The real cost of life extension advocacy

Date Posted: July 20, 2017

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There is a persistent view that life extension advocacy is something that does not require any investment and can be done in your spare time. Fundraising for overhead expenses is like the proverbial elephant in the room: it is hard not to notice it is there, but people try to avoid talking about it.

The truth is that it all depends on how ambitious the goal of that advocacy is. Without a doubt, talking to friends about the promise of rejuvenation technologies or reposting research news on your Facebook feed is useful and can be done for free.

However, what if the goal is more ambitious – to change local legislation to become more longevity-friendly, to convince decision makers in a government grant system to allocate more money to rejuvenation research, or to reach out to wealthy individuals who can fund more studies? These activities require money. In this article, we will help you become more familiar with the notion of advocacy and the expenditures behind it.

First, let’s make it clear what we mean by life extension advocacy

Advocacy is an activity that aims to influence decision making within political, economic, and social systems and institutions to promote a specific cause and thus ensure positive changes in relation to this cause on multiple levels.

Advocacy implies dealing with the general public as well as academia, business, and government agency representatives who have the formal authority to make policy decisions. The scope of advocacy initiatives can range between regional, national, and global. The suggested changes are usually made on the basis of existing evidence, so data that proves the importance of the problem and the potential of the proposed solution is necessary for successful advocacy.

Life extension advocacy combines two well-known categories: health advocacy (including patient advocacy) and research advocacy.

Health advocacy was born from the early patient rights movement, and today its main concerns involve directly serving the individual or family in order to ensure the fulfillment of their right to health as well as activities that promote health and better access to healthcare for the general public or among specific groups and communities. Public education regarding a specific health issue, such as aging, its social implications, and potential solutions, is an important part of health advocacy.

Research advocacy means efforts to raise public, academia, business and policymaker awareness about the importance of a specific field of research in order to ensure sufficient resources (including funding, workforce and equipment) and a positive regulatory landscape for fundamental and applied research and the development of new technologies. In our case, it is fundamental and translational gerontology that are the focus.

Goals of life extension advocacy

It is probably reasonable to say that every member of our community hopes for rejuvenation therapies to be developed, implemented, and delivered at an affordable price as soon as possible, preferably in their and their relatives’ lifetime. Even though there is steady progress, it would be good to see it speed up. How? Mostly by removing things that are holding us back.

The list of bottlenecks include the following aspects:

Insufficient research funding due to rejuvenation projects being innovative and not well understood by the decision-makers of different funding bodies
Flaws within the grant system: unnecessarily detailed grant applications and reports, making the scientists spend time on them, rigid rules on how money should be used during the project, and delays in funding delivery
Young scientists turning to mainstream topics like single diseases instead of rejuvenation to avoid reputational risks and problems with funding
A need for many more basic studies and unwillingness of business to fund basic science that does not produce a final product that can be sold in order to provide a return on the investment
Local legislation that can be unfriendly towards animal studies or some specific topics of research like stem cells or gene therapy and local legislation that slows down the process of foreign scientific equipment acquisition and delivery
Authors needing to pay high costs to be published in a peer-reviewed journal
Paywalls (paid access to full-text articles) blocking scientific communication and dissemination of knowledge from scientists to the public
Lack of public awareness on the promise of rejuvenation technologies and the positive aspects for our society of their wide implementation
Usage of counterproductive messages by comminuty members, leading to rejection of the idea by the members of the general public

One could call a life extension advocate successful if he or she were gradually removing or mitigating some of these bottlenecks so that the overall situation in the field were measurably improving.

So, what exactly are life extension advocates doing to achieve that? There are three main aspects: study of the field to acquire appropriate expertise, presenting the cause to the public, and internal activities to ensure the widest coverage possible.

An analysis of the field

For any activity, be it education, fundraising, or lobbying for a new law, a reliable body of evidence should be at hand in order for an advocate to be able to explain and justify suggested changes and initiatives.

Study and analysis can include many focal points, but here are the most important ones for the life extension field. Yes, being a good advocate means to study them all, at least to some extent.

Biological aging as a phenomenon (the hallmarks of aging, the relationship between aging and age-related diseases, the stage of development of different interventions to address different aging processes, data on healthspan and lifespan extension in animal studies, and equivalent data in human studies)
Demography (population structure and dynamics, corresponding morbidity and mortality dynamics both locally and globally, dependence ratio dynamics)
Economy (economic development in relation to population aging, social welfare, and healthcare expenditure dynamics)
Core decision makers, specificially in the fields of healthcare and aging (people and organizations) as well as the process of decisionmaking
Core aging researchers and research organizations (their topic, their progress) along with bottlenecks in rejuvenation research
Global and local policies related to healthcare and scientific activities
The problems of scientific development (decisionmaking in science development, research priorities, the grant system, other sources of funding, the dynamics of funding, scientific publications, and related problems)
The main global and state programs for older persons.
Public perception of rejuvenation research and methods to influence it.

A few examples of the time investment needed to prepare different advocacy materials

To write one popular but accurate article about aging research progress in a specific field, an activist has to spend 2-3 hours to familiarize himself with the latest publications on the topic. Writing 2-3 pages with scientific references can also take several hours. So, one article usually takes a half of the working day.

If the writer is also involved in social media development (which requires posting new original materials every day) this can no longer be considered a hobby: it becomes at the least a part-time job, and that should be paid. Have a look at the level of salaries of scientific writers for financial reference.

To write a large educational article like the ones relating to public concerns about life extension, the activist has to spend about a week to gather appropriate materials from different fields and then has to spend a few days writing the article.

An article on a topic such as overpopulation requires collecting official reports and scientific publications regarding topics such as population dynamics, food production and consumption, water production and consumption, different sources of energy and the forecast for their development, agricultural development, ecology, transportation, comparison of different technologies, and many others. It should be no surprise that one article of this type may need a couple of weeks of part-time activity to prepare.

To prepare a proposal for changes to a law, the activist has to read all related laws (5-10 items that are each 20-30 pages long), find and get familiar with the corresponding body of evidence (for instance, demography dynamics and forecasting), and compose a detailed document covering the propositions of the existing law and suggesting new revisions.

Aside from that, to present these changes at a public event where the law will be discussed, the activist has to prepare a presentation and a speech to inform and engage the audience. Analysis of these laws can take several weeks or even months of full-time work (such a position is called a legislative analyst), and preparation of the document takes at least several days. This does not include the process of lobbying itself; this additional time expenditure will be discussed below.

As you can see, when an activist is deeply involved with advocacy activities, it requires a significant time investment to get familiar with different aspects of our cause that do not really fit into the frame of volunteering. To ensure sufficient progress in the activities involving analytics and writing, an organization has to consider spending money on salaries for its team.

Presenting the cause and networking

The usual places to promote rejuvenation research and corresponding policies are scientific conferences, public events, and meetings of working groups discussing necessary changes in a law. While the last type of events are most often free (thanks to the principles of democracy), this cannot be said of conferences.

Here are the fees of large conferences that relate to aging and biotechnologies as well as several innovation and VC events to give you an understanding of the expenditures that an advocacy organization has to make to send a representative there (on-site registration for a regular visitor):

The 21st IAGG World Congress of Gerontology and Geriatrics (June 2017): $899

Global Biotechnology Congress (July 2017, Session Speaker Corporate): $1690

Global Innovation Forum (November 2017): €2000

20th Annual Venture Capital + Innovation Conference (February 2018): $350

2018 Aging in America Conference (March 2018): $945

In addition to the fee (which is normally paid way in advance to reduce the cost), going to a conference implies travel expenditures and booking a hotel, which can cost several hundred to a few thousand dollars per person, depending on the region where the conference takes place and its duration. Promotion of a cause on a regular basis means that an organization has to be represented at 10-20 events per year and often even more. Even if half of them do not have a registration fee, it means spending around $10k on the registration and up to $20k on travel and accommodation per person per year.

The truth is, sudden phone calls from charities to the directors of a company (who can make decisions about donations) are most often declined, and mails from charities can be ignored multiple times unless they come from someone whom the director already knows. So, to have an opportunity to talk to a potential philanthropist face-to-face, we have to attend conferences and other public events where we can meet in person.

So, before asking representatives of a life extension advocacy group “Why don’t you guys engage wealthy people to support rejuvenation research?”, it is probably useful to remember these expenditures related to advocacy activities and compare them to the organization’s current budget.

Costs aside, going to a conference for advocacy reasons is a significant workload. First of all, the advocate has to be properly prepared to freely discuss the topic with other participants. Most of the networking, such as talking with decisionmakers, is done during coffee breaks and lunch, which does not leave a chance to rest in between sessions. Gala dinners and culture events for the speakers represent an additional working period during the evenings. Not only are such activities a full-time job, they also require a certain level of mental and physical stamina.

After the conference is over, the activist has to engage in follow-up activities, exchanging emails, preparing new proposals for collaboration, and setting and going to meetings with new partners – or engaging other team members to do so.

In the case of lobbying for changes in the law (which can take several years), the activist has to attend from 5 to 20 meetings of the working group per year to ensure that the proposed changes are still being considered and keep being included in the new version of the law. Each meeting can take a half of a working day and implies some follow-up analytical and networking activities. You can check these links to have an estimate of salaries of professional lobbyists or government relations managers.

Internal activities

As we previously discussed, one of the main bottlenecks in rejuvenation research is funding. Because government and business do not provide sufficient support to these studies, the only alternative source of funding is the general public. However, due to rejuvenation research being a relatively novel topic, not many people know about it and consider it important enough to express their support. This means that activities aimed at dissemination of knowledge are crucial for faster progress.

Educational tool development includes writing popular articles, recording video interviews, writing books, designing infographics, making educational and promotional movies, organizing and broadcasting public discussions and webinars, and hosting conferences. To ensure that this coverage is sufficient to promote the cause, all the materials and all the events should be promoted in social media channels – the development and maintenance of which are an independent part-time to full-time activity.

While a non-profit can engage volunteer support and avoid some (but not all) expenditures on video production and social media management, certain aspects inevitably imply a significant monetary investment.

For instance, organization of a decent scientific conference requires $30-50k (the size of an NIA grant for a scientific conference). This money is spent on booking a conference hall, appropriate sound equipment, arranging meals for the participants, travel and accommodation for the top speakers, translation services, video recording, broadcasting, and technical support.

Editing of the video coming from a one-day conference usually requires a few weeks of part-time work. This is why in case the organization is hosting events on a regular basis, or is producing other video content, it can mean that a video editing specialist should be a part of the core team.

If the conference venue and the list of speakers are not impressive, it is often hard to persuade government representatives to pay a visit, and without that, the interest of newsmakers to report about the event and the cause can be weaker – which, in turn, reduces the impact. This is why while most advocacy organizations look at the costs very carefully, they do not always agree on the cheapest scenario.

The event management, depending on how large the conference is, can require part-time commitment of 2-5 team members for about a year and full-time commitment during the month when the conference takes place. Volunteering in event management is usually not an option: when dealing with VIP participants and partner organizations, it is better to avoid sudden breaks of communication.

