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Looking Back at 2017: A Year in Rejuvenation Biotechnology – Article by Nicola Bagalà

Looking Back at 2017: A Year in Rejuvenation Biotechnology – Article by Nicola Bagalà

Nicola Bagalà


 

Editor’s Note: In this article, Mr. Nicola Bagalà highlights various events of rejuvenation biotechnology in the year 2017.  This article was originally published by the Life Extension Advocacy Foundation (LEAF).

                   ~ Kenneth Alum, Director of  Publication, U.S. Transhumanist Party, January 11, 2018

Winter kick-off

This year has been pretty intense, with a lot going on both at LEAF and in the rest of the community. January saw the launch of the LEAF website, shortly followed by both the Lifeboat Foundation and Trust me – I’m a biologist partnering with us. Given that it’s been only a year, we’re amazed at how enthusiastic and supportive the community has been—and how fast it has grown, with nearly 30,000 Facebook followers late in December! We’re also very grateful to our friends at Fight Aging! for their encouragement, support, and appreciation for our work, including honoring us by featuring it on their website!

In February, the CellAge campaign launched in late 2016 concluded successfully, also thanks to the matching fund put together by Longecity. That’s also when LEAF President Keith Comito met Mikhail Batin to discuss the Russian initiative Open Longevity and when Series A funding was announced for LYSOCLEAR, a LysoSENS-based approach to treating macular degeneration.

An eventful spring

The Lifespan Heroes campaign was launched in the spring, and thus far, it has greatly helped us carry out our activities, especially in terms of web development—so thank you to all our generous donors!

In the spring, we also started our advocacy projects with global policymakers. During April 10-15, LEAF Board Director Elena Milova attended a training program conducted by the International Institute on Ageing (INIA) in Saint Petersburg, where she met and interviewed INIA director Dr. Marvin Formosa and former Head of the UN Programs on Ageing Dr. Alexandre Sidorenko.

Later in April, the SENS Research Foundation announced a collaboration on a cellular senescence project with the Buck Institute for Research on Aging.

The month of May was busy with conferences and networking; at the International Longevity and Cryopreservation Summit in Madrid, Elena Milova had the opportunity to interview life extension advocate Didier Coeurnelle, London Futurists Chair David Wood, Dr. Jose Luis Cordeiro, Senior Scientist at CONICET Dr. Rodolfo Goya (we hope to support his studies related to Yamanaka factors in 2018 via crowdfunding at Lifespan.io), and SRF’s Chief Science Officer Dr. Aubrey de Grey. Elena herself gave a talk about effective life extension advocacy methodologies; LEAF board member Paul Spiegel also gave a talk about the need for society to adapt to longer lives. In Paris, the International Cell Senescence Association (ICSA) held a conference discussing senescence triggers, physiological functions of senescence, and pathologies and therapies. We announced the event here.

Our Journal Club series was also launched at the end of May, for a total of eight Journal Club episodes this year, which you can watch here. The Journal Club is a monthly science show on which Dr. Oliver Medvedik hosts guests, and this show is supported by our patrons, the Lifespan Heroes. We broadcast this show live to our Facebook Page every month, where we invite the audience to ask questions and join in with the discussion.

Summer news

In the summer, LEAF and MMTP co-hosted a panel featuring Dr. Alexandra Stolzing, Dr. Aubrey de Grey, and Dr. Oliver Medvedik. This live broadcast included discussions about funding, research progress, and advocacy, providing some interesting insights into the field. They were joined by Alen Akhabaev, one of the project donors who supported the MMTP project on Lifespan.io, as well as Steve Hill and Elena Milova from the MMTP and LEAF.

The AgeMeter campaign was launched on Lifespan.io by Elliott Small in July, and in August, we celebrated the first birthday of our crowdfunding platform—you could say Lifespan.io’s birthday present was the MouseAge campaign launched shortly thereafter. The campaign was successful, and the MouseAge app is now ready and expected to be launched shortly. The use of AI is trending more and more in the field of aging research, so this app is certainly only one of many that will be employed in the future.

