Rejuvenation Roundup September 2018

Date Posted: October 1, 2018

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Happy autumn—or spring, if you live in the southern hemisphere! Be as it may, in a post-aging world, the season of your health would always be summer; let’s see how much closer we got to that world during last September.

LEAF News

To get things started, the new episode of the Rejuvenation Roundup podcast is available today.

Highlight: The NAD+ Mouse Project on lifespan.io

On September 18, we launched the NMN Mouse Project—a crowdfunding campaign to finance a mouse study by the Sinclair lab at Harvard University. The study involves testing the NAD+ precursor NMN on normally aged mice and accelerated-aging mice in order to confirm the anti-aging benefits that were previously demonstrated in smaller-scale studies by the same laboratory; this could take us one step closer to human clinical trials for NMN as a therapy against aging.

Thus far, the campaign has been a smashing success; much to our astonishment, 50% of the campaign goal was reached within the first 48 hours, collecting over $15,000 out of $30,000! We are extremely thankful to all donors for their prompt reaction, and a special shout-out goes to David Chambers and James Johnson, whose very generous contributions pushed the meter through the roof!

Having crossed the 10K threshold, the double matching fund by two kind, anonymous donors has been unlocked; this brought in an additional $20,000, making the NAD+ Mouse Project our first campaign to achieve success within a few days of its launch! We take this as a sign that the tide is turning and that awareness of the aging problem, as well as the potential to solve it within a relatively short time frame, is rising.

The collected funds currently stand at nearly $40,000, pushing the stretch goal of $45,000. Stretch goals will allow the Sinclair team to perform a longer, more thorough study—so more donations are absolutely welcome, even though the main goal has already been reached.

Once again, we thank everyone helping us build a world free of age-related diseases—be it through donations, volunteering, raising awareness, or any other way. You’re true heroes!

Team and activities

Lifespan-X event in Leiden. As you might remember, in the last roundup, we mentioned that an independently organized event in support of lifespan.io—a Lifespan-X event—was going to be held in September in the Netherlands. Indeed, the talk “A Cure for Aging: Where Do We Stand Today?” took place on September 29 in Leiden, held by philosopher and bioethicist Tatjana Kochetkova; we should have a report about the event soon, so keep an eye on the blog.

Out for a coffee with Death. On September 21, our Outreach Director Elena Milova attended an unusual event: Death Cafe. Death Cafe is a place where people are encouraged to discuss everything related to death over a cup of coffee with cake. Started by sociologists and people dealing with the terminally ill, this initiative has rapidly spread around the globe: more than 7000 meetings were held since 2011. After listening to people’s stories and telling her own story of joining the movement for healthy life extension, Elena believes that there is a potential for synergy: people attending Death Cafe seem much more receptive to the idea of ending aging by medical means. You can read more in Elena’s recent article about her visit.

lifespan.io conference. Last month, we have published another video from our conference held in New York City last July; the video is a talk from Dr. Stephen Hilbert from Oisìn Biotechnologies, discussing the company’s SENSOlytic technology for senescent cell ablation and cancer treatment. You can watch it on our YouTube channel as well as on our conference page.

lifespan.io campaign updates

We’ve received some updates from the team leaders of three of our previous campaign—the historical MitoSENS campaign, which marked the launch of our crowdfunding platform; the MMTP campaign, our first project on senolytics; and the CellAge campaign, our fourth campaign and our second one focused on senescent cell clearance technology.

The MitoSENS researchers report that they’ve improved upon their allotopic expression technique for mitochondrial genes, allowing the expression of more genes—in the paper that resulted from the study funded on lifespan.io, only two mitochondrial genes could be successfully expressed allotopically; also, the original MitoSENS campaign is soon to going have a baby sister! Make sure to keep an eye on lifespan.io in the coming months. If you want to know more on MitoSENS, check out this podcast interview of the head of MitoSENS, Dr. Matthew O’Connor, by LongeCity.

The researchers at CellAge let us know that they’ve began looking for new senescent cell promoters together with Circularis; being able to identify these promoters might lead to better detection techniques to seek and destroy senescent cells, which is what CellAge is after.

Good luck to the three teams! We look forward to hearing from them again.

Advocacy on LEAF

Paywall: The Business of Scholarship. LEAF doesn’t advocate only for rejuvenation biotechnologies, we also advocate open science—a crucial factor that, if lacking, might seriously slow down research in general and aging research in particular. Most of the world’s research papers are currently behind paywalls; that is, if you want access to the papers, you need to pay, and quite a pretty penny at that, despite the fact that technically, as a taxpayer, you’ve already paid for the research and it would be only logical to expect that you have free access to it. This huge problem has been brought to public attention by initiatives such as Sci-Hub, which allows people to circumvent paywalls and grants access to innumerable otherwise locked-up papers, and the documentary Paywall: The Business of Scholarship—a freely available movie that discusses how this huge business endangers science and the diffusion of knowledge. LEAF has had the privilege to contribute original footage to this movie as well as to produce a Russian version of it. The documentary premiered on September 5th, and it will be screened in several countries in the coming months.

The Status Quo of Aging. One of the biggest challenges faced by rejuvenation biotechnologies is that they question the status quo, the very way we’ve been going about life since pretty much day one. This conservatism is going to be hard to eradicate, but the reward will be well worth all the effort.

lifespan.io interviews

We had a number of great interviews last month, starting with Methuselah Foundation‘s founder, David Gobel. On the off chance the name don’t ring a bell, Methuselah Foundation is a charity that has been funding and advocating for rejuvenation biotechnology research since the early 2000s; Dave’s interview was a long, thorough, and insightful one on the state and progress of rejuvenation research, speculative timeframes for research translation, the story of the foundation, and more—it’s well worth a read!

Michael Bonkowski, a member of Dr. David Sinclair’s NAD+ Mouse Project team, also kindly granted us an interview in which he delved into the details of NAD+ biology, the study to be funded through our current campaign, the innovative ICE mouse model that the team has engineered, and more. Be sure to check it out, and maybe consider heading over to the campaign page to help us reach the next goal, if you haven’t done so already!

Research roundup

Stem cells

As we age, our reservoir of stem cells depletes; this phenomenon, known as stem cell exhaustion, is one of the reasons we age. While losing stem cells is really bad news for your health, as it can lead to a variety of age-related ailments, the good news is that the field of stem cell research is one of the most advanced and well-funded. For example, a human clinical trial of induced pluripotent stem cells (iPSCs) to treat heart disease will begin next year in Japan; it follows a similar clinical application against macular degeneration, which also took place in Japan.

Addressing the stem cell exhaustion hallmark will also be necessary for the sake of brain health, as neural stem cell activity declines with age; interestingly, a recent study discussed on FA! found out that enhancing lysosomal activity improves neural stem cell function, which once again hints at how aging is basically an intricate web woven by the interaction of several phenomena (lysosomal dysfunction being another one). Stem cells are also crucial to the immune system; indeed, innate immune cells are also generated by hematopoietic stem cells as part of the hematopoiesis process. If you’re curious about this, this article on Fight Aging! might be interesting.

Cellular senescence

A recently published review discussed cellular senescence and senolytics, covering topics such as methods to target clear unwanted senescent cells as well as the senescence-associated secretory phenotype (SASP) and its implications for human cancer. Especially if you are new to the subject and would like to learn more, this paper might interest you.

Like most hallmarks of aging, cellular senescence is involved in a wide range of pathologies, and for this reason, researchers all over the world are studying the best methods to identify and eliminate senescent cells; an entire association—the International Cell Senescence Association (ICSA)—exists for that very purpose, and it has recently held a meeting, which you can read about here. A broader view of the field of senotherapeutics, which encompasses all strategies to reduce the senescent cell burden, can be found in a paper briefly discussed here.

Other

Gene therapy without autoimmunity. It might be not immediately clear that gene therapy is accompanied by an autoimmune reaction; but it is to be expected, because adding or modifying genes means that a different protein begins to be produced by your body—one that your immune system has never seen before, which is enough for the protein to be blacklisted and attacked. However, Stanford scientists may recently have figured out a way to have the cake and eat it too—as we reported here, they were able to administer gene therapy to mice without triggering an autoimmune reaction.

A discussion of AGEs. Advanced glycation end-products, or AGEs, are really nasty chemicals—they are thought to be responsible for the stiffening of our tissues, most notably arteries, as well as one of the drivers of age-related chronic inflammation. AGEs are part of the loss of proteostasis hallmark, as they are essentially glycated proteins that the body can’t break down. Recently, the Buck Institute for Research on Aging published an article on the inflammatory nature of AGEs; you might like to take a look at it as well as Reason’s thoughts on the subject.

Introduction to mitochondrial dysfunction on LEAF. Mitochondrial dysfunction is one of the nine hallmarks of aging; as we get older, free radicals produced by the mitochondria themselves end up harming mitochondrial DNA. You can learn more about how this happens and how we might go about fixing it by reading our recent article on the matter.

News Nuggets

M Fund closes funding round successfully. Methuselah Foundation’s venture fund, Methuselah Funds, LLC (M Fund) successfully completed an initial funding round, as reported by the official press release. M Fund, an accelerator program for rejuvenation biotech startups, includes a number of promising companies in its portfolio, such as Leucadia and Oisín.

Covalent Bioscience expands patent portfolio. Two patents by Covalent Bioscience, a company working on catalytic antibodies against different amyloid proteins and even HIV, have recently been approved in both the US and Europe. The company has recently been networking with angel investors and participating in several anti-aging conferences—including LEAF’s Ending Age-Related Diseases.

A strong positive correlation between life expectancy and productivity. According to a recent study published by the International Longevity Centre in the UK, greater life expectancy is correlated with greater economic productivity. This suggests that the advent of rejuvenation biotechnology to undo the damage of aging may actually bring economic benefits, rather than exacerbate existing crises as some people fear.

Role models vastly more likely to be older people. By employing a very large dataset of more than 1.5 million questionnaires, Northwestern University scientists managed to identify four distinct personality types—average, reserved, self-centered, and role model. The four types are based on five widely accepted personality traits, namely neuroticism, extraversion, openness, agreeableness, and conscientiousness. Particularly, the role model personality type, which scores low in neuroticism and high in all the other traits, is typical of dependable and open-minded people. Data analysis shows that the likelihood of someone being a role model increases dramatically with age. This suggests that concerns that rejuvenation biotechnology might lead to a conservative, gerontocratic society may well be unjustified.