This means that, apart from the expenditures of the conference hall and participants’ travel and accommodation, the advocacy group also has to find resources for several part-time salaries for the event managers in order to ensure that the conference will be prepared in time and to a good standard. All of us welcome events where a registration fee is absent, but have you ever thought where else the money for the conference comes from?

It is provided by fundraising for administrative needs (you can check the salaries of fundraisers here), running projects bringing some revenue, or capitalizing on the assets that an organization has (for instance, advertisement on the website); most often, the funds come from all of these activities combined.

Conclusion

Looking at all these costs above, it is really hard to understand why some members of the public expect an advocacy group to effectively promote the cause while also condemning any fundraising efforts to meet these administrative expenditures. Isn’t it more logical to ensure enough resources for a company to operate to its maximum potential in order to have a bigger impact?

American humanitarian activist Dan Pallotta, whose successful campaigns for AIDS and breast cancer research (which later became a case study of Harvard Business School) were explained by significant investments into fundraising activities, was crucified “for greed” and had to go out of business for having spent 40% for overhead while only 5-10% are considered “normal” for a charity. Watch his TEDx Talk to learn this sad story.

Then again, nobody questions the commitment of volunteers. But the studies show that “healthy” volunteering takes no more than 2 hours per week [1], and if it is more, a volunteer can burn out quickly and leave the organization.

This amount of time, even if spent regularly, is not enough to acquire and maintain the necessary level of expertise for networking and lobbying projects. It is also not enough to ensure regular educational activities either.

Life extension advocacy groups are constantly seeking grant opportunities to cover their administrative needs. All of the same problems that impede scientists trying to receive grants for rejuvenation research also impede advocacy projects in our field. Due to the novelty of the idea of aging prevention, not many grant givers are keen to provide resources for its promotion.

So, before you ignore the “Donate” button that you see on the site of a life extension advocacy group, and before you frown at the administrative costs in their annual report, consider this: you and other members of our community are, so far, the only part of population who dislikes aging strongly enough to invest in the solution. The best time to step in is always the same: now.

There is too much work for volunteers to do, and sustained high-quality advocacy and activism comes at a cost; if you agree and want to help us make a real difference, then perhaps consider supporting our work.

Literature

[1] Grant, A. (2014). Give and take: Why helping others drives our success. Penguin books.

Date Posted: July 6, 2017

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Reprogramming Cells to Seek and Destroy Brain Cancer

A new type of cell that can seek and destroy brain cancer and then dispose of themselves has just been successfully tested in mice. The cells are able to home in on brain tumors and reduce them to between 2 to 5% of their original size[1].

This new approach could potentially give doctors a new weapon against aggressive cancers like brain cancer (glioblastoma), which normally kills in 12-15 months.

Interestingly, it only took the researchers four days to create and deploy these cells in the mice, which is an amazing accomplishment.

As we have mentioned in previous articles, the approach of reprogramming cells in situ to combat diseases is gaining traction in the research community. Earlier this year, a study saw researchers change astrocytes (a common type of brain cell) into dopamine-producing neurons to replace the losses caused by Parkinson’s.

Homing in on cancer

Glioblastomas are particularly difficult cancers to treat as they are very challenging to remove from the brain. They spread through the brain creating a complex network of cancer cells, somewhat like a spider web, and this is what makes it almost impossible to extract safely.

As glioblastomas grow, they give off signals that tell the body there is an injury, and so the immune system sends in roaming stem cells that detect these signals to make repairs. Stem cells are cells able to create various types of specialized cells on demand, and can be thought of like the Swiss army knives of the cell world.

The research team here believe they can take advantage of stem cells and their ability to detect injury signals that allow them to home in on cancer cells. They could adapt these cells to carry anticancer drugs and deliver them with precision to the target cancer cells. This could allow doctors to make surgical strikes against aggressive brain cancers.

Building on previous research

This is not even the first time researchers have hijacked this homing ability of stem cells either. Researchers have previously used the method using neural stem cells to seek and destroy brain cancer in mice and deliver a cancer drug payload[2].

However, this approach has not been widely tested in people due to it being difficult to obtain these neural cells. Currently, to collect such cells you would have to either harvest them from another person or reprogram other adult cells in a two-step process using reprogramming factors to change the cell type.

Unfortunately, harvesting cells requires risky invasive surgery, and reprogramming adult cells and making them into stem cells runs the risk of the cells becoming cancerous. Finally, using cells from other people often triggers an immune rejection response from the immune system.

Taken together, these issues make the approach impractical and risky, so researchers needed a better way to achieve the same results.

Cellular reprogramming

In answer to the issues mentioned, the research team in this new study decided to see if they could skip a step in the cell reprogramming process. Normally, during the process you have to turn an adult cell into a regular stem cell and then into the desired cell, but the researchers tried something different.

They treated skin cells with a mix of factors that promote neural stem cell properties and it appeared to work. The skin cells turned into the desired cells with only one step, confirming that the process worked as desired.

The researchers then wanted to know if these new cells would home in on tumors. The good news was they did. The researchers observed the cells moving towards the tumors and that they were able to dig into tumors grown in the lab. The cells moved a distance of 500 microns in 22 hours.

Next, the team engineered the cells to deliver payloads of common cancer treatments to tumors in mice. Mouse tumors that were injected directly with the reprogrammed cells shrank between 20 to 50 fold in no more than 28 days.

Moving to clinical trials

The big question now is how effective this approach will be in a human brain. In the brain, the cells would have to travel much longer distances to reach tumors and may have to move many millimeters or even centimeters, many times farther than the 500 micron distance observed in lab dishes.

The research team is currently working on this question and is now testing how far their homing cells can move using larger animal models. They are also obtaining skin cells from glioblastoma patients to ensure the method works in the people they need to treat.

The research team is hoping to move to human clinical trials as soon as possible and are doing everything they can to speed up the process and ensure their therapy is as safe and efficient as possible.

Conclusion

Cancer is one of the diseases of aging and caused by the hallmark genomic instability. Therefore, progress in bringing cancer under effective control is of great interest to LEAF. This approach so far is very promising.

If we wish to enjoy healthy and longer lives through rejuvenation biotechnology then it is paramount that solutions to cancer are found, and research progress like this makes us extremely hopeful.

The traditional approaches to cancer are moving to more novel and innovative methods using the power of cellular reprogramming and boosting the body’s own defences to fight it.

President Nixon started the war on cancer in 1971; it could be that, in the not-so-distant future, the war will finally be won.

If you enjoyed this article and would like to support us to create more articles, events, livestream panels, talks and scientific advocacy please consider becoming a Lifespan Hero.

Literature

[1] Bagó, J. R., Okolie, O., Dumitru, R., Ewend, M. G., Parker, J. S., Vander Werff, R., … & Hingtgen, S. D. (2017). Tumor-homing cytotoxic human induced neural stem cells for cancer therapy. Science translational medicine, 9(375), eaah6510.

[2] Aboody, K. S., Najbauer, J., Metz, M. Z., D’Apuzzo, M., Gutova, M., Annala, A. J., … & Garcia, E. (2013). Neural stem cell–mediated enzyme/prodrug therapy for glioma: Preclinical studies. Science translational medicine, 5(184), 184ra59-184ra59.

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

Date Posted: July 1, 2017

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Adjusting Macrophages to Heal Peripheral Nerve Injury

Researchers studying peripheral nerve damage have adjusted the behaviour of macrophages to facilitate healing. [1]

What is peripheral nerve injury?

The peripheral nerves are located outside of the brain and spinal cord. They carry signals to the muscles to initiate movement as well as transporting sensory information back from the extremities and other tissues to the spinal cord and brain.

When peripheral nerves are injured, they distort or interrupt the messages between the brain and the rest of the body and are a major source of disability. Peripheral nerve damage often results in painful neuropathies which can impair sensation, movement, gland or organ function and other aspects of health, depending on the type of nerve that is damaged.

Macrophages to the rescue

Macrophages are derived from monocytes, a type of immune cell which can change into one of a number macrophage types, depending on the local signalling environment when they arrive at an injury site. The macrophage types of interest here are the M1 and M2 cells.

In general, M1 macrophages produce pro-inflammatory signals and high levels of oxidative metabolites, and M2 macrophages make the environment supportive for tissue repair by producing anti-inflammatory signals that facilitate tissue regeneration.

As discussed in our previous article, adjusting the ratios of M1 and M2 type macrophages is the focus of the therapeutic approach here. By changing the populations of macrophages to favour the M2 type, the researchers here are seeking to repair nerve damage.

The researchers here demonstrate that injuries even in tissue types not normally repaired reliably, such as nerve tissue, can be encouraged to heal by altering the population of macrophages in the tissue.

Conclusion

There is now a good amount of supporting evidence showing that macrophages play a key role in tissue repair and regeneration [2]. Researchers have demonstrated in a number of studies that adjusting the ratio of macrophages to favour the M2 “healing” cell type can improve healing and outcomes and encourage regeneration that would not usually occur reliably in nerve tissues [3].

The study discussed today is another example of the direction researchers are heading, i.e. encouraging the body’s own repair systems to heal injuries when it would not normally do so.

Literature

[1] Mokarram, N., Dymanus, K., Srinivasan, A., Lyon, J. G., Tipton, J., Chu, J., … & Bellamkonda, R. V. (2017). Immunoengineering nerve repair. Proceedings of the National Academy of Sciences, 201705757.

[2] Simkin, J., Gawriluk, T. R., Gensel, J. C., & Seifert, A. W. (2017). Macrophages are necessary for epimorphic regeneration in African spiny mice. elife, 6, e24623.

[3] Mokarram, N., Merchant, A., Mukhatyar, V., Patel, G., & Bellamkonda, R. V. (2012). Effect of modulating macrophage phenotype on peripheral nerve repair. Biomaterials, 33(34), 8793-8801.

Alexandra Elbakyan is the creator of Sci-Hub.

Date Posted: June 27, 2017

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Alexandra Elbakyan – Science Should Be Open to All, Not Behind Paywalls

A few days ago, at the international exhibition Geek Picnic 2017 in Moscow, LEAF director Elena Milova had the opportunity to talk with the founder of Sci-Hub, Alexandra Elbakyan. The Sci-Hub website is devoted to providing scientists, students, and researchers with free access to scientific publications that would otherwise be locked behind paywalls.

In this exclusive interview, Alexandra talks about the history of the project and shares her vision on how to stimulate the transition to an open access system globally.

Before you watch the interview, we would like to remind you why progress in this direction is so important for science, particularly rejuvenation biotechnology.

70% of scientific publications are behind paywalls

A typical scientific project requires a review of everything that was investigated previously. Depending on the subject, this can mean collecting up to several hundreds of full-text scientific publications and having them at hand for analysis for several years.

However, up to 70% of these publications are paid ones, which means having to obtain the journals for a fee ($30-50 per publication) or under the terms of a subscription (several hundred dollars per year for an individual user, or 5-30 thousand dollars per year or even more for an institution). An individual researcher may need to pay around $15,000 out of pocket just to collect all the information necessary for a mandatory review of the literature.