A great autumn

The autumn has been, without doubt, the busiest time of the year. The Undoing Aging conference was announced by the Forever Healthy Foundation in September, as was a series of small-scale human senolytic pilot studies by Betterhumans. Almost at the same time as the AgeMeter campaign reached 100% of its goal, Dr. Aubrey de Grey joined our SAB (Scientific Advisory Board), shortly followed by Dr. Robert Shmookler Reis. At this time, SRF and the Spiegel Lab launched a collaboration on developing monoclonal antibodies against glucosepane.

September also saw the Basel Life 2017 conference held in Basel, Switzerland, where Dr. Alex Zhavoronkov chaired the Artificial intelligence and block chain in healthcare and the Aging & drug discovery forums. Insilico Medicine’s Young.AI aging-rate tracking app was officially announced at this conference.

Juvenescence by Jim Mellon and Al Chalabi—a thorough, investor-focused introduction to the science of aging and the world of rejuvenation biotech—was published on September 25. LEAF has published two reviews of the book, which you can read here and here.

Open Longevity ICO, a Russian project focused on conducting clinical trials of geroprotective therapies and introducing diagnoses of aging into clinical practice, was launched in September. It is currently entering the second phase of pre-ICO, and we wish Anastasia Egorova’s team good luck.

In October (which is traditionally considered the Longevity Month) we launched the #IAmTheLifespan campaign, inviting all our supporters to make videos describing what brought them to join our cause, and you can watch some of them here. To help out MouseAge, and for Inktober 2017, our volunteer Laura Weston launched a fundraiser offering her beautiful artwork as a reward for donors.

The Pathways to Healthy Longevity 2017 conference was organized on October 15th by Dr. Ilia Stambler, a famous longevity activist, in Bar Ilan University (Israel), with Prof. Nir Barzilai and Prof. Haim Cohen as key speakers.

In late October and early November, the popular YouTube channel Kurzgesagt published End Aging? and Cure Aging?, which were both created with help from the Lifespan.io team. We saw overwhelming support from old and new members of the community, showing that healthy life extension is much more popular with the public than one might think.

As MouseAge reached and surpassed its goal, news started to spread that WHO was planning to leave healthy aging out of the general programme of work 2019-2023; thanks to the advocacy efforts of the community, though, WHO has received plenty of feedback on the issue and may hopefully reconsider.

During November 8-10th, the TransVision conference was held in Brussels. It was organised by Didier Coeurnelle, the head of HEALES, the Healthy Life Extension Society. Among its other objectives, the Technoprogressive declaration presented at the conference mentions the defeat of aging; it’s good to see that this objective is now considered to be of primary importance by a growing number of organisations.

During December, LEAF took part in Project4Awesome; many amazing videos were made to support us, and we’re really grateful to the community for that. It was a truly beautiful display of generosity, and not the only one; thanks to many fantastic donors, including the mysterious Pineapple Fund creator, the SENS Research Foundation has smashed its funding goals for the year. You can read more about the December highlights here.

Coming up in 2018

In 2018, we will be working towards creating more major media collaborations with awesome content creators to spread further awareness about the problem of aging and the upcoming advent of rejuvenation biotechnologies.

Our web development team will be, and in fact already is, working on improving the overall user experience of our followers and scaling our systems up to meet the needs of a larger user base; we experienced a significant growth in this sense after our collaboration videos with Kurzgesagt were published, and we’re most definitely looking forward to this happening again!

Our Journal Club will, of course, continue discussing and providing commentary on the latest aging research news in the company of special guests from the biogerontology world. More livestream events are in the cards too, so keep an eye on our Facebook page, and subscribe if you haven’t already!

As the community grows larger, so does the need to establish and develop regional presences; our next objective will be starting the Russian chapter of LEAF to engage with a wider audience. Aging is a global problem, so the more communities and audiences we can get involved in the fight against age-related diseases, the better.

LEAF will naturally take part in as many events in the healthy longevity world as possible to keep our readers in the loop. A big must is definitely the March 15-17 Undoing Aging conference in Berlin, Germany, as is the April 22-26 Interventions to Extend Healthspan and Lifespan conference in Kazan, Russia. There will certainly be much exciting news to share, so stay tuned!

The Eurosymposium on Healthy Ageing—a scientific conference organized by the European aging research advocacy group HEALES—will be held in Brussels on November 8-10. It is likely that at least a few of the LEAF team will be at the event, and it is sure to be an interesting one.

Finally, of course, more exciting crowdfunding projects are in the works!

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.

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.