Life extension on Forbes Africa. The science and possibility of life extension was recently presented in a positive light by Forbes Africa writer Ancillar Mangena, who correctly acknowledges the benefits that would be derived from defeating aging and extending our healthy, productive lives. The article features the opinion of several experts, such as Dr. Susan Coetzer, Dr. Aubrey de Grey, and LEAF Vice President Dr. Oliver Medvedik.

Coming up in October

Longevity Day. On October 1st, the world celebrates the International Day of Older Persons, an occasion to draw attention to the elderly and their needs. Our community likes to think of this as a Longevity Day and makes it an occasion to bring attention to, and discuss, rejuvenation biotechnology as the most effective means to address old people’s health needs. What better occasion could there be to talk about rejuvenation than the International Day of Older Persons?

Longevity Film Competition. On October 1st, the results of the Longevity Film Competition will be announced. This contest is organized by the SENS Research Foundation, HEALES and ILA in order to stimulate talented activists to produce more educational videos to spread the word and address the typical public concerns related to healthy longevity.

The international school “Mechanisms of Aging and Age-Related Diseases” is taking place at the Moscow Institute of Physics and Technology from September 30 to October 3, and it features a number of leading researchers, such as Claudio Franceschi and Vladimir Anisimov.

ISOAD conference on aging. On October 5-8, ISOAD is hosting the 3rd International Conference of Aging and Disease (2018 ICAD), which will be held at Le Saint Paul Hôtel, Nice, France. We want to congratulate Dr. Ilia Stambler, who was crucial in organizing this conference, on building a wonderful program featuring a number of renowned researchers of aging and advocates of life extension.

MediaForum “All Russia 2018”. On October 6-12, our own Elena Milova is attending MediaForum “All Russia 2018”, which has been organized by the Union of the Journalists of Russia in Sochi, and she will chair Longevity Journalism, a discussion aimed at educating mass media representatives from many regions of Russia about the development and implementation of rejuvenation technologies.

Imagine Science Film Festival. New York City will be hosting the forthcoming Imagine Science Film Festival on October 12-19, an occasion where filmmaking meets science. lifespan.io is proud to be an official sponsor of this year’s event, whose theme—survival—is very much related to our work. If you happen to be in New York at the time, you can get your ticket here, and as one of our readers, you are entitled to a 25% discount—just use the code ISFF11LIFESPAN for all events at the festival, except those at the Rubin Museum and the Margaret Mead Festival.

Awareness campaign in Israel, Cyprus, and Pakistan. An awareness campaign for healthy longevity has been organized by Dr. Ilia Stambler of the Israeli Longevity Alliance, and it will take place throughout next month in Israel. A similar event will be held by the Pakistan Aging Research Society and the National Academy of Young Scientists in Pakistan, and the Rotary Club of Larnaca will also host an event to celebrate Longevity Day; however, it will be held on October 2 at the Sun Hall Hotel at 8 PM and will feature a lecture by geriatrician Dr. Kyriacos Adamou.

Ask LEAF Anything. To celebrate Longevity Month, we will have a special, livestreamed “Ask LEAF Anything” event on October 16 from 12:30 to 2:00 PM ET. We will be answering the questions that our followers ask most often, as well as any that you might ask live in the stream comments! Be sure to save the date!

A screening of Paywall: The Business of Scholarship will take place at the United Nations Headquarters, New York City, on October 22, 2018 as part of International Open Access Week. LEAF contributed a piece of original footage with Sci-Hub creator Alexandra Elbakyan to this documentary, and we are happy to see multiple screenings to be held around the globe. Viva Open Science!

Given that September was such a great month for the world of rejuvenation, we hope that it may be an indication of what we can expect the rest of the autumn to be like. There is much to look forward to in the next coming months, as we slowly but steadily move closer and closer to a world where aging was only a long, bad dream.

Date Posted: October 1, 2018

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The Winners of the Longevity Film Competition

As you probably remember, a few months ago, we wrote about the Longevity Film Competition—an initiative by the Healthy Life Extension Society, the SENS Research Foundation, and the International Longevity Alliance. The promoters of the competition invited filmmakers everywhere to produce short films advocating for healthy life extension, with a focus on dispelling four usual misconceptions and concerns around the concept of life extension: the false dichotomy between aging and age-related diseases, the Tithonus error, the appeal to nature fallacy, and the fear of inequality of access to rejuvenation biotechnologies.

The competition is now over; the deadline for submissions was September 15, and fittingly, the winners have been announced today, October 1, in occasion of Longevity Day. “I want to say that this was a big challenge,” commented LEAF Outreach Director Elena Milova, who served as a judge of the competition. “The creators have used very different techniques and tools, which made most of the videos in the shortlist very hard to compare. Each video has its own advantages, and I can’t help but congratulate every team on their personal success in delivering the message! This year’s shortlist is a wonderful collection of perfectly unique stories.”

The three winners

The winner of the first prize of the Longevity Film Competition is the film “The End of Aging” by Adam Ford. Running almost 20 minutes long, this film goes into great detail about the challenge presented by aging, the benefits that would come from its defeat, and the biotechnologies that might be developed for this purpose; it also discusses several concerns traditionally related to healthy life extension.

The second place was won by the movie “8 Years On” by Tim Maupin, who also won the first prize (ex aequo) of the Longevity Film Competition 2015. Short and to the point, this film talks about how present-day medical science saved Tim’s elderly father from a stroke in 2011, making a very convincing case that it also counts as life extension and that there is no reason why more advanced life extension technologies shouldn’t be developed.

The third place winner was “Undoing Aging”, which presented the idea of rejuvenation and answered common concerns in a humorous way and with an unexpected twist.

Congratulations to all the winners and participants for their advocacy efforts as well as to the organizers of this competition for the success that their initiative has had and will hopefully continue to have in years to come.

Date Posted: September 28, 2018

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Death Cafes and Life Extension: The Possibility of Synergy

Even with an increasing number of articles about aging and rejuvenation technologies in mass media, the general public’s lack of information remains a problem. Pro-longevity organizations try to spread useful information; however, it’s clear that this information is, quite often, only delivered to current members of the community instead of to a new audience. My work at LEAF is partially focused on finding ways to break this border and explore new social territories as often as possible. Last week, this journey brought me to a meeting with a title that speaks for itself: Death Cafe.

What is Death Cafe?

A Death Cafe is not a place. It is a meeting at which people are encouraged to discuss everything related to death over a cup of tea. The official mission of this community is defined as follows: “Our objective is to increase awareness of death with a view to helping people make the most of their (finite) lives.” It is not a form of group therapy, not a support group or a survivors’ group (though only the living can attend…); rather, it’s just a space where people can talk to each other about a topic that is usually excluded from public dialogue.

Jon Underwood and Sue Barsky Reid had the idea to create such a space and were inspired by the work of sociologist and thanatologist Bernard Crettaz. Jon was fascinated by Bernard’s custom of meeting with people in a cafe to talk about death. Jon and Sue formed Death Cafe as a social franchise, allowing anyone who shares their views and agrees with the founding principles of the group to run his or her own Death Cafe anywhere in the world. Despite Jon’s sudden death in 2017 at the age of 44, the initiative survived and keeps developing; as of now, more than seven thousand meetings were held since 2011 in at least 60 countries. This number makes me wonder how many meetings were held by life extensionists in the same period, but that is a question for later.

It turns out that Death Cafes were started in Russia in 2016 by Katerina Pechurichko, an expert in oncopsychology. After she hosted a few meetings in Voronezh and Moscow, the group attracted the attention of mass media, and this is how I knew that one of the Cafes would be taking place in a nearby library.

To be honest, it was not an easy decision to go there. As you may know, the reason why I joined the movement in 2011 was the tragic death of my mother from cancer. In the same period, I have also lost both grannies, which, apart from grief, caused me to think quite a bit about life and death. These events significantly upgraded my system of values and my social environment, which now consists of absolutely amazing people, death has never ceased to be a painful topic, and my fear of death was never quelled.

However, the duty of a life extension advocate (in this case, more of a scout) outweighed personal matters, so I grabbed some books on aging, just in case, and jumped in.

Discussing death… and life.

There were around 50 people in the room. I took a strategic place near the teapot and napkins and next to the moderator, PolyTech Museum’s librarian, Galina Nagoryanskaya. After a brief welcome speech and an explanation of what the Cafe is, the action began. Galina asked the first question, and, after that, the discussion didn’t stop for three hours.

The question was “What is your ideal death?” While the room went silent, I decided to introduce the topic that I wanted to talk about: the undesirability of death. So, I raised my hand and said that my ideal death is to have my body put in liquid nitrogen and kept there until medical technologies have progressed enough to allow my return to life; looking at how fast they develop, I think that this scenario is highly possible.

It started a very intense discussion of why, how, when and if we should or not get rid of death. People were initially describing their “ideal” deaths but then jumping back to either admitting they would like to avoid it or ardently being defensive. What I particularly liked was when one of the participants introduced the idea that each person is unique, so, when each person dies, it leaves a hole in the body of human culture, and this loss is as finite as the person is irreplaceable. I feel very much the same way, and my sadness is especially sharp when it is a notable person dying. However, I didn’t expect the same view to come from someone who seems to have a very different worldview in general. It made me think that maybe we humans have much more in common than we believe when just looking at each other.

At some point, I introduced the possibility of developing therapies that address the mechanisms of aging and might be able to cure age-related diseases, extend healthy life, and maybe even restore youth. After I mentioned that some of these therapies show quite interesting results in animals and are now being tested in human clinical trials, the discussion turned into an interrogation: people were asking me to tell them more. I kept my answers reasonably brief in order to respect people who wanted to talk about other things. However, the final part of the event was focused almost completely on the individual and social consequences of ending aging, even though I was not steering the conversation. The list of concerns, as you can imagine, was exactly the same as usual.

At the very end, I thanked everyone for their thoughts and stories, and I offered the books on aging prevention that I brought with me. The pile of 20 items was gone in a few minutes. After the official closure, we chatted a little bit more before we said goodbye.