This amount is comparable to a small research grant in size; if the money is used this way, then what remains to run the study itself?

Research institutions have to buy subscriptions to get access to these publications for their scientific groups, but they often struggle to do so, because there are many journals covering each area of science, so they need to subscribe to many journals at once, which drains their modest budgets even more.

This has provoked several attempts to boycott the big publishing houses in order to force them to change their price policies.

Open access research – better for progress

There is an alternative type of publication, called ‘open access’. Under this model, scientific publications are available for free to whoever needs them, but, in exchange, the authors of the project have to pay a fee of 2 to 5 thousand dollars to the journal per publication – money usually taken from the funds of their research grant.

This system again greatly benefits the scientific journals financially, as most of the work preparing it for publication and peer review is done by the authors for free and not by the journal.

So, what does this mean in terms of the distribution of scientific information within academia and the general public? And, most importantly, what are the consequences for scientific progress?

The system is hindering scientific progress

Well, most scientists who face paywalls in their work agree that this system hinders progress and disrupts both scientific communication and the distribution of up-to-date scientific knowledge among the general public.

They are almost certainly right: imagine that you are a young medical practitioner and read a news article about an exciting study to reverse some age-related damage with a well-known intervention.

You want to learn more, so you look for the original publication on Pubmed, but the only part you can see is a small summary (the abstract), which often provides nothing but the description of the study goals, and the rest is locked behind a hefty fee.

How would this help you to adjust what health and longevity advice that you offer to patients?

The right to benefit from scientific advancement

The Universal Declaration of Human Rights contains a section dedicated to setting an appropriate standard for the results of scientific advancement:

Article 27 1. Everyone has the right freely to participate in the cultural life of the community, to enjoy the arts and to share in scientific advancement and its benefits. 2. Everyone has the right to the protection of the moral and material interests resulting from any scientific, literary or artistic production of which he is the author.

This set of standards together with the growing tension within the scientific community requires changes to local and global legislation. These changes should enable scientists all over the world to freely exchange the results of their work, and they should remove inequalities related to access so that the representatives of federal agencies, civil society organizations (including civil scientists), and the general public can benefit from evidence-based data as much as the members of research institutions.

Thanks to the activities of the movement for open access, the issue was recently raised as high as the European Commission. All projects receiving Horizon 2020 funding are required to make sure that any peer-reviewed journal article that they publish is openly accessible free of charge.

Bypassing the system

However, the changes in legislation to remove the barriers to dissemination of scientific information need time to be implemented, and the researchers need access right now. It is no surprise that they are seeking ways to bypass these obstacles.

One of the most successful initiatives in this direction is Sci-Hub – a site allowing people to get free access to scientific publications regardless of their open or paid status. Sci-Hub was founded back in 2011 by Alexandra Elbakyan, a neuroscience researcher from Kazakhstan.

As she mentions in her interview with LEAF, she first faced the problem of closed publications when she was still a university student, and, since then, she has been trying to find a way to help her fellow researchers solve this problem.

Sci-Hub now claims to contain more than 60 million publications and proceed hundreds of thousands of requests per day.

While publishing houses in several countries are seeking to sue Alexandra and stop the activities of Sci-Hub under the pretext of copyright violation, the scientific community does nothing but welcome the initiative and spread the word about this open access platform around the world.

Despite the common expectation that the service would be mostly used by researchers in the least developed countries (as they can least afford access to publications), a recent study shows that a great share of the Sci-Hub audience comes from the most developed countries and is located at big universities.

Another recent study of Sci-Hub was performed by Bastian Greshake, researcher at the Institute of Cell Biology and Neuroscience, Goethe University Frankfurt (Germany), and has shed light on what areas of science require more accessibility and which journals are the most requested – the leaders being Elsevier, Springer Nature and Wiley-Blackwell.

Alexandra Elbakyan speaks to LEAF

We spoke to Alexandra about the history of Sci-Hub and her vision of why science should be freely available to all in this exclusive interview, and we hope you will enjoy it as much as we enjoyed spending time with Alexandra and learning about her work. The original interview is also available here for Russian speakers.

What the future holds for scientific knowledge access

While the legal status of open access initiatives like Sci-Hub remain controversial (unlike the robust moral grounds of these initiatives), we should not forget just how much we all depend on the pace of scientific and technological progress.

The availability of scientific information to researchers as well as to advocacy groups can influence the pace at which we can proceed to clinical trials and then to the implementation of rejuvenation technologies into clinical practice.

In closing, it is worth keeping in mind that a longevity-friendly legislation landscape should promote open access by default and that we should all be pushing to change the current status quo for the betterment of scientific knowledge.

If you enjoyed this article and would like to support us to create more articles, events, livestream panels, talks and scientific advocacy, please consider becoming a Lifespan Hero.

Date Posted: June 9, 2017

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Dr. Jose Luis Cordeiro – Cryonics and Rejuvenation Biotechnology

During the recent International Longevity and Cryopreservation Summit in Madrid, LEAF Board member Elena Milova had the opportunity to speak with Dr. Jose Luis Cordeiro, new fellow of the World Academy of Art and Science (WAAS) and long-term proponent of innovation technologies in many fields.

Jose shared his vision on how public perception of rejuvenation technologies is changing over time and what are the main outcomes of the groundbreaking show he and his team managed to organize.

Dr. Cordeiro got his B.Sc. and M.Sc. degrees in Mechanical Engineering at the Massachusetts Institute of Technology (MIT) in Cambridge, USA, with a minor in Economics and Languages. He is President Emeritus of the Future World Society (Venezuela), and since its foundation about two decades ago, Jose managed to become an influential futurist.

He is a founding faculty at the Singularity University, created by NASA in Silicon Valley. The goal of the research centre is to tackle global problems such as health, nutrition, poverty, and education, using the medium of technology. He is also on the board of directors for the Lifeboat Foundation.

Jose is part of Fundacion VidaPlus, promoting rejuvenation technologies as well as cryonics, as he believes that people who are too old to make use of the emerging biotechnologies should be granted a plan B in form of cryopreservation.

Apart from travelling all over the world to promote innovative ideas in his inspiring talks, Jose has written more than 10 books and co-written over 20 more in five languages, including sections of the State of the Future by the Millennium Project.

His extensive associations and achievements are far too numerous to list in this short article, and we invite you to read more about Jose here and also watch his awesome TEDx talk here.

Date Posted: June 8, 2017

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Boosting Autophagy to Treat Atherosclerosis

Today, we decided that it was a good time to take a look at a new study that demonstrates that increasing autophagy is a good approach to slowing aging and could be the foundation for a variety of therapies to treat age-related diseases.

What is Autophagy?

Autophagy is an intracellular degradation system that delivers unwanted cell components to a cellular garbage disposal system known as the lysosome. The lysosome uses powerful enzymes that break down the unwanted material for recycling.

However, as we age, the lysosomes become clogged up with materials that are so fused together that not even the potent enzymes can destroy them. This causes the lysosomes to become dysfunctional, and eventually the cell dies.

This is a particular problem for long-lived cells with a very low rate of replacement, such as the heart, the back of the eyes, nerve cells, and other cells that rarely divide if at all. Ultimately, as more and more cells become dysfunctional over time due to lysosome dysfunction, tissue function becomes impaired and age-related disease sets in.

Macrophages and heart disease

Macrophages are responsible for cleaning up many kinds of cellular waste, including misfolded proteins, excess fat droplets, and dysfunctional organelles, and they are the housekeepers of the body. They protect our blood vessels from damage by the toxic byproducts of cholesterol, and they work by surrounding these toxic byproducts and breaking them down in their lysosomes into useful materials.

However, macrophages can become dysfunctional from the accumulation of lysosomal waste that they cannot break down. Over time, macrophages consume ever more amounts of toxic materials, and eventually their lysosomes become filled with insoluble waste that cannot be destroyed.

This causes the macrophages to eventually stop functioning and either become trapped and immobile in the artery wall or simply die. It is the buildup of trapped macrophages in the arterial wall that is the basis of arterial plaques, which lead to heart disease. Eventually, once the plaques grow too large, the injury swells and bursts, sending out clots that trigger strokes and heart attacks.

One of the potential ways to address this problem is by increasing autophagy in macrophages, which makes them better at dealing with the toxic waste and helps them to resist stress. It is the hope of some researchers to find ways to improve autophagy, thereby making macrophages more robust and slowing the accumulation of lysosomal waste, thus reducing the risk of heart disease.

Improving autophagy could help combat heart disease

A new study published in Nature Communications demonstrates that finding ways to make macrophages more efficient and more resistant to stress can help to slow the progression of atherosclerosis [1]. The approach also has the potential to treat other diseases, such as fatty liver disease and type 2 diabetes.

The research team found that a natural sugar known as trehalose boosts autophagy in macrophages, encouraging them to improve their housekeeping efforts. These enhanced macrophages are then better able to deal with the toxic materials and break down the atherosclerotic plaques that have built up inside arteries and cause heart disease.

In the study, the researchers showed that mice prone to atherosclerosis had reduced plaque in their arteries after being injected with trehalose. The sizes of the plaques measured at the aortic root were variable, but on average, the plaque size measured 0.35 square millimeters in control mice versus 0.25 square millimeters in the mice given trehalose. This was approximately a 30 percent reduction of plaque size and is therefore statistically significant.

The effect was not observed when mice were given trehalose orally or when they were injected with other types of sugar, even ones that are structurally similar. The sugar is broken down by the digestive system when eaten, so its ability to trigger autophagy is destroyed as well.

So what is trehalose?

Trehalose is a naturally occurring sugar that consists of two glucose molecules bound together. It is approved by the Food and Drug Administration for human consumption and is commonly used as an ingredient in various pharmaceuticals.

Past work by many research groups has shown trehalose triggers autophagy [2-3]. However, exactly how it boosts autophagy has remained unknown until now. The study authors showed that trehalose activates a molecule called transcription factor EB or TFEB. TFEB is a master regulator of lysosomal biogenesis, the creation of lysosomes in the cell, as well as autophagy in mice and humans.

Once activated by trehalose, TFEB then goes into the nuclei of macrophages and binds to the DNA. When the molecule binds to the DNA, this causes various genes to be expressed, instructing the cell to create additional housekeeping components – in this case, more lysosomes to gobble up toxic waste.

So, interestingly, this process isn’t just enhancing the existing cellular machinery already in place: it actually triggers the cell to make new housekeeping machinery, boosting cellular autophagy.

The researchers are continuing to study trehalose and its potential as a therapy for heart diseases, particularly since it is safe for human consumption. The researchers are hoping to overcome the need for injections, potentially by blocking the digestive enzyme that breaks trehalose down when eaten. This would allow trehalose to retain its structure, and thus its ability to trigger autophagy, and would offer a convenient way to deliver the sugar to the macrophages.

