are all linked to the chronic age-related inflammation to which senescent cells contribute.

ApoptoSENS: How to solve this problem, and how far we’ve got

The proposed SENS solution is straightforward: if senescent cells become too numerous, then they need to be purged. Since they are useful in small amounts, the optimal solution would be periodically removing excess senescent cells without eradicating them entirely—and more importantly, leaving other cells unharmed.

This could potentially be achieved by either senolytic drugs or gene therapies that selectively target senescent cells and trigger programmed cell death. Indeed, a great deal of recent focus by researchers have been on finding ways to remove senescent cells using senolytic therapies.

Another approach that could complement senolytics is to address why the immune system stops clearing senescent cells effectively in the first place. This approach focuses on macrophages and other immune cells involved in clearing senescent cells, aiming to reduce inflammation so that these cells begin to function properly again. The irony is that as inflammation rises with age, the immune system that is supposed to clear senescent cells and keep inflammation levels down actually starts to create more inflammation and becomes part of the problem by not doing its job properly.

SRF has funded a number of studies on the subject of cellular senescence, and it’s recently begun working on a project in collaboration with the Buck Institute for Research on Aging, which is focusing on the immune system and its role in clearing senescent cells. Another extramural project, again with the Buck Institute, is focussed on SASP inhibition.

Senescent cell clearance has been all the rage for the past two years or so; Lifespan.io has hosted the MMTP project, which focused on testing senolytics in mice, and this was later followed by CellAge’s project to design synthetic biology-based senolytics.

There are other companies that have joined the race to add senescent cell clearance to the standard toolkit of doctors, such as Unity Biotechnology and Oisin Biotechnologies.

Unity’s approach uses a drug-based approach to senolytics and is scheduled to enter human clinical trials in 2018. A number of other research teams are also developing drug-based approaches to removing senescent cells, and the competition looks set to be fierce in this area in the coming years.

Oisin’s approach, which we discussed here, makes use of suicide genes and hopefully will be tested in clinical trials not too far into the future, thanks to venture funding presently being collected. If this system can be made to work, it will allow very selective targeting of senescent cells by destroying only those giving off a target gene or genes. Thus, if a unique gene expression profile for senescent cells is determined, it would mean only those cells were destroyed, with less risk of off-target effects.

Oisin owes its existence to the SENS Research Foundation and the Methuselah Foundation, which provided the necessary seed funding. Kizoo Technology Ventures has also invested in Oisin.

Extracellular crosslinks

The so-called extracellular matrix is a collection of proteins that act as scaffolding for the cells in our body. This scaffolding is rarely if ever replaced, and a really bad consequence of this is that its parts eventually end up being improperly linked to each other through a process called glycation—the reaction of (mainly) blood sugar with the proteins that make up the extracellular matrix itself.

The resulting cross-links impair the function and movement of the linked proteins, ultimately stiffening the extracellular matrix, which makes organs and blood vessels more rigid. Eventually, this leads to hypertension, high blood pressure, loss of skin elasticity, and organ damage, among other problems.

While there are different types of cross-links—known as AGEs, short for advanced glycation end-products—glucosepane is arguably the worst, being the most common and long-lasting of all, and the body is very ill-equipped to break it down.

GlycoSENS: How to solve this problem, and how far we’ve got

In order to eliminate unwanted cross-links, the SENS approach proposes to develop AGE-breaking molecules that may indeed sever the linkages and return tissues to their original flexibility. Of course, in order to do so, crosslink molecules need to be available for research to attempt to combat them with drugs, and especially in the case of glucosepane, this has been a problem for years.

Glucosepane is a very complex molecule, and very little of it can be extracted from human bodies, and not even in its pure form. This has been greatly hampering the progress of research against glucosepane, but thankfully, this problem is now solved thanks to a collaboration between the Spiegel Lab at Yale University and the SENS Research Foundation, which financially supported the study. It is now possible to fully synthesize glucosepane, allowing for researchers to create it on demand and at a cost-effective price.

The Spiegel Lab’s scientists are now developing anti-glucosepane monoclonal antibodies to cleave unwanted cross-links. The collaboration between the Spiegel Lab and SRF dates all the way back to 2011, but it was in 2015 that the Lab announced its success and published a related paper [4] in the journal Science.

Further information on glucosepane cross-link breakers can be found in this interview with Dr. David Spiegel from Yale University on Fight Aging!; a list of studies on the subject funded or otherwise supported by the SRF is available here.

SRF also worked with the Babraham Institute on a cross-link quantification project.

Let’s help SRF move forward

Readers who wish to donate to SRF to help the organization in its crusade against the ill health of old age can do so by contributing to its winter fundraiser or even becoming SRF patrons. Have a look at SRF’s donation page to find out more.

NB: Dr. Aubrey de Grey (Chief Science Officer and Co-founder of SENS Research Foundation) himself held an AMA (“ask me anything”) on Reddit on December 7, at 14:00 PST (22:00 UTC, 17:00 EST). The questions and Dr. de Grey’s responses can be found here.

Literature

[1] Boominathan, A., Vanhoozer, S., Basisty, N., Powers, K., Crampton, A. L., Wang, X., … & O’Connor, M. S. (2016). Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant. Nucleic acids research, 44(19), 9342-9357.

[2] Gaspar, J., Mathieu, J., & Alvarez, P. (2016). A rapid platform to generate lipofuscin and screen therapeutic drugs for efficacy in lipofuscin removal. Materials, Methods and Technologies, 10, 1-9.

[3] Mathieu, J. M., Wang, F., Segatori, L., & Alvarez, P. J. (2012). Increased resistance to oxysterol cytotoxicity in fibroblasts transfected with a lysosomally targeted Chromobacterium oxidase. Biotechnology and bioengineering, 109(9), 2409-2415.

[4] Draghici, C., Wang, T., & Spiegel, D. A. (2015). Concise total synthesis of glucosepane. Science, 350(6258), 294-298.

 

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.