Of course, not all 50 people in the room were involved; most of the exchange happened between me and maybe 15 other people. What surprised me is that step by step, with every new round of discussion, the group was picturing a future in which preventable death from aging and age-related diseases might be eradicated — and that it might be a good thing.

Should we attend Death Cafes to introduce rejuvenation technologies?

I see a potential for synergy with Death Cafes, as they are spaces where it is allowed and even welcomed to talk about death. It is okay to see death from all sorts of causes, including aging, as a problem, even as a problem that can be solved. People who come to these meetings seem to be more open to the idea of possible life extension than the general public. One reason is probably that many of them see death as a scary and negative thing (even if they will not admit it), so they are keen to explore other options. They give us an opportunity to speak freely, and in return, we offer them a new option to consider.

I would say that if a Death Cafe is held in your city, it makes sense to go. At the very least, it will be an evening full of revelations. However, you should understand that this space is not meant to be an advocacy playground. The only acceptable way to introduce the topic is to tell your personal story and share your genuine perception and emotions. I know that this might be difficult, and as a long-term outreach activist, I know why. Still, it is worth doing.

Consider that once you have seeded the idea that aging is amenable to intervention, it can affect many people’s future decisions. It may be that these people will be able to use rejuvenation technologies and have amazingly long lives because, on a grey and rainy day, they had met you at a Death Cafe.

Date Posted: September 25, 2018

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NAD+ and Aging With Mike Bonkowski

Today, we have an interview with Dr. Michael Bonkowski, an expert on NAD+ biology and aging from the David Sinclair Lab, Harvard Medical School.

Michael Bonkowski aims to advance our understanding of the links between metabolism, aging, and age-associated diseases. He has published 35 peer-reviewed journal articles and has conducted multiple successful longevity studies. In Dr. David Sinclair’s lab, his research efforts are focused on the role of nutrient sensors’ regulation of endocrine signaling and aging in the mouse. He is also working on direct and indirect ways to drive the activity of these nutrient sensors by using dietary manipulations, small molecules, and chemical treatments.

Michael is trained as a pharmacologist, physiologist, and animal scientist. Some of his areas of expertise include animal physiology, genetics, glucose, and insulin homeostasis, metabolism, assay development, protein biochemistry, and transmission electron microscopy imaging.

As we are currently hosting the NAD+ Mouse Project on lifespan.io, which includes Michael on the research team, now is an ideal time to talk to him about his work and why the project is important for aging research.

For those new to the topic, can you tell us what NAD+ is?

NAD+ is a bioactive metabolite. It is well known for its role as a high-energy hydride carrier between glucose and mitochondria. It is involved in over 500 enzymatic and biochemical reactions, with multiple research groups reporting an age-related decline. NAD+ is also studied for its role in the body as a resistance sensor against diseases of aging.

Some people simplify the role of NAD+ in metabolism as just being part of nutrient sensing and often see it as only being a caloric restriction mimetic. NAD+ has a lot more roles in metabolism than this; could you tell us what some of them are?

NAD+ is most well-known for its role in redox metabolism, as a cosubstrate for enzymatic reactions and as a downstream metabolite of Vitamin B3 (a.k.a. niacin or nicotinic acid). Its levels do go up during calorie restriction and exercise, which are currently the best-known interventions for slowing aging.

More information can be learned by looking at these reviews by our group and others: Canto et al. 2015, PMID: 26118927; Verdin, 2015 PMID 29031725; Bonkowski & Sinclair 2016, PMID 27552971; Rajman et al. 2018, PMID 29514064.

There are a number of what we call NAD+ precursors, including NR, niacin, and NMN. Can you explain how they are different from each other and what makes NMN potentially the most interesting in regards to NAD+ repletion?

There are many metabolic routes by which NAD+ is produced. The body can make it de novo from tryptophan or from external vitamins, such as niacin or NR. Most importantly, free nicotinamide in our cells, the product of NAD+ hydrolysis, can be remade into NAD+ through the salvage pathway. In this pathway, NMN is the direct precursor to NAD+ – just one enzymatic step away. In our lab, we found that giving NMN exogenously can raise NAD+ in most of the tissues that we have tested (liver, muscle, kidney, immune cells, and blood).

Why use precursors; why not just introduce NAD+ into the bloodstream for the cells to uptake?

We find that administering NMN can significantly increase cellular and tissue pools of NAD+.

NAD+ is known to facilitate DNA repair by preventing PARP1 and DBC1 binding; can you explain a little bit more about how this happens?

Our lab was the first to show that NAD+ is involved in mediating protein-protein interactions between DBC1 and PARP1. With age-associated declines in NAD+, we find that DBC1 is bound to and inhibits PARP1. Increasing NAD+ levels through exogenous NMN supplementation decreases this interaction and restores PARP1 activity and DNA repair (Li, Bonkowski & Sinclair et al. 2017, PMID:28336669).

Does NAD+ also influence mitochondrial DNA (mtDNA) repair by this same PARP1/DBC1 mechanism?

We have shown that NAD+ in mitochondria is important for cell survival. While PARP1 is present in the mitochondria, we have not found evidence that DBC1 is present in the mitochondria.

Has anyone looked at how NAD+ repletion affects mitochondria; does it help to improve their function and/or reverse aberrant age-related dysfunction?

Many groups have looked at the effects of NAD+ repletion on mitochondria function and biogenesis. These studies have reported that administering NAD+ boosting compounds increases mitochondrial NAD+ altering activity and biogenesis (reviewed in Canto et al. 2015, PMID: 26118927). Work from our lab has found that with the age-associated waning of NAD+ levels, there is miscommunication between the nucleus and mitochondria. We also found that supplementing NMN to raise NAD+ could restore this communication breakdown, leading to a youthful phenotype (Gomes & Sinclair et al. 2013 PMID: 24360282).

NAD+ and SIRT1 were shown to mediate crosstalk with muscle tissue and blood vessels earlier this year. Could we potentially boost NAD+ levels to combat age-related frailty and sarcopenia?

We are very excited about this study. We found that advanced aged mice received a benefit in muscle vascularization and running endurance from consuming NMN in their drinking water. NAD+ may or may not have a role for other muscle pathologies, such as sarcopenia.

What types of mice are you using in the experiment?

For our advanced age longevity, behavior and cognition experiments, we are using the C57BL/6 mouse line, which is used frequently in the aging field. We chose to start treating these mice at an advanced age (20 months = ~50 in human years) to circumvent developmental issues associated with using transgenic or knockout mouse lines. In addition, we will use our progeroid mouse model for cognitive and behavioral testing to accelerate results.

So, you are using both normal mice and a progeric mouse that experiences “accelerated aging”. How is your progeric model different to the progeric mouse strains already available, or how is it a closer analog to regular aging?

Our progeroid model is an accelerated aging model driven by induced changes to the epigenome (ICE). This model has many changes similar to human aging, and we will use these mice to address certain behavioral or physiological questions to accelerate data collection.

Some people criticize the use of progeric mice as not really representing normal aging; how do the modified mice you are using address some of those concerns?

The ICE mouse is a novel and, we believe, an accurate model of aging that is based on accelerating an underlying cause of aging.

You are conducting a lifespan study with normally aging mice, which is a world first for NMN, but does NAD+ work the same way in mouse cells as it does in human cells?

While there are indeed many differences between mice and humans. NAD+ is a common metabolite across all of life, and at the biochemical level, its functions are similar between species.

Conducting a lifespan study is difficult with all kinds of potential confounding factors that could affect the data, such as diet, environment, and so on. What are the biggest challenges for you and your team conducting a lifespan study?

We have conducted multiple longevity studies in mice and have experience in conducting these types of experiments. We house mice in a completely controlled environment and put a lot of thought into the design of the studies to reduce the confounding factors to an absolute minimum. We have already started a pilot study that is in progress and seeks funds to execute and complete the comprehensive experiments.

How large is your lifespan mouse cohort, and how did you determine that these amounts would be statistically sound and avoid the statistical “noise” some studies fall foul of?

We plan to use approximately 40 mice per group. Based on our statistical power analysis, with this N value, we are powered to detect small differences in average and maximal lifespan. In addition, we will conduct behavioral and cognitive tests.

Given that NMN is already in human trials, what could this experiment on lifespan.io add to our knowledge of NAD+ and aging?

There are phase 1 studies underway at Metrobiotech, and David Sinclair is one of the founders of this company. If we wish to know if NMN has a longevity benefit and improves many age-related diseases, we can have that answer using this mouse study in less than two years. Currently, there are no human trials in the U.S. looking at aging or longevity in response to dietary NAD+ supplementation.

Regarding the NAD+ Mouse Project on lifespan.io, why does the lab need to do this when it is part of a prestigious University?

Conducting research is very costly. We rely on grants and donations just like the majority of University labs. We are performing comprehensive tests and appreciate any monetary contribution allowing us to complete this important study.

Will the data be open access?

We would aim to pre-publish in biorxiv then publish in a peer-reviewed journal following that. The pre-published data would be open access which anyone can read though it will not have gone through the peer review process at this point.

We would like to thank Michael for taking the time to speak with us about his work and if you would like to learn more about the NAD+ Mouse Project check out their project page over at lifespan.io.

Date Posted: September 14, 2018

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The Status Quo of Aging

One of the reasons why the idea of rejuvenating people isn’t all that easy to sell is that it challenges the status quo. For good or bad, we’re used to the fact that our health goes south on us as time goes by, ultimately killing us if nothing else does.

That’s not a nice certainty to have, but our species is one of planners; we tend to prefer bad certainties to uncertainty. For example, some people want to be certain that, at some point, they won’t be fit for work anymore and will need to retire; they prefer this over the uncertainty of not knowing how they’d make a living at age 150.

That’s not the only reason. Radical change requires radical rethinking of anything affected by the change itself; as rejuvenation would affect our social contracts, the job market, future planning, our idea of life milestones, of family, what it means to be old, and many other things, it would take a lot of rethinking—which is something humanity generally does only grudgingly and on its own sweet time.

Think about it: “Granny” is more likely to make you think of a sweet, gray-haired lady with large glasses on her nose baking a cake than of an attractive girl out one late night with friends; similarly, “grandpa” will more likely evoke the image of a friendly bald man in an old-fashioned waistcoat sitting down on an armchair reading the paper than of a good-looking college freshman with curly brown hair.