Conclusion

It is important to note that this work is in preclinical testing and has some way to go before it could move into human phase 1 clinical trials. Certainly, if such a therapy can be translated to humans, and there is reason to be optimistic that it might, it may offer a potentially valuable approach to treating heart disease and other diseases caused by plaque accumulation, such as Alzheimer’s and Parkinson’s.

Another, more direct, approach might be to remove the toxic waste in the first place before it has a chance to accumulate to dangerous levels, and this is the approach that the SENS Research Foundation is taking with its LysoSENS program. Which of the two approaches will arrive first is anyone’s guess, but either would be a good step for treating heart disease and helping people to continue living healthy, independent, and long lives.

If you enjoyed this article and would like to support us to create more articles, events, livestream panels, talks and scientific advocacy, please consider becoming a Lifespan Hero.

Literature

[1] Sergin I, Evans TD, Zhang X, Bhattacharya S, Stokes CJ, Song E, Ali S, Dehestani B, Holloway KB, Micevych PS, Javaheri A, Crowley JR, Ballabio A, Schilling JD, Epelman S, Weihl CC, Diwan A, Fan D, Zayed MA, Razani B. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nature Communications. June 7, 2017.

[2] Sarkar, S., Davies, J. E., Huang, Z., Tunnacliffe, A., & Rubinsztein, D. C. (2007). Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and α-synuclein. Journal of Biological Chemistry, 282(8), 5641-5652.

[3] Aguib, Y., Heiseke, A., Gilch, S., Riemer, C., Baier, M., Ertmer, A., & Schätzl, H. M. (2009). Autophagy induction by trehalose counter-acts cellular prion-infection. Autophagy, 5(3), 361-369.

Date Posted: June 7, 2017

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Friday June 9th 13:00 EST/18:00 UK “How to Promote Longevity?”

LEAF/Lifespan.io is teaming up with the Major Mouse Testing Program (MMTP) for a special longevity panel with Dr. Alexandra Stolzing, Dr. Aubrey de Grey, Dr. Oliver Medvedik and a number of guests. The MMTP will be streaming the panel live to their Facebook page and we invite you to join us. The panel will also be recorded and will be made available later to view on the LEAF/Lifespan.io Youtube channel and on the MMTP Facebook page. This was originally scheduled for the 6th June, but had to be rescheduled due to technical problems. We apologize for the inconvenience.

Date Posted: May 27, 2017

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The Need for Better Aging Biomarkers

As human life expectancy has increased throughout the 20th and 21st centuries, this has led to a steady increase in the population of older people. With that increase has come the rise of age-related diseases and disabilities.

As a result, it is becoming ever more important to develop preventative strategies to monitor and maintain health as well as therapies that directly address the various aging processes to delay or prevent the onset of age-related diseases.

One of the ways we can do this is by developing more effective ways to measure how someone is aging; this means developing high-quality aging biomarkers. The challenge in creating such biomarkers has always been the fundamental question of what we measure.

Chronological age is a poor indication of how someone might be aging and is not a good way to ascertain an individual’s risk factor for various age-related diseases. This is simply because everyone ages differently and at different rates. While everyone ages due to the same processes, the speed at which these different processes occur can vary between individuals.

While individual biomarkers are good for measuring a certain aspect of aging in a very focused way, and they are indeed useful in this capacity, they do not give an overall picture of how someone is aging and where to focus preventative efforts [1].

The literature is replete with examples of biomarkers that measure physical function, anabolic response, inflammation levels, and immune system aging [2-10].

Biomarkers have their limitations

Taken individually, these are useful, but many biomarkers have their limitations. Biomarkers such as β-galactosidase, which is very popular among researchers investigating cellular senescence, has some limits, especially if used as the only or one of few biomarkers during an experiment [11].

Another popular biomarker of aging is the measurement of telomeres. However, this also has some limitations, depending on the particular method used [12-13]. Indeed, some studies have investigated its validity as an aging biomarker and argue that, while useful, it is not really an aging biomarker in the strict sense [14].

A system analysis approach to aging biomarkers

In order to get the bigger picture, we need to move beyond simple approaches to a systems analysis approach that examines multiple biomarkers at once [15].

A number of approaches to this issue have been proposed and even tested. Arguably, one of the most well-known methods for ascertaining biological age is the DNA methylation clock developed by Horvath; it can, in many ways, be considered the gold standard for aging biomarkers[16].

Other approaches that consider multiple biomarkers have also been proposed; such systems evaluate a number of biomarkers to give a ‘score’ as an overall indication of aging rate [17-20]. More recently, a package of 19 biomarkers has been suggested as another approach to evaluating age [21].

There are numerous similar proposals in literature to evaluate aging with a wider set of biomarkers, and curious people do not have to search far to find them.

There is an urgent need to not only develop more accurate biomarkers but also to package them into a systems analysis approach. This would allow researchers developing drugs and therapies that target the aging processes to ascertain efficacy to a much greater degree. It could also allow better monitoring of an individual’s health and allow physicians to identify and address areas of concern to a far greater degree of accuracy.

Conclusion

The development of better biomarkers and systems capable of packaging them into compact solutions is very important to aging research. The rising popularity of health wearables and other personal health monitoring equipment also has the potential to allow the average person to take more control over his or her health. Such approaches could be combined with other functional aging tests, such as the H-Scan or the updated version being developed as part of a fundraising project at Lifespan.io. The development of biomarkers and systems that deliver them efficiently and at an affordable cost should, therefore, be a high priority.

Literature

[1] Karasik, D., Demissie, S., Cupples, L. A., & Kiel, D. P. (2005). Disentangling the genetic determinants of human aging: biological age as an alternative to the use of survival measures. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 60(5), 574-587.

[2] Gruenewald, T. L., Seeman, T. E., Ryff, C. D., Karlamangla, A. S., & Singer, B. H. (2006). Combinations of biomarkers predictive of later life mortality. Proceedings of the National Academy of Sciences, 103(38), 14158-14163.

[3] Walston, J., Hadley, E. C., Ferrucci, L., Guralnik, J. M., Newman, A. B., Studenski, S. A., … & Fried, L. P. (2006). Research agenda for frailty in older adults: toward a better understanding of physiology and etiology: summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults. Journal of the American Geriatrics Society, 54(6), 991-1001.

[4] Stenholm, S., Maggio, M., Lauretani, F., Bandinelli, S., Ceda, G. P., Di Iorio, A., … & Ferrucci, L. (2010). Anabolic and catabolic biomarkers as predictors of muscle strength decline: the InCHIANTI study. Rejuvenation research, 13(1), 3-11.

[5] Banerjee, C., Ulloor, J., Dillon, E. L., Dahodwala, Q., Franklin, B., Storer, T., … & Montano, M. (2011). Identification of serum biomarkers for aging and anabolic response. Immunity & Ageing, 8(1), 5.

[6] Franceschi, C., & Campisi, J. (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 69(Suppl 1), S4-S9.

[7] Bürkle, A., Moreno-Villanueva, M., Bernhard, J., Blasco, M., Zondag, G., Hoeijmakers, J. H., … & Gonos, E. S. (2015). MARK-AGE biomarkers of ageing. Mechanisms of ageing and development, 151, 2-12.

[8] Cohen, A. A., Milot, E., Li, Q., Bergeron, P., Poirier, R., Dusseault-Belanger, F., … & Fried, L. P. (2015). Detection of a novel, integrative aging process suggests complex physiological integration. PLoS One, 10(3), e0116489.

[9] Catera, M., Borelli, V., Malagolini, N., Chiricolo, M., Venturi, G., Reis, C. A., … & Ostan, R. (2016). Identification of novel plasma glycosylation-associated markers of aging. Oncotarget, 7(7), 7455.

[10] Peterson, M. J., Thompson, D. K., Pieper, C. F., Morey, M. C., Kraus, V. B., Kraus, W. E., … & Cohen, H. J. (2015). A novel analytic technique to measure associations between circulating biomarkers and physical performance across the adult life span. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glv007.

[11] Yang, N. C., & Hu, M. L. (2005). The limitations and validities of senescence associated-β-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells. Experimental gerontology, 40(10), 813-819.

[12] Montpetit, A. J., Alhareeri, A. A., Montpetit, M., Starkweather, A. R., Elmore, L. W., Filler, K., … & Collins, J. B. (2014). Telomere length: a review of methods for measurement. Nursing research, 63(4), 289.

[13] Bernadotte, A., Mikhelson, V. M., & Spivak, I. M. (2016). Markers of cellular senescence. Telomere shortening as a marker of cellular senescence. Aging (Albany NY), 8(1), 3.

[14] Der, G., Batty, G. D., Benzeval, M., Deary, I. J., Green, M. J., McGlynn, L., … & Shiels, P. G. (2012). Is telomere length a biomarker for aging: cross-sectional evidence from the west of Scotland?. PLoS One, 7(9), e45166.

[15] Zierer, J., Menni, C., Kastenmüller, G., & Spector, T. D. (2015). Integration of ‘omics’ data in aging research: from biomarkers to systems biology. Aging cell, 14(6), 933-944.

[16] Horvath, S. (2013). DNA methylation age of human tissues and cell types. Genome biology, 14(10), 3156.

[17] Levine, M. E. (2013). Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age?. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 68(6), 667-674.

[18] Belsky, D. W., Caspi, A., Houts, R., Cohen, H. J., Corcoran, D. L., Danese, A., … & Sugden, K. (2015). Quantification of biological aging in young adults. Proceedings of the National Academy of Sciences, 112(30), E4104-E4110.

[19] Peterson, M. J., Thompson, D. K., Pieper, C. F., Morey, M. C., Kraus, V. B., Kraus, W. E., … & Cohen, H. J. (2015). A novel analytic technique to measure associations between circulating biomarkers and physical performance across the adult life span. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glv007.

[20] Lara, J., Cooper, R., Nissan, J., Ginty, A. T., Khaw, K. T., Deary, I. J., … & Mathers, J. C. (2015). A proposed panel of biomarkers of healthy ageing. BMC medicine, 13(1), 222.

[21] Sebastiani, P., Thyagarajan, B., Sun, F., Schupf, N., Newman, A. B., Montano, M., & Perls, T. T. (2017). Biomarker signatures of aging. Aging Cell.

Date Posted: May 26, 2017

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Treating Diseases with a Protein Missile System

Researchers at the University of Dundee have shown that it is possible to target and destroy specific proteins within cells using a new directed protein missile system. This is very interesting, as it raises the possibility of targeting aberrant proteins present in diseases that currently have no drug that affects them.

This opens the door to treating a range of diseases, as well as potentially being useful in directly targeting proteins involved in the aging process. Before we take a look at the research, let’s recap on why proteins are important, what they do, and how they relate to aging and diseases.

So what are proteins?

Proteins are often called the building blocks of life, and they are critical to the operation of our cells and therefore to our lives. Proteins are produced by the cell and perform a huge variety of functions, such as activating the immune response against pathogens, and regulating metabolism and cellular functions. They do the majority of the work in cells and are required for maintaining the structure, function, and regulation of the body’s tissues and organs.

Proteins are made up of hundreds or even thousands of smaller units called amino acids, which are linked together in long chains. There are twenty different amino acids that can be combined to make a protein. The sequence of amino acids determines each protein’s unique structure and its function. Proteins can be categorized according to their function within the body.

Function	Description
Antibody	Antibodies bind to specific foreign particles, such as viruses and bacteria, as part of the immune response and to help protect the body.
Enzyme	Enzymes perform almost all of the thousands of chemical reactions that take place within cells. They also assist with the formation of new molecules by interpreting the genetic information stored in DNA.
Messenger	Messenger proteins, such as some hormones, transmit signals to coordinate biological processes between the different cells, tissues, and organs.
Structural component	These proteins provide structure and support for cells. In a larger context, they also allow the body to move.
Transport/storage	These proteins bind and carry atoms and small molecules within cells and through the body.

Undruggable proteins

In the majority of diseases, the protein function is altered due to genetic mutation (damage to our DNA) or a deregulated environment where there are too many proteins or too few produced. This change in the function of proteins then causes havoc in the cell and leads to diseases and drives the aging processes too.

During aging, proteins can become misfolded, which leads to protein aggregation and the onset of diseases like Alzheimer’s and Parkinson’s, where damaged proteins build up and destroy brain cells. If these damaged proteins could be targeted effectively, it could potentially be a way to treat neurodegenerative diseases.

Some researchers suggest that only a small number of proteins can actually be targeted by conventional drugs, and the majority of proteins remain untouchable or undruggable. So, being able to target and degrade the proteins in the cell has a vast scope for treating many diseases both age-related and otherwise.

Introducing AdPROM

A research team at Dundee University, led by Dr. Gopal Sapkota has created an Affinity-directed PROtein Missile (AdPROM) system that allows for the precise and rapid targeting and destruction of proteins in the cell. The paper published recently here follows on from earlier work by the same team [1-2].

AdPROM uses small affinity probes, termed nanobodies or monobodies, which bind and recruit target proteins to the cellular protein degradation system to be destroyed.

In a university press release, Dr. Sapkota commented “For the first time we have shown that it is possible to target endogenous proteins for complete degradation with AdPROM,” and “This is extremely exciting and has far-reaching applications and implications for both research and drug discovery. Being able to selectively degrade target proteins in cells rapidly is desirable in research and therapeutics.”

The targeting and rapid destruction of specific proteins could potentially allow scientists to determine the effect of removing these proteins and the possible reversal of disease state by doing so.

The removal of excessive malfunctioning proteins from cells and tissues using AdPROM could be a huge step for medicine but there is much work to be done. Before this technology can be deployed in humans, it would need to pass through the clinical trial process so until then there is much more work ahead for the researchers here. Dr. Sapkota believes that scientific developments in gene delivery techniques could be the way to use AdPROM in the future.

“The AdPROM technology is quite simple to assemble and versatile for use in any cell,” said Dr. Sapkota. “Basically, it requires an affinity probe that selectively recognises the endogenous target protein of choice. With rapid advances in technologies, it won’t be too long before we have access to affinity probes against pretty much every target protein.”

This is true, as technology is advancing rapidly and gene therapy delivery systems are becoming more sophisticated and refined with each passing year.

“This is technology that we can hopefully use to expedite and prioritise drug discovery. Getting a single molecule developed against a target protein costs a lot of money and resources so it is impossible to do this for every protein. AdPROM allows us to manipulate proteins, study their individual functions and find out what happens when they are destroyed. It will allow us to refine the list of targets very, very quickly. Indeed, we are already collaborating with major pharmaceutical companies to streamline drug targets with AdPROM,” Dr. Sapkota concludes.

Conclusion

Should clinical trials pan out, the AdPROM system could be a potent weapon in the fight against all kinds of diseases, including age-related diseases like Alzheimer’s, Parkinson’s, heart disease, and cancer. We wish Dr. Sapkota and his team the best of luck, and we will be watching progress with great interest.

Literature

[1] Fulcher, L. J., Hutchinson, L. D., Macartney, T. J., Turnbull, C., & Sapkota, G. P. (2017). Targeting endogenous proteins for degradation through the affinity-directed protein missile system. Open Biology, 7(5), 170066.

[2] Fulcher, L. J., Macartney, T., Bozatzi, P., Hornberger, A., Rojas-Fernandez, A., & Sapkota, G. P. (2016). An affinity-directed protein missile system for targeted proteolysis. Open Biology, 6(10), 160255.

Date Posted: April 25, 2017

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How Population Aging First Became an International Concern

Today, we bring you an interview with Dr. Marvin Formosa, director of the International Institute on Ageing of the United Nations, Malta (INIA). First, let’s find out how the issue of population aging was first introduced into the agenda of the United Nations and why the UN body focused on aging is located in Malta.

Malta was the first to recognise aging as an international problem

There are plenty of philosophers who have tried to understand aging on both the individual and social levels, and there are many scientists who have been increasingly improving our knowledge of aging as a set of biological processes. There have also been certain moments in time when humanity has made crucial steps towards a better future for everyone. One of these steps was the recognition that aging is a matter of international concern.

The matter was successfully brought to the attention of the United Nations by the government of Malta in 1968. This led to a number of regional conferences aimed at analyzing the situation and preparing a report on population changes in different parts of the world.

After nearly a decade, the nature of the received data resulted in the decision to hold the very first World Assembly on Aging, which took place in Vienna, Austria in 1982. This assembly brought together more than 1,000 participants from 124 member states. International bodies and non-governmental organisations have sent their representatives to help elaborate the first-ever International Plan of Action on Aging (also known as the Vienna Plan on Aging).

This first strategic document made clear the economic and social consequences of population aging and provided guidance to the member states on how to adapt to the growing needs of older people. The need for a coordination and education center on the problems of aging also became evident; this is why the UN Economic and Social Council recommended that the UN leaders they establish the International Institute on Aging.

Malta becomes the UN International Institute on Ageing

Due to the role that Malta has played in promoting this important matter, in October of 1987, the United Nations signed an official agreement with the government of Malta in order to found a new specialized body under the auspices of the United Nations.

The International Institute on Ageing (INIA) was inaugurated on April 15th, 1988 by Javier Perez de Cuellar, who served as the Secretary-General of the United Nations during that period. The main activities of the Institute include multi-disciplinary education and training in specific areas related to aging along with data collection, information exchange, technical co-operation, and research and publications.

Close international cooperation allows the Institute to organize multiple “in situ” education programs to analyse local socio-economic conditions and needs of the elderly in developed and developing countries, facilitate knowledge dissemination, and hence foster the development of evidence-based policy and action plans on aging.

To date, more than 3000 specialists from all over the world have participated in these international education programs, such as the School on Gerontology and Geriatrics. The changes related to population aging that our society is going through require all stakeholders to have a systemic vision on the issue in order to make wise decisions.

This is why we at LEAF/Lifespan.io decided that I should attend the closest “in situ” INIA training program, which was held in Saint-Petersburg, Russia on April 10-15, and share my knowledge and impressions with the team and the community.

I took the opportunity during the conference to interview Dr. Marvin Formosa, the director of the International Institute on Ageing, United Nations – Malta (INIA).

We would like to thank Dr. Formosa for taking the time to speak with us at the event, and we appreciate his insights.

Date Posted: April 23, 2017

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Error CORRECTion for CRISPR

The CRISPR system (Clustered Regularly Interspaced Short Palindromic Repeats) has exploded onto the biotech sector as a relatively simple, highly efficient, and fast method for precisely introducing breaks into genomic loci [1-2]. The realization that it is a prokaryotic acquired immune system, although less often mentioned, has been equally paradigm changing [3]. Ironically, it’s the system’s high efficiency that poses a problem when editing mammalian genomes, a problem that Paquet et al. ingeniously solve in this new study.

In very brief summary, two components are required for the CRISPR system to function: a protein endonuclease, termed Cas9 in the original system, and a short “guide” RNA (gRNA) that guides the endonuclease to a complementary genomic site corresponding to the 5′-terminal 20 bases of the gRNA. These are usually expressed from one plasmid.

A second necessity for the system to function is the presence of a short sequence present in the genomic target site that is adjacent to the gRNA target site. This is termed the Protospacer Adjacent Motif (PAM) and varies between different versions of Cas proteins, with NGG being recognized by the original system adapted from the bacterium S. pyogenes.

Since then, the CRISPR system toolkit has been expanded to not only to nick and induce double-stranded breaks in DNA but also cleave RNA, activate and repress genes, fluorescently label genomic loci, recognize different PAM sites, and introduce epigenetic modifications [4-8]. Its original use, however, has been to create a precise double-stranded break at genomic loci for the purpose of accurately modifying genomes.

This second modification step requires the presence of a homology mediated repair (HMR) DNA template, which the cell’s endogenous repair enzymes use to copy in the modified sequence. This is the troublesome step in which low efficiency still plagues researchers who wish to genetically modify loci accurately in mammalian cells. Because the CRISPR system is so efficient, it can re-bind to the endogenous PAM site and re-cut the locus.

A problem with accuracy

In mammalian cells, the error prone NHEJ (Non Homologous End Joining) repair pathway is dominant, leading to insertion/deletion mutations in the majority of targeted cells. Thus, only a small percentage of CRISPR-altered mammalian cells actually have the precise modification that you want. This also makes it difficult to generate heterozygote cell lines, as the majority of the time, both alleles on both chromosomes will be targeted and altered.

To solve this problem, Paquet et al. have developed and expanded a technique initially shown to work in prokaryotes to now avoid such re-cutting in mammalian cells in an Alzheimer’s model system [9].

In what is possibly one of the most contorted recursive acronyms ever devised, their ingenious system, termed CORRECT (COnsecutive Re-guide or Re-Cas steps to Erase CRISPR/Cas-blocked Targets), works by introducing “blocking” mutations into either the PAM site or the guide RNA binding site on the HMR template. Doing so means that, after the CRISPR system has recognized either the native PAM or guide RNA binding site in the genomic locus, the introduced modification will also contain new mutant PAM and/or guide RNA binding sites that are not recognized.

This greatly enhances the frequency of correct mutants from about 20% in HMR targeted cells to about 80%. Furthermore, the mutant PAM and guide RNA binding sites can then be reverted back to normal using a second round of CRISPR, generating a truly scar-less site. Not content there, the authors also present two additional techniques that can readily generate heterozygote mutant cell lines as well. This year, Kwart et al. have published the detailed protocols for these methods [10]. At least one additional problem needs to be solved to make CRISPR work optimally in mammalian cells.

This is centered on the very low efficiency of HDR vs. NHEJ, with the latter being favored. Although the authors demonstrated that the efficiency of obtaining correct HMR modified cells rose to 80-90%, one must realize that this percentage is only out of those cells that initially used HMR. That total is only 1-10% of all modified cells; the majority of 90-99% used error-prone NHEJ.