Yet, in a world in which comprehensive rejuvenation is common, the granny and grandpa that inhabit our collective imagination would simply not exist; rather, you’d find that grannies and grandpas in their late 80s can’t be told apart from people in their 20s; elderly would look just as young as “truly young” people, would be just as healthy, and would be engaged in the activities they prefer rather than having their activities limited by their declining health. To some people, though hopefully not many, this picture of grandma and grandpa is almost sacrilegious; they are supposed to look old, do things old people do, and have enough serious ailments that looking after their grandchildren is the most they can aspire to.

Similarly, “family” is a term used to indicate a rather fleeting human social structure, with parents, children and grandparents that all grow old and die; in a few decades, every family is totally eradicated, even though new families may have originated from pre-existing ones. To be fair, families are unlikely to last “forever” even if aging is taken out of the equation; once the children are grown up, they are likely to go their own ways and no longer live with their parents, however biologically young or old their parents may be. However, in a post-aging world, families could last “forever”, at least in principle.

Currently, there comes a point when, if you want to go and see your dad, you need to go to the cemetery; in a world with rejuvenation, you’d only need to go to his place. Maybe he and your mother still live together, or maybe they decided to split, move away, and start new families and new careers; the point is that as long as the members of your family are alive, you have the option of catching up. You may no longer all live together, but you can keep in touch and maintain your family in some form, if you so wish. Right now, aging forces all families into extinction, whether they like it or not; in a world without aging, how long our families last would be in our hands.

These are only two examples out of many more new situations that we, having grown up in a world plagued by aging, would have to get used to; newer generations born in a post-aging world would hardly have any problem with it and would probably end up wondering how anyone could possibly have opposed it in the past. Examples like this are different from concerns such as overpopulation in that they don’t represent a potential but tangible issue that might arise as a consequence of rejuvenation; people may have problems with biologically young elderly people and with a new “version” of families simply because they’re new and unfamiliar ideas, not because they pose any actual problem.

For example, women entering the workforce, rather than just looking after the kids and the house, wasn’t really going to cause any huge problem or pose insurmountable difficulties; actually, it yielded global benefits, yet it took a while before the idea that women belonged in the kitchen was finally abandoned entirely and the new paradigm was accepted. The fact is that our society was long used to thinking that there were jobs for men (the vast majority) and jobs for women (the minority); that was the idea that virtually everyone grew up with, and abandoning it in favor of a new model required dealing with a new and unfamiliar idea; it required questioning the current state of things, discarding long-held beliefs, and working on a (slightly) different way for society to function—all of which was far more difficult, and hence much less appealing, than simply dismissing the possibility that women could be in the workforce and sticking to the status quo.

The same can be said of concerns about how rejuvenation may change our traditional ideas of old age or of family; the new ideas of them that it would bring about are actually better than the old ones, but abandoning the old way of thinking and embracing the new one can be a challenge in and of itself—one that is well worth rising to nonetheless.

Date Posted: September 12, 2018

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Paywall: The Business of Scholarship Documentary in English and Russian

Today, we want to let you know that the documentary Paywall: The Business of Scholarship is now available in both English and Russian. This is a documentary exploring the crisis in scientific journal publication and the excessive fees that some publishers charge to access knowledge.

Holding scientific knowledge to ransom

Around 70% of scientific publications are hidden behind paywalls, restricting access to knowledge and holding back progress. We believe that this is unfair and that putting profit before the health of others is unacceptable, and this is one reason why we support the concept of open science here at LEAF.

We believe that the paywalling of scientific knowledge is a disgrace, especially when it means that doctors, patients, and carers cannot access important health information because the cost of access is extortionate. It also has implications for students of scientific fields who need access to these papers in order to learn and complete their studies, and it puts budding scientists who cannot afford these costs at a disadvantage.

We applaud the work of people fighting for Open Science, such as Alexandra Elbakyan, the creator of Sci-Hub, a website devoted to providing scientists, students, and researchers with free access to scientific publications that would otherwise be locked behind paywalls.

Paywall: The Business of Scholarship

We also appreciate the hard work of journalist and filmmaker Jason Schmitt, who felt so strongly about the issue that he and his team created a documentary that explored the problems with the current scientific publishing system and offered some potential solutions. The documentary is called Paywall: The Business of Scholarship. We were happy to contribute original footage featuring Alexandra Elbakyan to the movie.

On September 5th, the global premiere of Paywall: The Business of Scholarship took place at 5:30 PM at the Landmark Theatre in Washington, D.C. We organized the screening on our Facebook page a few hours after the official premiere.

In October, there is to be a screening at the United Nations Headquarters in New York City, where it will be included in the annual festival in support of Open Science. Information on the other screenings happening in the U.S. and other countries can be found here.

The goal of this initiative is to reach more people outside academia and engage in wide public discussion in order to find a solution that would suit everyone. We are happy to note that one of the big science communities on Facebook, Trust me, I am a “Biologist”, joined us and also organized a screening, and by now, the movie has more than 30,000 views on this page.

In order to spread the word further, LEAF director Elena Milova, with the help of Joshua Conway and a LEAF volunteer who prefers his name to remain undisclosed, also translated the entire documentary into Russian!

Spread the word about the paywall problem

The current system of scientific publications is broken and unfair and does not facilitate the sharing of knowledge. If you agree with us, then we urge you to not only watch the documentary but also to share it widely. The reason that some publishers have been abusing the system for so long is the lack of awareness of the problem among the general public and decision makers. By showing this documentary to friends, family, and coworkers, you can help bring the problem into the light and bring a solution closer. Help science and progress today by sharing this documentary!

Date Posted: September 7, 2018

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From Within Your Own Failing Shell

Some time ago, I noticed a stock photo of an old lady seeing her geriatrician, who was a much younger woman. Nothing special was happening in the picture, which showed just two people talking; however, it made me wonder what it must feel like to be an elderly person consulting a geriatrician.

One initial assumption could be that it isn’t much different than seeing a GP, but that seems unlikely. If you are seeing a GP, the odds are your disease or ailment is not debilitating, let alone life-threatening. Whatever it might be, you went to see your doctor knowing that, most likely, he or she would be able to cure you; especially if you are young, it’s probable that just taking a medicine for some time, or doing physical therapy, will make you better. You know that you will recover, and the discomfort or the suffering you’re going through is destined to go away. You will get back to your life as it used to be, healthy as ever.

Things are rather different when you are seeing a geriatrician. A geriatrician is a specialist who takes care of the needs of elderly patients, an activity that can be summarized as ensuring the highest possible life quality of a patient in spite of his or her failing body, which becomes increasingly less resilient and less able to respond to treatment with the passing of time. Existing drugs and exercise programs, for example, can ameliorate the symptoms that an elderly person experiences and improve his or her life quality, but the vast majority of age-related diseases simply cannot be cured right now.

When you go to see a geriatrician, you do so with the knowledge that your doctor will most likely be unable to make you any better, despite his or her best efforts; you simply can’t shovel water with a pitchfork. You are aware that, as you keep aging, your condition is likely to worsen, and all your doctor will be able to do is help you manage your symptoms. You know that you are not going to get back to your life as it used to be and that you are not going to be as healthy as ever—that’s not what old people generally are like. In fact, one day, one of the conditions that brought you to see a geriatrician in the first place is going to worsen to the point that you will die of it.

Most of us are familiar with the feeling of going to see a general practitioner, getting a prescription for some mild ailment, and going back home, thinking about our plans for the rest of the day or the week, which possibly involve a big project that we have been working on for a while and can’t wait to take to completion. What if, instead, you are going home after seeing a geriatrician because of osteoarthritis in your knees? Whatever you might be thinking then, you probably are distracted by the pain that you feel in your knees with every step you take, and the thought that it’s not really going to ever improve doesn’t make it any better. It is unlikely that you have any big project going on that you are looking forward to finishing; it’s not that you wouldn’t like to have one, but your deteriorating health makes it difficult to do anything too demanding. Probably, your much younger doctor is going to go back home thinking about an exciting upcoming trip or her next night out, but you are not.

It’s impossible not to wonder what it must feel like to watch others get back to their own lives from within your own failing shell, knowing that the life that you are getting back to is likely going to be short and decreasing in quality; to hear your doctor say that your ailments can be managed, but not cured; to know that, as time passes, you are more and more likely to lose your independence and cause problems or suffering for your loved ones.

Putting on a smile and trying to look at the bright side of things may help you cope and avoid making things worse than they have to be, but it’s not going to make them better either. A positive attitude is a great prescription for any disease you might have, regardless of your age, but it is not the only prescription that you would be given for any serious illness that might strike you before old age. There is no reason why staying positive and palliative care should be the only medicines against aging—not now that rejuvenation biotechnology is becoming an ever-more concrete prospect.

People of all ages should have the right to go to see their doctors knowing that, most probably, whatever diseases they have may be cured; that any others they might get in the future can be prevented; that their discomfort or suffering is going to go away; and that they are going to get back to their lives as they used to be, healthy as ever.

Date Posted: September 6, 2018

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Administering Gene Therapy Without Triggering Immune Response

Scientists at Stanford University School of Medicine managed to administer effective gene therapy in mice without triggering an autoimmune reaction. The research, led by Dr. Peggy Ho, Ph.D., was published in the Proceedings of the National Academy of Sciences [1].

Study abstract
In gene therapy for Duchenne muscular dystrophy there are two potential immunological obstacles. An individual with Duchenne muscular dystrophy has a genetic mutation in dystrophin, and therefore the wild-type protein is “foreign,” and thus potentially immunogenic. The adeno-associated virus serotype-6 (AAV6) vector for delivery of dystrophin is a viral-derived vector with its own inherent immunogenicity. We have developed a technology where an engineered plasmid DNA is delivered to reduce autoimmunity. We have taken this approach into humans, tolerizing to myelin proteins in multiple sclerosis and to proinsulin in type 1 diabetes. Here, we extend this technology to a model of gene therapy to reduce the immunogenicity of the AAV vector and of the wild-type protein product that is missing in the genetic disease. Following gene therapy with systemic administration of recombinant AAV6-microdystrophin to mdx/mTRG2 mice, we demonstrated the development of antibodies targeting dystrophin and AAV6 capsid in control mice. Treatment with the engineered DNA construct encoding microdystrophin markedly reduced antibody responses to dystrophin and to AAV6. Muscle force in the treated mice was also improved compared with control mice. These data highlight the potential benefits of administration of an engineered DNA plasmid encoding the delivered protein to overcome critical barriers in gene therapy to achieve optimal functional gene expression.

Gene therapy and autoimmunity

Gene therapy may be extremely useful to replace defects in the genome of a patient. A defective gene encodes for a faulty protein, which may lead to crippling or even lethal diseases. By replacing broken genes with working ones through gene therapy, cells can be instructed to produce functional proteins instead of faulty ones, thereby eliminating the very root of genetic diseases.

However, the new, working protein produced by a newly introduced gene is foreign to the patient’s body; his or her cells have never produced it before, and the immune system is bound to recognize it as a threat and treat it as such, mounting a dangerous immune reaction that might even result in death. For this reason, gene therapy has always been a bit of a double-edged sword.

Finding ways to administer gene therapy and eliminate or mitigate autoimmune reactions is thus a central problem, and Stanford researchers think that they’ve found a way to do it, at least in mice.

The study

The researchers carried out their experiment on a murine model of Duchenne muscular dystrophy—a progressive, crippling pathology that affects all voluntary muscles and, eventually, cardiac and breathing muscles as well. In humans, it occurs primarily in males and exceedingly rarely in females. The rate of incidence of the disease is about 1 in 5,000 males at birth, most of whom will be unable to walk by the time they reach the middle of their teenage years; in a best-case scenario, affected individuals can expect to live to their 30s.

The reason why the researchers chose this disease is that it originates from a single faulty gene. This gene is responsible for the production of a protein called dystrophin; if the protein is lacking or dysfunctional, it will lead to the disease. As curing the disease requires fixing only one gene, it is a relatively simple target.

The researchers’ patients were fifteen 6-week-old mice who had been bioengineered to lack functional dystrophin. In order to deliver a working copy of the dystrophin-encoding gene to the mice, the researchers employed viral vectors—that is, they modified viruses to render them harmless while preserving their cell-penetrating ability, and they equipped them with the gene they wanted to splice into the mice’s genetic code. This gene wasn’t exactly the one encoding for dystrophin, which would be simply too large to fit into the chosen viral vector; instead, they created a smaller version of it that produces microdystrophin, a suitable substitute for dystrophin. The viral vector, designed by one of the study’s authors, would then go on to infecting the mice’s cells and insert the replacement gene into their DNA.

However, this approach may actually worsen immune reactions; the recipient’s immune system would react not only to microdystrophin but also to the viral vector itself. To circumvent this problem, the authors of the study made use of plasmids—small DNA molecules that are most commonly circular, double-stranded, and found in bacteria. These molecules are generally transferred directly from one bacterium to another—a process known as horizontal gene transfer—sometimes facilitating the transmission of antibiotic resistance.

The immune systems of the mice would mount a response against some of the sequences in the DNA contained in the plasmid as well, but in this case, the scientists had replaced those sequences with others capable of dampening the immune reaction to both microdystrophin and the viral vector.

After the mice received the microdystrophin gene through a viral vector, they were divided into three groups, which, for 32 weeks, received a weekly intramuscular injection of a placebo, a placebo plus the plasmid without the dampening sequences, or the immunity-dampening plasmide. At the end of this treatment, the latter group had much stronger muscles and higher levels of microdystrophin than the other groups as well as little immune response to microdystrophin and few inflammatory signals between immune cells.

Conclusion

While an experiment in mice is not sufficient to absolutely determine whether the same approach would work in people, the researchers are optimistic that this method might translate; the same approach has been used to induce immune tolerance to myelin protein and proinsulin in people with multiple sclerosis and Type 1 diabetes, respectively, so there’s reason to believe that it might work for human gene therapy as well.

Literature

[1] Ho, P. P., Lahey, L. J., Mourkioti, F., Kraft, P. E., Filareto, A., Brandt, M., … Steinman, L. (2018). Engineered DNA plasmid reduces immunity to dystrophin while improving muscle force in a model of gene therapy of Duchenne dystrophy. Proceedings of the National Academy of Sciences, 201808648.

Date Posted: September 6, 2018

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A Review of Cellular Senescence and Senolytics

Today, we want to point out a new publication that dives into the world of senolytics, which are drugs or therapies that seek and destroy harmful non-dividing cells that resist the programmed cell death known as apoptosis.

These cells linger in the body, and, as we age, more and more of them accumulate and contribute to the chronic age-related inflammation known as “inflammaging” while reducing tissue regeneration and repair and contributing to the development of various age-related diseases.

One approach to dealing with these problem cells is to tip them over the edge and cause them to self-destruct, thus removing them and the inflammation they cause. A new class of drugs known as senolytics was discovered a few years ago, and the interest in developing them to potentially combat age-related diseases has been growing rapidly.

Abstract
Cellular senescence is a process that results in irreversible cell-cycle arrest and is thought to be an autonomous tumor-suppressor mechanism. During senescence, cells develop distinctive metabolic and signaling features, together referred to as the senescence-associated secretory phenotype (SASP). The SASP is implicated in several aging-related pathologies, including various malignancies. Accumulating evidence argues that cellular senescence acts as a double-edged sword in human cancer, and new agents and innovative strategies to tackle senescent cells are in development pipelines to counter the adverse effects of cellular senescence in the clinic. We focus on recent discoveries in senescence research and SASP biology, and highlight the potential of SASP suppression and senescent cell clearance in advancing precision medicine.

There are already a number of companies poised to enter human trials with these drugs, so keep an eye on our research roadmap, a curated database of the major aging therapies in development, if you would like to keep up with their progress.

The paper in question takes a look at the biochemistry of cellular senescence, one of the hallmarks of aging, and presents information on all the known senolytic compounds, the studies behind them, and their development progress.

Naturally, like 70% of all scientific publications in the world, this important health and medical knowledge is hidden behind a paywall; however, thanks to projects like Sci-Hub, which bypasses such extortionate fees, anyone can read it for free. We also recently interviewed Alexandra Elbakyan, the creator of Sci-Hub, about the problem of science being held for ransom behind paywalls.

Conclusion

This paper is a great primer on the subject of cellular senescence and senolytics, and it should be of interest to both new and long-time readers. We anticipated that senolytics would be the first repair-based therapy to arrive, and given historical timelines for clinical trials and assuming that everything goes according to plan, we may see senolytic therapies being available in the next 4-5 years. That will be a game changer for medicine and how we think about treating age-related diseases.

Literature [1] Sun, Y., Coppé, J. P., & Lam, E. W. F. (2018). Cellular Senescence: The Sought or the Unwanted?. Trends in molecular medicine.

Date Posted: September 5, 2018

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NAD+ Repletion Shows Potential Against Aging

Science is advancing rapidly, and the field of aging research is no exception. Our understanding of aging has grown a great deal in the last decade, and we are now reaching the point at which the first therapies that target aging are starting to arrive. Unlike the snake oil of previous years, some of these might actually work; today, we are going to have a look at NAD+ repletion, one such promising therapy.

In the near term, nicotinamide adenine dinucleotide (NAD+) is showing potential for addressing some of the aging processes. NAD+ levels decline significantly during aging in both humans and animals, and studies on old mice have shown that restoring NAD+ levels causes them to look and act like younger mice while increasing their lifespan.

What is NAD+?

NAD+ is a molecule that is present in all living cells and is essential for a myriad of cellular processes, including regulating metabolism, performing signaling, facilitating DNA repair and blood vessel growth, and regulating some aspects of aging.

In the body, NAD+ is created from simple building blocks, such as the amino acid tryptophan, and it is created in a more complex way via the intake of food containing nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and other NAD+ precursors.

These different pathways ultimately feed into a salvage pathway, which recycles them back into the active NAD+ form. This salvage pathway, shown on the bottom right of the diagram, includes NAM, NMN, NAD+, and their associated steps.

As this diagram shows, NA has many chemical steps that it must go through before it is converted into NAD+, NR is closer to the salvage pathway, and requires fewer steps to become NAD+ and NMN is within the salvage pathway. Some research suggests that NMN brought in from outside of the cell generally has to convert back into NR to pass through the plasma cell membrane of most cells, but this does not appear to be a bottleneck given how fast it increases NAD+ throughout the body in mice [1].

Unfortunately, it is difficult to infuse cells directly with NAD+ as the molecule is too large for most cell types to take it in through the plasma cell membrane, so adding NAD+ to the bloodstream would not enter most cells. However, there is some research that suggests that NAD+ and NMN might enter certain types of cells directly and this is something researchers are currently trying to ascertain, we will talk about that in a future article.

Making old mice younger

In March 2017, researcher David Sinclair and his team published a study in the journal Science showing that by feeding mice the NAD+ precursor, NMN, they were able to restore lost NAD+ levels within hours [2]. In just a week, some signs of aging in muscle and other tissues had been reversed so much so that the researchers could no longer tell the difference between these 2-year-old mice and the tissues of 4-month-old mice.

This study also showed the exact mechanism by which NAD+ facilitates DNA repair via a special pocket-like structure. The study has implications for cancer survivors, aging research, and even potentially space travel, given that DNA damage is the primary reason for genomic instability and makes us prone to cancer and aging. Being able to boost our DNA repair would be very useful indeed for repairing DNA damage from aging, cancer, and environmental radiation, which is prevalent in space.

In 2018, a study by David Sinclair and his team showed that vascular aging could also be reversed using NMN [3]. Compromised blood flow plays a key role in aging, since it starves tissues and organs, including the brain, of the essential nutrients and oxygen they need. This loss of blood supply is also implicated in sarcopenia, the age-related loss of muscle mass that leads to frailty and loss of independence in older people due to poor mobility.

In this study, Sinclair and his team found that they could restore lost blood flow in old mice using NMN to encourage blood vessel growth. The cells took up the NMN and converted it into NAD+, spurring the formation of new tiny blood vessels to improve muscle tissue; in fact, the mice treated with NMN increased the treadmill running time by an impressive 60% compared to control animals that did not receive NMN. In some cases, the old mice had endurance levels that matched and, in some cases, even exceeded those of younger mice.