Conclusion

Once this hurdle is finally overcome, and many groups are actively working on solving this problem, the CRISPR system for genome modification may very well become as close to perfect as is physically possible.

Literature

1. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. Science. 2012 Aug 17;337(6096):816-21. 2. Multiplex genome engineering using CRISPR/Cas systems. Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F. Science. 2013 Feb 15;339(6121):819-23. doi: 3. Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements. Mojica FJ, Díez-Villaseñor C, García-Martínez J, Soria E. J Mol Evol. 2005 Feb;60(2):174-82. 4. Imaging genomic elements in living cells using CRISPR/Cas9. Chen B, Huang B. Methods Enzymol. 2014;546:337-54. 5. Programmable repression and activation of bacterial gene expression using an engineered CRISPR-Cas system. Bikard D, Jiang W, Samai P, Hochschild A, Zhang F, Marraffini LA. Nucleic Acids Res. 2013 Aug;41(15):7429-37. 6. Programmable RNA recognition and cleavage by CRISPR/Cas9. O’Connell MR, Oakes BL, Sternberg SH, East-Seletsky A, Kaplan M, Doudna JA. Nature. 2014 Dec 11;516(7530):263-6 7. Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Hilton IB, D’Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, Gersbach CA. Nat Biotechnol. 2015 May;33(5):510-7. 8. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y, Zhang F. Cell. 2013 Sep 12;154(6):1380-9. Erratum in: Cell. 2013 Oct 10;155(2):479-80. 9. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9. Paquet D, Kwart D, Chen A, Sproul A, Jacob S, Teo S, Olsen KM, Gregg A, Noggle S, Tessier-Lavigne M. Nature. 2016 May 5;533(7601):125-9. 10. Precise and efficient scarless genome editing in stem cells using CORRECT. Kwart D, Paquet D, Teo S, Tessier-Lavigne M. Nat Protoc. 2017 Feb;12(2):329-354.

Date Posted: April 18, 2017

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Dr. Alex Zhavoronkov – A.I. Versus Aging

The battle against aging is not going to be an easy one, and it will likely require the most refined tools modern science has to offer. Among them, artificial intelligence may be one of the most promising and is being extensively used by biogerontology researchers such as Dr. Alex Zhavoronkov.

Helping to drive progress in rejuvenation biotechnology

Boasting an impressive collection of degrees—among which a Ph.D. in biophysics, an MSc in biotechnology, and a BA in Computer science—Dr. Zhavoronkov has had an equally impressive career in the fields of biogerontology and regenerative medicine. He is the director of IARP—the International Aging Research Portfolio—and of the UK-based charity Biogerontology Research Foundation.

For several years now, he has been head of the Regenerative Medicine Laboratory at the Centre for Pediatric Hematology, Oncology and Immunology and adjunct professor at the Institute of Physics and Technology in Moscow.

Since 2014, he’s also the CEO of Insilico Medicine, a bioinformatics company which he co-founded. The company, which was awarded the ‘Most Promising Company’ title at the Palo Alto Personalised Medicine World Conference in 2015, focuses on extending healthy longevity using A.I. to discover new drugs and develop biomarkers for aging.

One of its most notable projects is OncoFinder, an algorithm used to analyze the activity of molecular pathways involved in both normal and pathological conditions, from growth and development to aging and cancer. The algorithm can be used to predict which drugs could prove the most effective in the treatment of cancer, for example, or to determine which pathways are involved in age-related diseases.

Dr. Zhavoronkov is a longevity enthusiast and he believes we can push the longevity record past the current 122 years.

Poised for a revolution in rejuvenation research

He compares the current state of radical life-extension research to that of computer science in the late 70s, when all the building blocks of the upcoming revolution were either in place already or about to be. To maximise his odds to see the dawn of rejuvenation biotechnology, Alex maintains a strict, healthy regimen that includes regular exercising, monitoring his health conditions and a variety of drugs and supplements tailored to his specific situation.

His current ambitious yet achievable goal is to reach 150 years of age, and he certainly does not think it would be boring to live for that long. He argues life should never be boring and that the way to go to avoid it is finding research interests and passions to motivate oneself.

In fact, he further argues, the major challenge to overcome to defeat aging is represented by psychological aging—the tendency people have to accept the decline that comes with age and the changes in behavior and attitudes that this imposes on them.

This aspect is one of the topics he discussed in his book The Ageless Generation: How Advances in Biomedicine Will Transform The Global Economy. Together with an ever-growing number of specialists of the field, Dr. Zhavoronkov endorses the idea that aging is nothing but a complex, multifactorial disease, and that it should be officially classified as such.

Whilst we haven’t brought the aging processes under medical control yet, Alex thinks it is possible, and that eliminating the pain and suffering that currently characterizes late life is a worthy and achievable goal. Already today, he argues, people who are reasonably healthy in their 70s stand a fighting chance of living past 150.

We took the opportunity to catch up with Alex and ask him a few questions about his work and the field of aging research.

Hi, Alex, could you begin by explaining what first attracted you to science and in particular the study of aging and why you believe aging is a problem to be solved?

Since very early childhood I asked myself one question: “Why in Star Wars, Star Trek and other Sci Fi movies and books people invent space travel, medical droids and other marvelous technologies, but still grow old, age and die?”. In order to go into space for the extended periods of time, one would need to live longer and be resistant to all kinds of stress including radiation. Plus, I had a crush on Madonna and really did not want her to age and there are many other reasons.

One reason above all is that there is no point in living if you can’t keep continuously improving no matter how hard you try. People, who accumulate wealth do not really own anything, they rent assets for as long as they live. But before going all-in into biomedicine, I went into computer science, did my first bachelor degrees at Queen’s University in Canada and made some money to ensure that I can sustain for a few years and support my own research.

I went into high-performance computing and managed to get into the high-level position at a graphics processing unit (GPU) company called ATI Technologies at a reasonably young age fifteen years ago. When I reached a reasonably comfortable financial situation, I decided to quit and went to do my graduate work in biosciences looking for ways to extend healthy productive longevity. I worked in a number of areas related to aging research and along the way, I got my masters and Ph.D. degrees, got two laboratories and worked for a number of biotechnology companies.

In 2010, after a decade of education and research, I realized that aging is a very complex multifactorial process and that humans are very different from model organisms. And we need to focus on developing the core technology that can be used to build a sustainable business around aging research so that it can unfold and demultiplex into many directions to prevent the transformation of aging into a disease.

Since January 2014 I have been running Insilico Medicine, which takes an umbrella view on the field with over 170 research projects and over 150 collaborators worldwide. I have no doubt that aging is a problem that can be solved within our lifetimes unless we see a major economic crisis, a global war, or both.

Your work focuses on computational medicine, how would you explain this relatively new field of science to our readers?

Computational biomedicine is a very broad field of research, where computational methods and tools are applied for diagnosis, treatment, and research. The field has been around since the invention of electronic analytical equipment, but in recent years it got a major boost due to the availability of Big Data, increases in computing power, breakthroughs in machine learning and convergence of the many fields of science and technology.

You are the CEO of Insilico Medicine. What are the main goals of the company for the next 5 years? Can we expect breakthroughs in personalized medicine?

Our long-term goal is to continuously improve human performance and prevent and cure the age-related diseases. In 5 years we want to build a comprehensive system to model and monitor the human health status and rapidly correct any deviations from the ideal healthy state with lifestyle or therapeutic interventions. Considering what we already have, I hope that we will be able to do it sooner than in 5 years.

One reason why we can manage over 170 projects is that we use agile development practices and approach every project as a software development project. We treat aging as a salami, constantly “cutting” thin slices and I think we are halfway through. In 5 years you can definitely expect breakthroughs in personalized medicine and we are not the only company working in the field, so there will be many breakthroughs on the many fronts.

The main breakthroughs I can promise from Insilico are in the area of multimodal biomarkers of aging, where we take as much data available for an individual from simple pictures and regular blood tests to very expensive molecular and imaging data and turn it into a model, which can be used to make a broad range of predictions, recommendations, and treatments. We are entering the era of personalized drug discovery and regenerative medicine.

One of our major contributions to the field was the application of deep neural networks for predicting the age of the person. People are very different and have different diseases. But if you want to find just one feature, which is biologically relevant and can be predicted using many data types – it is the person’s date of birth.

So we build all kinds of predictors of chronological age and then look at what features and at what levels are most important and can be used to infer causality and be targeted with interventions. I think that this approach is novel and will result in many breakthroughs. Here are the two slides that illustrate this idea:

Another set of breakthroughs is likely to come from our work in the generative adversarial networks (GANs) and reinforcement learning (RL), where we are experimenting with the design of new molecules with the desired properties and reconstruct the incomplete data sets with missing values. Here is a public version of our current drug discovery pipeline:

We published some of the proofs of concept for at least some of these steps so that other people could go this route and to save time when explaining this approach to our partners in Big Pharma.

How do you decide what projects to get involved in?

The way we prioritize projects at Insilico Medicine is by looking at the number of QALY each project can generate. Most pharmaceutical companies, governments, and philanthropists do not realize that aging research generates the maximum number of QALY per dollar spent. It is the most altruistic cause and the most effective investment.

If you add just one year of life to everyone on the planet, you generate over 7 billion QALY. The average reasonable cost per QALY is around $50,000. So it is possible to generate several hundred trillion dollars by extending the life of everyone on the planet with a simple intervention.

Will you tell us a little bit about your team at Insilico? Is it easy to get on board or do you have some sort of test?

Over the past two years, we hire through hackathons and mini-competitions that we either organize or support. Several of our core deep learning specialists and bioinformaticians were hired in this manner. We also work with the young bright scientists, who come to us looking for a project.

We usually give them a difficult or impossible task and if they come up with a solution, we integrate them into the team. We usually want to ensure that the person is not driven by the monetary aspect of employment and will stay with us for over a year. And sometimes we allow and even encourage the person to remain part-time in academia.

Today we have R&D resources in Baltimore, Brussels, Moscow, St. Petersburg, Oxford, and Seul. This year we will try to grow Insilico Korea, conduct one or two SkinHack hackathons using our AgeNet.Net system and establish closer collaboration with the partners in Korea. We also like hiring people in Russia. The level of programming talent is very high, people are loyal, curious, dedicated and mission-driven.

And if you have any negative feelings with regards to Russia, remember that there are several countries considered to be friendly that are actually kingdoms. So you need companies like ours with strong humanitarian values to create new industries and reduce the country’s dependence on oil.

We have heard you make your team members pass a course on bioinformatics to join the Longevity Pride club, can you tell us a bit more about that?

All team members join voluntarily and usually through hackathons or collaborations. Longevity Pride is more than a club or a fraternity. It is a philosophy centered around the idea that we can model the human biological processes so well that at some point in time we could develop personalized interventions that are safe and effective.

We are a community of like-minded individuals with strong background in IT or bioinformatics, who embrace the computational approach for extending healthy human longevity. We have a code of conduct, a specially-designed ring. It is not a secret society. But if you see someone with a ring of this design, the person is likely to be very good in bioinformatics and is contributing to aging research.