In a broad sense, NMN improves blood flow in the same way that exercise does, as it interacts with a family of molecules called sirtuins. This means that if NMN works as hoped, it would be an exercise mimetic, and using it would have similar benefits to actual exercise; this could be useful for older people who are already suffering from loss of mobility and cannot exercise. It also has potential as a preventative for vascular aging in general and for improving tissue regeneration and wound healing.

This is great if you are a mouse, but what about humans?

Scientists are hoping to translate these murine findings to humans, and in 2017, a group of researchers ran a randomized control trial using NR [4]. These researchers reported that there was a significant and sustained increase of NAD+ levels over a two-month period in people taking the supplement. We should, however, take this study with a pinch of salt, as it was partially funded by the sole producer of NR as well as public money via the NIH.

Meanwhile, David Sinclair and his team are running a small-scale human trial on NMN at the Brigham and Women’s Hospital in Boston, Massachusetts, which is adjacent to Harvard Medical School, where Sinclair has his lab. This initial study is important, as in the past, the results of various “anti-aging” compounds shown to be effective in mice have not translated to humans.

David Sinclair and his team are keen to rigorously test NMN in humans and gain clear results. He plans to test NMN in healthy elderly people to see if they receive the same improvements in blood flow that animals receive.

Conclusion

While you can buy NMN as a supplement, the usual concerns about purity and efficacy are there, and until there are clinical trials we advise waiting for the results from those to come in before deciding if it’s worth taking or not. However, if you must self-test, we suggest using a science-based approach.

It is also fair to say that while NMN does not address all of the aging processes, it does address altered nutrient sensing and genomic instability somewhat in mice. There is little doubt that more robust therapies will arrive in time, but NMN could be useful as a stop-gap, assuming, of course, that the results translate from mice to men. The good news is that we may not need to wait too long to find out.

Literature

[1] Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., … & Yoshino, J. (2016). Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell metabolism, 24(6), 795-806.

[2] Li, J., Bonkowski, M. S., Moniot, S., Zhang, D., Hubbard, B. P., Ling, A. J., … & Aravind, L. (2017). A conserved NAD+ binding pocket that regulates protein-protein interactions during aging. Science, 355(6331), 1312-1317.

[3] Das, A., Huang, G. X., Bonkowski, M. S., Longchamp, A., Li, C., Schultz, M. B., … & Treviño-Villarreal, J. H. (2018). Impairment of an Endothelial NAD+-H 2 S Signaling Network Is a Reversible Cause of Vascular Aging. Cell, 173(1), 74-89.

[4] Martens, C. R., Denman, B. A., Mazzo, M. R., Armstrong, M. L., Reisdorph, N., McQueen, M. B., … & Seals, D. R. (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nature Communications, 9(1), 1286.

Date Posted: September 5, 2018

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An Interview With David Gobel

David Gobel is an inventor, philanthropist, futurist, and passionate rejuvenation advocate and supporter; he’s known for co-founding Methuselah Foundation with Dr. Aubrey de Grey and for proposing the intriguing concept of “longevity escape velocity”, but his achievements and successes extend far beyond that. David has kindly granted LEAF a most interesting and detailed interview.

If you’re not familiar with the Methuselah Foundation, it is possibly the oldest organization active in the field of rejuvenation advocacy and support; it also works as an incubator for startups working in rejuvenation research and has helped kickstart many of the projects we talk so much about on our website.

We hope you enjoy Dave’s replies as much as we did!

David, you’re well-known in the life extension community for being the co-founder of the Methuselah Foundation. Nonetheless, you have been involved in several different ventures and projects, not all of which involve life extension. Can you briefly discuss your career?

I am fortunate to have experienced much as an entrepreneur. From selling candles off the back of my motorcycle when I was a teen to working with IBM, my entrepreneurial bent has taught me a lot at every turn. I became a serial entrepreneur by creating several software companies. To give you a couple of examples, in 1991, I co-founded Knowledge Adventure. There, we created non-linear video, in which the movement of the user’s mouse would link non-linearly to a database of video frames. This resulted in us producing six best-selling multimedia titles, including 3D Body Adventure.

In 1995, I partnered with Steven Spielberg, Intel, Sprint, and Tandem Computers to design and create Starbright World, a broadband network that allows sick children at home and in over 110 children’s hospitals to “go out and play” in a rich virtual world where they can communicate with friends and family.

After 9/11, I felt compelled to help improve public security and safety, so in 2002, I joined TSA and eventually became the Chief Venture Strategist in the Office of Security Operations. There, I spearheaded the development of the Department of Homeland Security’s first venture capital capability. In that capacity, I also conceived IdeaFactory, which was adopted by DHS and which won the Secretary of DHS’s Team Innovation Award.

How did your involvement in life extension begin; did you realize the problem of aging yourself, or were you introduced to it by someone else?

It started because of my awareness that the healthcare system was broken, like the growth of an unplanned city that has no rhyme or reason. Our healthcare system reacts to system failures rather than preventing them, because that is more lucrative. The incentives push science in poor directions, and then these become inferior technologies and treatments. I came to the conclusion that we need a system reset. After much research and reflection, it became my conviction that this reset should be to delay and reverse aging and rejuvenate robust health. I believe this will result in reduced suffering and the greatest opportunity for individual and civilizational growth.

You co-founded Methuselah Foundation in 2001 with Dr. Aubrey de Grey. Can you tell us about how the idea was born and how the Foundation has grown and evolved over the years?

I founded the charity in 2001. When Aubrey and I began collaborating, I suggested the new name, and then we went with that in 2003. Rather than tell a story, we’ll link to our newly minted history of the Foundation. Of course, we are a moving target and will be announcing several new initiatives this year.

Methuselah Foundation has given millions of dollars to regenerative medicine research, backing ventures such as Organovo, Oisin Biotechnologies, and SENS Research Foundation. Would you like to tell us about some of the results that these companies have obtained thanks to your charity?

Well, Organovo invented and is now selling high-fidelity 3D human liver and kidney tissues to the research market, is providing CRO services, and is on track to deliver a 3D liver patch to the clinic in two years.

Another portfolio alumnus, Silverstone Matchgrid, has saved the lives of over 1,000 people due to our investment in its paired kidney donation software. This software is now used in over 35 hospitals in the U.S., Europe, and soon, Saudi Arabia.

I don’t think I need to say anything about SENS Foundation – it is fantastic, and we at Methuselah Foundation couldn’t be prouder of its success and contributions.

We have very high expectations for Oisin Bio and OncoSenX. We anticipate that it will be in Phase 1 safety trials by mid-2019. We hope to provide it to some patients much sooner than previously possible, as the FDA is liberalizing treatment availability via the recently passed “Right to Try” legislation.

Leucadia Therapeutics is a startup focused on defeating Alzheimer’s disease. This is progressing and promising. We hope to have major news later this year. The research community is realizing that the newly discovered brain clearance structures are perhaps key elements to fix, which is what Leucadia has been advancing since 2015.

Rather than go on, I’d like to say that we at Methuselah Foundation tend to be modest about proclaiming our successes. We prefer that the companies and scientists behind them get famous. For us, we focus on “Return on Mission”: how many people have not suffered; how many people have not died; and how much peace and happiness has been enjoyed because of our donors, stakeholders, non-profits, and new companies started. We absolutely expect to have failures; if we don’t, we’re not trying hard enough. Thankfully, so far, our strategies are working well.

A rather impressive name among your partners is NASA; in 2016, the American space agency launched the Vascular Tissue Challenge alongside your organization. Can you say some things about this particular project, Methuselah Foundation’s involvement in it, and how it has been progressing?

Methuselah Foundation, via its NewOrgan Alliance initiative, has been responsible for attracting the current 13 world-class competitors. We have held 3 conferences to promote the prize in collaboration with NASA and NASA Ames Laboratory. The prize expires at the end of 2019, but we believe that the prize will be won before that, based on the competitors and their progress. Once the solution to the vascularity limit is achieved, 3D engineered human tissues can really take off!

Also, NASA has started releasing a series of videos that it’s produced about the Vascular Tissue Challenge. Here are two links to sample videos on their Facebook pages.

SENS Research Foundation spun off from Methuselah Foundation in 2009; however, SENS was initially a part of Methuselah’s research program. Why was it decided to separate them into two organizations?

Aubrey has an amazing mind for the details of biology, and it was his desire to exploit this growing body of knowledge to pursue his SENS initiative. I, on the other hand, have expertise in getting the “impossible” off the ground and into the sky without it blowing up. He wanted to do lab work which would require vast capital, and I wanted to start companies that could bring products to market/clinic, go public, and recycle the funds back into the mission. With his pharma experience, Mike Kope made it possible for both Aubrey and myself to play to our unique strengths while keeping in sync. This has allowed us to independently drive the mission, likely faster than could otherwise have been possible.

The timeline of MFoundation’s achievements is frankly impressive. One of the latest was the launching of the Methuselah Fund in early 2017, an LLC subsidiary of your charity. Can you tell us about it and how its mission differs from that of Methuselah Foundation?

The Methuselah Fund, or M Fund, is designed to give donors a chance to get a return on equity now that the longevity field is maturing. Many of our donors have been faithfully donating for years, and now that opportunities are emerging, we wanted to give them the first opportunity to invest.

We are delighted to announce that we just successfully closed the M Fund’s Founder’s Round. We now have four companies in our portfolio and have been looking at helping form some promising new ventures. We are particularly proud to say that every single one of our members is a mission-driven individual who wants, more than anything, to see an end to the aging problem.

Lastly, we will be announcing several new company start-ups over the next few weeks, so stay tuned.

Does Methuselah Foundation engage in advocacy and educational activities alongside financing research?

The Methuselah Foundation has created Public Service Announcements to educate the public on the importance of having conversations about aging as a disease and its implications for society. We did a total of five videos, and these aired on Hulu and YouTube.

We believe that our Methuselah Mouse Prize went a long way toward proving that the pursuit of longevity is a legitimate science goal in the biogerontology community. We are decidedly and committedly apolitical. We simply believe that healthy life is good and that more of it is better.

Our form of advocacy is to prove that healthy life extension is scientifically inevitable. Our goal is to deliver solutions to the clinic. We do this with prizes, grants and company formation.

Can you tell us something about the future projects or activities that MFoundation is planning to start?

We have many projects that we are shepherding, but some are not ready to be publicized. We look forward to telling you about them in the upcoming weeks!

The 300 is your charity’s way of honoring a group of early supporters who forwarded the cause of healthy life extension in the face of the public ridicule that, in the early 2000s, was standard for anyone advocating for the defeat of aging. Unfortunately, even today, although the topic has gained significant acceptance among experts, the idea of defeating aging is still often met with ridicule, indifference and, at times, opposition that borders on religious fervor. Why do you think this happens, and how can we change it?

We fervently believe in everyone’s right to express themselves for or against the view of aging as a disease. We recognize the ethical issues that scare or intimidate many individuals who see living longer as a societal problem. We understand that not everyone will want to live significantly longer and that some people would purposely live lives that age their bodies prematurely. We don’t aim to change those feelings, but we aim to inspire tolerance among different opinions.

Science and technology have improved our standards of living, so we can all have choices that we can take or leave. For example, we can go to our fridges and decide to eat chicken, steak, or vegetables in a given meal, knowing that the ingredients not used will be safe to eat another day. Just about 150 years ago, humans did not have that luxury. As a species, we thrive on having options and enhancing our access to novelty. Also, thanks to refrigeration, we are able to diet in numerous ways that make us healthier individuals. We could even say that we are living longer because we can plan our meals now. However, very few individuals would have strong feelings against the invention of refrigerators.

The mainstream view of aging as an engineering problem and not a natural one will change as the view of other vilified industries changed with time. For example, it was once the mainstream view that flying was best left to the birds. The thought was, “If God wanted us to fly, he would have given us wings.” What we say is, “If God wanted us to fly, he would have given us imagination (which of course, we have).” Clearly, flying was engineered, and so can longevity.

You were the first to put forward the concept of longevity escape velocity, or LEV. How far are we from LEV, assuming the current pace of research and no serious showstoppers?

I anticipate that within 3 years, some interventions will be available via safety trials and that people who are treated will receive benefits that put them on a path toward LEV. I believe things will accelerate from there, as vastly more attention is triggered by early advances. We are seeing the first glimmers of this already.

Editorial note: The response to this question about LEV has been clarified in response to comments from David on Fight Aging.

MFoundation’s motto—”Making 90 the new 50, by 2030″—is not as bold as the concept of LEV, which many people are very skeptical about. Then again, 2030 is only 12 years away, so your motto might also appear too bold. Are you still confident that the industry will meet this deadline?

Yes, as long as the early companies get sufficient funding so that they can be accessible to the public without being diverted from the mission. The science is there, so this issue is about meeting necessary funding and regulation. The ability to meet this goal is real, so we are working on all elements of the problem that we can.

Other than not dying of aging, do you have a special dream that may only come true if significant life extension is achieved?

At the age of 65, we are still children. I believe that every 10 years of life can produce a profoundly different and improved person if the host body is kept youthful. The danger is that once we return to youth while drenched with knowledge and experience, we will either become diabolically clever or productively wise. I hope to continue to grow toward greater productive wisdom and joy from regaining youth.

You’re also a futurist. Staying in the realm of speculation, how do you imagine the world might be in 50 years? Worst and best case scenarios.

Many of your readers are no doubt familiar with Kurzweil’s concept of the technological singularity. I make the argument that, as in physics, nothing entering the event horizon of a singularity survives the experience. It gets shredded to oblivion. We have already entered a socio-economic event horizon of similar magnitude to the one which started in 1453-5 with the invention of the printing press and the fall of the Byzantine, Holy Roman, and Catholic empires. Printing led to modest changes in its first 50 years but then absolutely exploded into the Renaissance and discovery of the New World(s). This was followed by the Reformation, which shredded the entire social and governmental fabric of the Western world. This phenomenon is happening again right now.

There is no word to describe these conditions, so I had to give it a name: Simulflation. Simulflation is the simultaneous implosion and explosion of a technologically-driven phase, and these changes are similar to the collapse and inflation of a star undergoing exhaustion of its fuel. As it collapses, a new element begins to burn.

We are experiencing technologically-driven “simulflation”, a situation similar to that of the period between 1910 and 1929, when technological innovations continuously accelerated capital investments in innovations to the point of bubbles, generating huge technological advances, cost reductions, and creative destruction. Now, Moore’s, Metcalf’s and other power laws (genomics) are collapsing industries, trade, and commerce barriers. This is leading to repetitive destruction of pricing power, resulting in deflationary labor costs. This is the highest component of business costs, which feeds back into further gravitational implosion via automation. Coincident with accelerating destructive deflation, currencies have been decoupled from commodity constraints (gold), so governments have no limit on how much money they can print. There is huge inflation in money creation, with said money being driven to invest in paper and digital (crypto) assets. This further accelerates the cost-push inflation. Deflation and inflation at the same time, simulflation, ultimately results from tidal/gravitational exhaustion and collapse of the reigning global socioeconomic system.

According to Martin Armstrong, in 1900, about 40% of the US civilian workforce was employed in agriculture. By the late 1920s, the economy had changed remarkably. There were exceptional gains in productivity due to electrification, which increased production of goods, and the combustion engine, which profoundly altered agricultural production. Previously, up to 25% of agricultural land had been used to feed horses and mules. With tractors replacing horses and mules, this land suddenly became available. The ability to produce food soared and exceeded market demand, creating overproduction and underconsumption. This Great Depression led straight to WWII. A supernova, if you will.

We are on the cusp of a new, even more powerful, event horizon. To answer your question, the next 50 years will either usher in a world of untold plenty and growing good will, or we will personally encounter the great filter of the Fermi Paradox. We will either suffer the fate of the Krell (Forbidden Planet), or we will learn to become Good in a profound sense. Because of the exponentially growing power of humans, there will be no middle ground. So, I am pleased that so many folks who support our work are doing so because it is good and not primarily for financial gain.

If you could tell everyone in the world one thing to remember for the rest of their lives, what would that be?

The concept of money is a mass psychosis that prevents us from being who we are and who we can become. It exists because we don’t trust each other – and perhaps don’t trust ourselves. We simply must transcend this. We must learn the meaning of satisfaction and appreciation and goodness without needing the “dog treats” we call money. Until we internalize this, longer life will not lead to happiness.

A big thank you to David for his thoughtful insights. His enthusiasm and optimism are contagious, and we certainly hope he’s correct in his prediction that the beginning of LEV might be only twelve years away. Without people with his dedication to the cause, the science of rejuvenation wouldn’t have progressed as far as it has.

Date Posted: September 4, 2018

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DNA Replication Can Happen Without ORC1

According to a study conducted by Hollings Cancer Center scientists at the Medical University of South Carolina, DNA replication in murine cells is possible even in the absence of origin recognition complex 1 (ORC1), a protein encoded by the homonymous gene that was previously thought to be indispensable [1].

Study abstract
The largest subunit of the origin recognition complex (ORC1) is essential for assembly of the prereplicative complex, firing of DNA replication origins, and faithful duplication of the genome. Here, we generated knock-in mice with LoxP sites flanking exons encoding the critical ATPase domain of ORC1. Global or tissue-specific ablation of ORC1 function in mouse embryo fibroblasts and fetal and adult diploid tissues blocked DNA replication, cell lineage expansion, and organ development. Remarkably, ORC1 ablation in extraembryonic trophoblasts and hepatocytes, two polyploid cell types in mice, failed to impede genome endoreduplication and organ development and function. Thus, ORC1 in mice is essential for mitotic cell divisions but dispensable for endoreduplication. We propose that DNA replication of mammalian polyploid genomes uses a distinct ORC1-independent mechanism.

DNA replication and ORC1

Multicellular life depends on the ability of individual cells to divide; new cells must be created from existing ones when an organism is developing or every time older cells die or are damaged. Each of an organism’s cells should contain an exact copy of its parent cell’s DNA, as mutated DNA might make newborn cells dysfunctional or, worse, cancerous. For this reason, multicellular organisms have evolved quality-control mechanisms that make DNA replication as perfect as possible as well as repair mechanisms to fix imperfect DNA.

Cells use the protein encoded by the ORC1 gene as a tool to make sure that their offspring cells have their same DNA. The protein binds to the DNA location where the process of replication is supposed to start on each chromosome, which is something that the DNA replication machinery needs to ‘know’ in order to accurately replicate the cell’s genome.

Until now, it was generally accepted that ORC1 was essential for DNA replication in all cells; however, the study authored by Dr. Takayuki Okano-Uchida and Dr. Gustavo Leone, among others, showed that, while ORC1 is indeed essential for murine development, liver and placenta cells appear to be able to replicate their DNA even in the absence of this protein.

The study

The scientists found out that DNA replication in two types of murine polyploid cells appears to be unaffected by the lack of ORC1. Polyploid cells, unlike most other (diploid) cells, have more than two copies of each chromosome. The cells in question were from the livers and placentae of the mice, and while they express high levels of ORC1 during division, ORC1 levels seem to fall as the animals age. At this point, the cells cease dividing but keep making copies of their own DNA (that is, they become polyploids)—a process known as endoreduplication or endocycling. This tipped off the scientists, who started to suspect that liver and placenta cells in mice might not need ORC1 to replicate their DNA. Indeed, the authors of the study tested their hypothesis by deleting the ORC1 in cells of the two polyploid tissues, and found out that in the absence of the protein, the cells would simply start endocycling sooner than normal. However, the same deletion in other tissues, such as embryo fibroblasts and adult diploid cells, ended up blocking DNA replication and cell division.

Future developments

While this study offers insight on how ORC1 relates to murine development, it is unclear whether its results are also true in humans; it also remains to be seen whether what has been observed in murine liver cells will happen in human liver cells as well, which is what the researchers seek to test next. ORC1 might also be important in cancer cell replication; processes similar to endocycling have been observed in some cancers, whose cells don’t express much ORC1 at all and yet manage to spread like wildfire. According to Okano-Uchida, it is possible that DNA replication in the absence of ORC1 may lead to an accumulation of mutations as the cell replicates, which, in turn, may well drive cancer.