How would you advise someone interested in working in computational medicine to get involved?

I recommend going to a few conferences on aging and AI. This year I co-organized two innovation forums during the EMBO/Basel Life conference (www.BaselLife.org): 4th Annual Aging Research for Drug Discovery Forum and 1st Artificial Intelligence and BlockChain Technology in Healthcare Forum 11-13 of September 2017.

If you want to get a very long introduction to aging research in the context of effective altruism, a few ideas on how to get involved, Insilico and economics of aging and longevity, here are the slides from a 2-hour presentation I recently gave to a group of IT students:

You have already used your approach for cancer with the OncoFinder study[1-2]. This seems like a radical new way of conducting research, how successful has this method been so far?

The OncoFinder demonstrated excellent results in helping personalized existing treatments for individual patients and improve clinical trials enrollment practices. But for drug discovery, we developed tools like the iPANDA algorithm and its derivatives to track the minute changes between the various signaling states in multiple tissues and identified the molecules that can target these changes. Some of these molecules have been licensed to professional drug developers and some are being validated by the contract research organizations (CROs) for Insilico Medicine.

Can we apply the lessons learned from OncoFinder to the various aging processes to treat age-related diseases for example? After all cancer and aging are closely connected right?

Yes, that was the original idea. We developed a set of highly sensitive differential pathway perturbation analysis algorithms like the OncoFinder and the iPANDA to understand the minute changes between the young healthy state, old state and diseases like cancer. The iPANDA is an excellent tool for the biologically-relevant dimensionality reduction for the training of the deep neural networks.

Aging and cancer are very closely related and cancer is the age-related disease. However, one of the reasons we study cancer is because tissue-specific cancer is a very good model for validating our biomarkers and drug scoring algorithms. Many other diseases are systemic and affect multiple tissues and it is very difficult to perform validation on human tissue.

AI is a very hot topic right now and its potential use in medicine, and of course you are heavily involved in that yourself [3]. Do you think AI could help us to bring aging under comprehensive medical control?

I think that applying AI to aging is the only way to bring it under the comprehensive medical control. Our AI ecosystem is comprised of multiple pipelines. With our drug discovery and biomarker development pipelines we can go after almost every disease and we even have several projects in ALS.

While our proof of concept studies are usually done in cancer, because it is easier to validate the predictions, we go after many disease areas. And since we are considering aging as a form of disease, many of the same algorithms are used to develop biomarkers and drugs to prevent and possibly even restore the age-associated damage.

Our technology also adds credibility to aging research for the pharmaceutical R&D. For example, some of the most significant breakthroughs in modern medicine were made in immuno oncology, where the patient’s’ immune system is used to attack the tumor. Many pharmaceutical companies that run clinical trials cut off enrollment into the clinical trials by age, so older patients will not be eligible.

We have many tools to evaluate the immune fitness of the patient and tools to boost the response rate to the immuno oncology drugs. Understanding aging in this context is extremely important, otherwise many patients will be left behind. According to recent studies, it may take up to 17 years to bring a new treatment from a lab to market, and the price of such an adventure can make around $2 billion.

The main problem with the current pharmaceutical drug development model is not the time from a lab to market, but the lack of ideas resulting in cures and the high failure rate. It costs on average $2.5 billion to develop a drug. This is primarily due to a large number of failures in clinical trials. In oncology, the success rate is ~5% and Phase II is the riskiest area. In many other therapeutic areas, there are no products resulting in complete cures.

The main costs are in clinical trials because of the lack of effective in silico tools and due to the poor translation from animal models to humans. And this is where I disagree with the many other scientists in aging research. If we see 95% failure rate when taking drugs that show both safety and efficacy in mice into humans in oncology and other fields, the probability that some of the completely new drugs developed to address aging in mice, are likely to have a higher failure rate.

To address this we need two things: 1. work primarily with human data for drug and biomarker development and 2. we need a very sensitive and accurate system to perform a cross-species analysis. Therefore, our short term goal is not to necessarily shorten the time but to increase the probability of the molecule passing the clinical trials and resulting in a cure or substantial amelioration of a disease.

Once the regulation of drug approvals adjusts for the advances in AI, it may be possible to significantly accelerate the process, but right now it is important to increase the success rate.

What is your estimate, when we could expect the first powerful treatment to slow down aging appear on the market? By powerful we mean, preventing some age-related disease and extending life by 10 years? What aging process will be addressed first?

I think that there are several very powerful treatments that are already available on the market and to get the extra 10–20 years or even more we just need to devise a way to turn these into therapeutic regimens. I think that a comprehensive regimen involving metformin, targeted rapalogs, senolytics, anti-inflammatory agents, aspirin, NAC, ACE inhibitors, beta-blockers, PDE5, PCSK9 inhibitors, NAD+ activators and precursors in combination with regenerative medicine procedures and also a set of cosmetic and lifestyle interventions could easily add 20 years to our life span. And I am sure that some people are already trying these interventions on themselves.

Unfortunately, nobody is tracking this data. I also hope that some of the interventions will be developed by our team. We apply our drug discovery pipelines to identify the compounds that are much more likely to pass through clinical trials and result in substantial health benefits. We also provide a set of companion biomarkers to ensure that we do not enroll patients, who are not going to respond to therapy.

In terms of addressing the specific aging processes, we are addressing the three low-hanging fruits. We found new mechanisms for clearing out the senescent cells and manipulating a few other cell-states in a very creative way and in a tissue-specific manner. We also found the new tools to go after several types of fibrosis. And finally, we have a few molecules to induce the endogenous repair processes.

Over the past few years, we saw many high-net worth individuals announcing their intent to focus on aging. Google launched Calico, Facebook announced a program to cure all diseases within this century, Peter Thiel is supporting the SENS Foundation and sponsoring blood transfusions from young to old patients. What do you think of this trend?

It is not surprising that the majority of the high net worth individuals supporting longevity research come from IT. In just three decades they transformed our lives beyond recognition. What is surprising is that there is so few of them and that they hire “old school” scientists and business people to run their initiatives instead of actively getting involved. The US government alone spends over $40 billion dollars annually on biomedical research through the NIH, NSF, DOE and other funding bodies, with just the National Institute on Aging spending over $1 billion every year for many years.

While we see many promising results from these government-funded initiatives, the contributions Google, Facebook, Oracle, and others could make if they really focused their efforts and applied their own minds to aging research, could be much greater and more disruptive. Putting slightly more resources in the hands of the scientists, who are doing science for the sake of science is not going to result in any dramatic changes or acceleration.

What we need is Facebook and Google brains working on the problem of aging in a disruptive way. And that is why I think that even within the Google universe, Verily is likely to contribute more to extending productive longevity than Calico. Unfortunately, they are not positioned as an anti-aging company.

As the high net worth individuals (HNWI) go, I really like Jim Mellon’s approach. Before he announced his intention to invest in the longevity business, he personally went on a long road trip visiting dozens of laboratories in the US and Europe and wrote a book called “Juvenescence”, where he described his vision and invited other people to invest. He really took the time and took a deep dive into the industry, technology, and people before making the bets. I think that the other HNWIs should follow Jim’s example each in their unique way. I am not sure about the space race, but a race for longevity among the HNWIs could transform our lives for the better.

Conclusion

We wish to thank Dr. Zhavoronkov for taking the time to do this interview with us and for providing such detailed and interesting answers about the exciting world of A.I. and research.

You may also be interested to learn that Dr. Zhavoronkov and the team he is part of are currently hosting the Mouseage project on lifespan.io, a project that aims to create a photographic biomarker of aging in mice using the power of machine learning. The goal of this project is to help speed up aging research and save the lives of animals. You can make a real difference by donating, helping them to create a valuable research tool and improve the lives of animals sooner. Visit the Mouseage campaign today and show your support.

Literature

[1] Buzdin, A. A., Zhavoronkov, A. A., Korzinkin, M. B., Venkova, L. S., Zenin, A. A., Smirnov, P. Y., & Borisov, N. M. (2014). Oncofinder, a new method for the analysis of intracellular signaling pathway activation using transcriptomic data. Frontiers in genetics, 5, 55.

[2] Artemov, A., Aliper, A., Korzinkin, M., Lezhnina, K., Jellen, L., Zhukov, N., … & Buzdin, A. (2015). A method for predicting target drug efficiency in cancer based on the analysis of signaling pathway activation. Oncotarget, 6(30), 29347.

[3] Aliper, A., Plis, S., Artemov, A., Ulloa, A., Mamoshina, P., & Zhavoronkov, A. (2016). Deep learning applications for predicting pharmacological properties of drugs and drug repurposing using transcriptomic data. Molecular pharmaceutics, 13(7), 2524-2530.

Date Posted: April 15, 2017

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Removing Aging Cells With a New Class of Senolytic Drug

The new research work on senolytic drugs by Baar et al. uses a rationally designed molecule that selectively targets senescent cells in vivo, both in an accelerated aging mouse model, and in normally aged mice as well, with few if any side effects [1]. Senolytics are a new class of potential anti-aging drugs that function by specifically killing senescent cells through apoptosis.

The phenotypic changes seen in non-dividing senescent cells, such as the senescence associated secretory phenotype (SASP), can in turn aberrantly influence nearby cells, leading to chronic inflammation and other changes that are detrimental to an organism [2].

Senescent cells

Senescent cells normally destroy themselves via a programmed process called apoptosis and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of these senescent cells escape this process and build up.

By the time people reach old age, significant numbers of these senescent cells have accumulated in the body, and inflammation and damage to surrounding cells and tissue. These senescent cells are one of the hallmarks of aging and play a central role in the progression of aging [3-4]. Senolytics focus on the destruction of these stubborn “death resistant” cells from the body in order to reduce inflammation and improve tissue function.

It has been demonstrated that senescent cells can be cleared selectively by targeting anti-apoptotic proteins Bcl-2 and Bcl-x, using a number of different inhibitors, leading to improved tissue function in mice [5-8].

A new pathway to trigger apoptosis

The molecule in the Baar et al study instead functions by disrupting the interaction between Foxo4 and p53, leading to p53 mediated apoptosis (cell death). The authors have shown that this interaction with Foxo4 inactivates p53 and is restricted specifically to senescent cells.

This leads to cell cycle arrest and an inhibition of apoptosis. The molecule itself consists of a small peptide of Foxo4, consisting of D-amino acids in a retro-reversed sequence, fused to an HIV- Tat domain. The D-amino acids block proteolysis of the compound while the HIV-Tat domain functions as a cell penetrating peptide, enabling the molecule to transverse plasma membranes.

Conclusion

There are of course many follow up experiments that need to be done. Are there truly no side effects? Can this or a similar drug work well in humans? Also, what are the long-term consequences of clearing senescent cells? It is known that senescent cells do play a positive role in promoting tissue repair [9]. Will stem cell replacement be required for the long-term maintenance of organ function?

All in all, however, this latest work is a truly significant step forward in the development of a feasible senolytic therapy and further validates the hypothesis that the clearance of senescent cells can promote improved organ function.

Literature

[1] Baar MP, et al. “Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.”Cell. 2017 Mar 23;169(1):132-147.e16. [2] Davalos, Albert R. et al. “Senescent Cells as a Source of Inflammatory Factors for Tumor Progression.” Cancer Metastasis Reviews 29.2 (2010): 273–283. PMC. Web. 10 Jun. 2010. [3] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217. [4] van Deursen, J. M. (2014). The role of senescent cells in ageing. Nature, 509(7501), 439-446. [5] Zhu, Yi et al. “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.” Aging Cell 14.4 (2015): 644–658. PMC. Web. 14 Aug. 2015. [6] Chang, Jianhui et al. “Clearance of Senescent Cells by ABT263 Rejuvenates Aged Hematopoietic Stem Cells in Mice.” Nature medicine 22.1 (2016): 78–83. PMC. Web. Jan. 2016. [7] Wang, Yingying et al. “Discovery of Piperlongumine as a Potential Novel Lead for the Development of Senolytic Agents.” Aging (Albany NY) 8.11 (2016): 2915–2926. PMC. Web. 19 Nov. 2016. [8] Zhu, Yi et al. “Identification of a Novel Senolytic Agent, Navitoclax, Targeting the Bcl‐2 Family of Anti‐apoptotic Factors.” Aging Cell 15.3 (2016): 428–435. PMC. Web. Jun. 2016. [9] Lujambio A. To clear or not to clear (senescent cells)? That is the question. BioEssays. 2016;38(suppl 1):S56–64.

Date Posted: April 11, 2017

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Reprogramming Brain Cells Offers Hope for Parkinson’s

Parkinson’s disease is one of the most well known of the neurodegenerative diseases. The symptoms include tremors and loss of motor control, which are caused by the loss of dopamine producing neurons in the brain. In fact, most of us lose these neurons as we age, but to a lesser degree. Parkinson’s sufferers have a genetic vulnerability, and so lose these neurons faster as they are less resistant to the underlying damages aging causes.

The rise of the stem cell field over the last few decades has given researchers hope that the lost dopamine-producing neurons might be replaced. Replacing lost neurons in this manner would potentially allow us to bypass the complexity and myriad factors contributing to their loss.

Therefore finding a way to replace what is lost has become somewhat of a holy grail in the stem cell field. There have been a number of attempts since the 1980s to deliver stem cells to the brain to replace those lost; however, there may be a more practical solution to the problem.

Exciting new approach to replacing lost neurons

This week saw researchers announce a promising new approach to Parkinson’s by the use of cellular reprogramming[1]. The team lead by Ernest Arenas used a cocktail of four transcription factors to reprogram support cells inside the brain. The research team placed the reprogramming factors into a harmless type of lentivirus and injected them en masse into a Parkinson’s disease model mice.

The viruses infected support cells in the brain known as astrocytes (support cells that regulate the transmission of electrical impulses within the brain) which are present in large numbers. The lentiviruses delivered their four-factor payload to the target cells, changing them from astrocytes into dopamine-producing neurons.

Within three weeks, the first cells had been reprogrammed and could be detected, and after fifteen weeks there were abundant numbers of dopamine-producing neurons present.

This is good news indeed, as it also confirms that once reprogrammed the cells remain changed and stable and do not revert back into astrocytes. Excitingly, five weeks after their injections, the mice which previously had an impaired gait due to Parkinson’s, walked normally just like healthy mice do. This suggests that direct in-situ reprogramming of brain cells has the potential to become an effective approach to treating Parkinson’s.

Conclusion

As always in medical research, we should temper our enthusiasm: the road to success is always a long one, with many unexpected turns along the way. Whilst progress is being made and a number of research teams are working on finding the holy grail of stem cell research, it will almost certainly be a number of years if not decades before we see these results translated to humans.

There is much more work to be done, and whilst we should be mindful that research takes time, we should remain hopeful that one day science will beat Parkinson’s.

Literature

[1] di Val Cervo, P. R., Romanov, R. A., Spigolon, G., Masini, D., Martín-Montañez, E., Toledo, E. M., … & Sánchez, S. P. (2017). Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson’s disease model. Nature Biotechnology, 35(5), 444-452.

Date Posted: April 10, 2017

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New Drug to Slow Aging Heading to the Clinic

The biotechnology company PureTech are moving towards human clinical trials with a new therapy that may slow down the aging process and combat age-related disease. The company has licensed two new drug candidates, derivatives of the drug Rapamycin, from pharmaceutical giant Novartis. PureTech have recently announced a joint venture with Novartis called resTORbio and are moving to clinical trials of the new drugs later this year.

The aim of the first test phase is to see if the new drug can rejuvenate the immune system of aged people, a key reason why we lose the ability to resist diseases as we grow older. Novartis already successfully completed two Phase IIa studies, exploring the immune-enhancing potential of mTORC1 inhibitors in elderly patients. resTORbio plans to build on those findings and start a Phase IIb study, with the two licensed candidates later this year.

Excitingly, the firm has also said that it plans to extend the program to other age-related disorders in the future. “mTORC1 inhibitors could lead us to a new paradigm for treating several aging-related conditions,” said Chen Schor, a PureTech senior executive involved in the resTORbio program. “We have a robust clinical development plan for the first indication and plan to explore the program across multiple aging-related diseases.”

PureTech has set aside $15 million to invest in resTORbio, which will give it about a 58% stake in the new venture; it also has the option to invest another $10 million, which would take its holding in resTORbio to 67%. This is a serious amount of money and a sign that things are starting to change in the world of rejuvenation biotechnology.

It’s all about the mTORC1

Rapamycin is a well-known immunosuppressant and is a substance originally discovered in soil bacteria native to Rapa Nui in Easter Island. Rapamycin blocks the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway, which regulates both intracellular and extracellular cell signaling and is a central regulator of nutrient sensing, protein synthesis, cell growth, cell proliferation, and cell survival. When mTORC1 signalling is blocked by rapamycin, it pushes the cells into a survival mode which causes them to live longer.

Rapamycin has been the focus of a number of studies due to its consistent ability to increase lifespan in other species including flies, worms, and rodents. Mice given rapamycin see an average increase of twenty-five percent to their maximum lifespan, which is very impressive indeed.

The key point about rapamycin is that these results are consistent and easy to reproduce, a very important thing in research. Numerous studies have shown rapamycin can influence lifespan and whilst there is currently a study underway in Seattle to see if it extends the lifespan of dogs, there have yet to be any studies in people.

Based on Rapamycin

The new drug is a variant of rapamycin, known as a rapalog, and is sold by Novartis under the brand name Afinitor, though it is more commonly known as Everolimus. The first step for resTORbio will be to use the drug to reverse immunosenescence, or what most people describe as the decline of the immune system.

As we age, the immune system becomes increasingly run down and unable to defend against pathogens, which eventually leads to age-related diseases. The decline of the immune system is a big reason why cancer risk soars from age sixty, for example – because there are fewer and fewer immune cells seeking out and destroying cancer cells.

The first human trials are focused on seeing if this age related decline can be reversed, and appear to include restoring populations of T cells whose levels decline in age.

Joe Bolen the PureTech Health CSO said “Consistent with our strategy of addressing the impairments of the brain, gut, and immune systems, targeting the mTORC1 pathway offers us a compelling opportunity to address conditions impacting these adaptive systems.” He further added “Impairment of adaptive and innate immune system robustness underlies age-associated immunosenescence. Inhibition of the mTORC1 pathway has proven to be effective in re-establishing T-cell composition and function, which in turn can revitalize immune homeostasis.”

The reason why anti-aging drugs are traditionally not developed

Historically, no drugs have been developed to target the aging processes; there are a number of reasons for this. Firstly, it is clinically very difficult to prove efficacy of life-extending drugs in humans, as relatively speaking we live for a very long time; it is easy to conduct tests in mice, rats, worms, and yeast, as they live far shorter lives.

Fortunately, the development of increasingly better biomarkers has started to improve this situation. Reasonable projections can be made for potential lifespan increases based on standard survival curves referenced against biological age. The way to solve this problem is to create comprehensive ways of measuring biological age and a number of companies are engaged in exactly that.

Secondly, the field of life extension has traditionally been viewed with extreme skepticism and was (and still is) haunted by quacks and snake oil salesmen hindering the legitimate researchers. It is hard for most people to tell the difference between a charlatan and a real researcher, so this leads many people to consider the entire field as quackery not to be taken seriously.

Thankfully, this has started to change in recent years, as more and more respected researchers have gotten involved and the results have started mounting up to support the idea. Groups like the SENS Research Foundation have existed for over a decade and have been advocating a repair approach to aging, and whilst it has been a slow uphill battle to change perceptions about aging, the tide is starting to turn in the face of ever more promising research.

Thirdly, current regulations mean aging cannot just be generally targeted, as it has various processes and none of them are officially accepted as a disease even though they lead to age-related pathology. This is the biggest problemm and whilst pressure to classify aging as a disease has increased in recent years, it will be some time before such things are potentially accepted. Solving this will be a long and hard slog to convince regulatory authorities combined with mountains of scientific evidence to support it.

Until then, companies are opting to get age-related therapies through the regulatory gauntlet by targeting the aging mechanisms but stating a particular disease condition. This is why resTORbio will focus on immunosenescence, as it is a well-documented phenomenon which can be easily measured to determine efficacy, and can be related to specific diseases.

Conclusion

Until the idea of preventative repair strategies directly targeting the aging processes becomes mainstream, companies will have to continue jumping through regulatory hoops in order to get these new drugs and therapies into practice.

Part of changing established ideas and creating that shift in paradigm is supporting fundamental and breakthrough research through grassroots fundraising. The more scientific evidence to support a repair approach to aging diseases, the sooner established ideas will change.

This is the power of a grassroots movement and what we do now could have huge impact in the years to come. We are hoping to play our part in this at LEAF using the Lifespan.io platform to fundraise for science and taking part in activism and education.

In closing, we are very pleased to hear the news that yet another large, well-funded company is getting involved in the science of longevity, and we can only hope that this encourages others to do the same.

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The Blog

Building a Future Free of Age-Related Disease

First, let’s make it clear what we mean by life extension advocacy

Goals of life extension advocacy

An analysis of the field

A few examples of the time investment needed to prepare different advocacy materials

Presenting the cause and networking

Internal activities

Conclusion

Literature

Homing in on cancer

Building on previous research

Cellular reprogramming

Moving to clinical trials

Conclusion

What is peripheral nerve injury?

Macrophages to the rescue

Conclusion

Literature

So what are proteins?

Undruggable proteins

Introducing AdPROM

Conclusion

Literature

Malta was the first to recognise aging as an international problem

Malta becomes the UN International Institute on Ageing

A problem with accuracy

Conclusion

Literature

Exciting new approach to replacing lost neurons

Conclusion

Literature

It’s all about the mTORC1

Based on Rapamycin

The reason why anti-aging drugs are traditionally not developed

Conclusion

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