Literature

[1] Okano-Uchida, T., Kent, L. N., Ouseph, M. M., McCarty, B., Frank, J. J., Kladney, R., … & Leone, G. (2018). Endoreduplication of the mouse genome in the absence of ORC1. Genes & development, 32(13-14), 978-990.

Date Posted: September 3, 2018

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Rejuvenation Roundup August 2018

We hope August has treated you well—it certainly did so for life extension, as this has been another month full of great news for the field. Don’t be upset with the departure of summer and the arrival of autumn, because little by little, we’re getting close to pushing away the autumn of years.

More investments against aging

The fight against aging is being taken more and more seriously by a growing number of investors, who realize the world-changing potential of effective rejuvenative treatments as well as the great opportunity for profit. Juvenescence Limited, which recently closed a 10-million deal with Ichor Therapeutics‘ Antoxerene, has now announced the purchase of 14.4 million shares of BioTime’s AgeX Therapeutics—a company focused on extending healthy human lifespan—for a total of over $43 million. AgeX’s work focuses on telomerase upregulation and cell therapies, and Juvenescence has invested in AgeX before. The news has been reported and commented on on Fight Aging! as well.

Ichor Therapeutics isn’t sitting about either, having recently launched its own strategic fund, Grapeseed.bio. Ichor already has a very interesting company portfolio, which includes Antoxerene and LysoCLEAR, and is now helping other rejuvenation startups grow by providing them seed funding, mentorship, and laboratory access in exchange for equity. Grapeseed.bio has, thus far, raised millions of dollars for rejuvenation startups and has recently been joined by Repair Biotechnologies, the company launched earlier this year by Fight Aging!’s editor Reason.

On August 6, San Diego-based biotech company Samumed announced having raised $438 million for the development of anti-aging therapies, with a focus on osteoarthritis, degenerative disc disease, idiopathic pulmonary fibrosis, and Alzheimer’s disease.

Speaking of investments, we’d like to remind you of LEAF’s Longevity Investors Network, our own initiative to foster investments in rejuvenation research. If you are interested in becoming an investor or want to pitch your own rejuvenation-related startup, or know anyone building a promising longevity-focused company, please make sure to get in touch with our Longevity Investor Network leader Javier at javier@lifespan.io.

LEAF News

Kicking things off, the new episode of the Rejuvenation Roundup Podcast is available today.

Team and activities

In August, three more renowned experts have joined our advisory boards: Steven A. Garan from the Center for Research and Education on Aging and Dr. Irina Conboy from UC Berkeley have joined our Scientific Advisory Board, and Michael Kope from SENS Research Foundation has joined our Industry Advisory Board We’re absolutely thrilled to have them on board, and we look forward to working with them!

Thanks to the generosity of our community, in late 2017, we crowdfunded the AgeMeter Biomarker System—a device to measure several aging biomarkers and estimate a patient’s functional age, which may differ from his or her chronological age. This device, the successor to the 1990s H-SCAN, is now an iOS-based tablet and has been endorsed by big names of the aging research field, such as Dr. George Church and Dr. David Sinclair; it can already be bought on the AgeMeter website and will be delivered to the crowdfunding campaign backers as early as September 4th.

Videos from Ending Age-Related Diseases, our conference that we held in New York City last July, are currently being released publicly; if you’re a Lifespan Hero, remember that you get early access! Thanks for supporting us!

Our own Elena Milova, tireless advocate for rejuvenation biotechnologies, has recently given a talk on the subject at the biggest Russian science festival, Geek Picnic, which was held in Saint-Petersburg last month. If you speak Russian, you can watch a video of her talk here.

lifespan.io Interviews

Last month, we’ve had the pleasure to have Didier Coeurnelle from HEALES, who talked about the Longevity Film Competition and rejuvenation advocacy; we are also happy to share Elena Milova’s new interview with Alexandra Elbakyan, the creator of Sci-Hub, a website devoted to removing paywalls in science and allowing for the free dissemination of scientific information. Thanks to the crucial work of Alexandra, the world is finally starting to pay attention to the problem of restricted access to scientific knowledge; we’re proud to help her carry out this important job. Finally, we also have an interview with Daria Khaltourina, one of the many extraordinary people we’ve got to thank for the introduction of the new “ageing-related” extension code in the latest version of the International Classification of Diseases

Research roundup

The brain and Alzheimer’s disease

Neuroplasticity and neurogenesis—the brain’s ability to remold itself and create new neurons, respectively—are hotly debated topics in neuroscience; it is generally accepted that these two abilities decline over time, but it’s as of yet unclear how much they actually do. While it was believed that they both essentially come to a grinding halt once a certain age has been hit, new evidence is challenging that belief. It appears that neuroplasticity decline can be mitigated if you exercise your brain, similar to how physical exercise helps you preserve your fitness as you age; speaking of neurogenesis, as discussed on FA!, recent studies have reached opposing conclusions, finding evidence for the existence of adult human neurogenesis and lack thereof. An intriguing hypothesis, again pointed out by FA!, is that humans and other mammals with large brains may exhibit decreased or absent neurogenesis as an evolutionary consequence of losing olfactory function over time.

Having a clear picture of what actually happens with neurogenesis and neuroplasticity with age is important, because nobody wants to live longer only to eventually lose his or her mind; for similar reasons, it is also important to address neurodegenerative diseases, such as Alzheimer’s. The prevailing hypothesis—that the accumulation of amyloid-beta proteins triggers the disease—has been seriously challenged by innumerable failed clinical trials in which clearing amyloids has yielded no real benefits as well as by the existence of people with abundant amyloids but no symptoms of the disease. Other hypotheses, such as the possibility that Alzheimer’s disease might arise as the extreme consequence of lifelong, persistent infection, are coming forward. Still, clearing aggregate tau protein from the brains of murine models of late-stage Alzheimer’s seems to yield cognitive function improvements; some forms of the protein are associated with altered neuronal activity, and it’s possible, though not certain, that reducing tau aggregates may benefit human AD patients as well.

Cellular Senescence

We’ve been talking a great deal about cellular senescence and senolytics and this month is nothing new.

Senescence and cancer are often thought to be rival demons: the former is a state of zombie-like quiescence in which cells cease dividing, and the latter is uncontrolled, furious growth. Cellular senescence is likely to have evolved as a defense against cancer, as damaged cells that might end up becoming cancerous generally turn senescent before this can happen; however, researchers have recently taken this a step further, developing drugs that are capable of triggering senescence in already cancerous cells in certain types of murine tumors. Having many senescent cells in your body is not good for you, but having cancer is worse; assuming these new drugs will become a therapy, the trade-off is good, especially if senolytics will then be able to clear out the tumor cells turned senescent. On Fight Aging!, you can find further commentary on this news.

Another interesting news item on cellular senescence is also discussed on FA!—it appears that delivering hydrogen sulfide into cells in culture slows down the pace at which cells turn senescent. Whether clearing excess senescent cells or slowing down the pace of senescence is the better option remains to be seen, although simply slowing down senescence is likely to result in a delay of its negative effects instead of eliminating these effects once they have started manifesting.

Senescent cell ablation appears to ameliorate, among many other ailments, tau pathology; it’s exciting to see that addressing a single hallmark of aging might have a beneficial effect on a broad range of age-related conditions.

In addition to the two “traditional” senolytic approaches—small-molecule drugs and gene therapy—nanorobots offer a third option. Senescent cells in different tissues exhibit different properties, so different senolytics will be needed to target them; however, multifunctional nanorobots capable of targeting different types of senescent cells at once may be designed and employed to address cellular senescence.

Gut microbiota

It’s a well-known fact that the inside of a human body is anything but aseptic—like all plants and animals, we’ve got bacteria all over and inside us. In particular, bacteria living in your guts are essential for your well-being, allowing you to better process the food you ingest; however, our relationship with these microscopic creatures is not all unicorns and rainbows, as they appear to have a role in aging—more specifically, they seem to contribute to the chronic, age-related background inflammation known as “inflammaging”. As discussed in a review pointed out by Fight Aging!, changes in the gut microbial populations with age might also be a contributing factor in the emergence of sarcopenia and frailty—the loss of muscle mass and increased vulnerability to minor physical stressors. One intriguing hypothesis is that a reduced ability to process dietary proteins might translate into a reduced ability to synthesize new muscle tissue.

Targeting the microbiota may therefore be a viable option to ameliorate aging; for example, Salk researchers recently stumbled upon the discovery that depleting gut microbiota in mice leads to better insulin sensitivity. Granted, you definitely don’t want to deplete your gut microbiota, but less drastic interventions might be able to yield similar benefits in humans.

News Nuggets

Over the past few years, Ichor Therapeutics has been making a name for itself in the rejuvenation biotech industry; besides actively conducting rejuvenation research and helping other startups in the field to thrive, the company has now teamed up with ESF, the State University of New York College of Environmental Science and Forestry, to help graduate students train in researching drugs to treat age-related ailments.

Unity Biotechnology, a biotech company currently running a Phase 1 human clinical trial for its candidate senolytic drug UBX0101, has recently released its second quarter financial results. The financial position of the company is strong, and it hopes to share preliminary data of its trial in the first quarter of 2019.

Videos of the Undoing Aging 2018 conference keep rolling out; you can now see the talk by Dr. Vera Gorbunova, Professor of Biology at Rochester University and member of our Scientific Advisory Board.

Coming up in September

Paywall: The Business of Scholarship

The more that scientific research is widespread and freely accessible, the faster that researchers can make progress—including in the field of life extension. However, scientific papers are behind paywalls more often than not, forcing scientists and universities to spend significant amounts of money on buying papers, if only for the purpose of reviewing the existing literature involving their fields of research. Academic literature is a billion-dollar business, which, as you might recall, is being openly opposed by initiatives such as Alexandra Elbakyan‘s Sci-Hub; now, the topic is receiving further attention thanks to the forthcoming release of Paywall: The Business of Scholarship, a documentary revealing the flawed nature of the current system of scientific publishing. The documentary was conceived and directed by journalist and filmmaker Jason Schmitt of Clarkson University, and it features librarians, researchers, students, and open access publishers who share their opinions on the problem and its potential solutions.

“Twenty-five billion dollars a year goes into academic publishers—for-profit academic publishers,” Schmitt said to LEAF for the Rejuvenation Roundup Podcast. “Away from education, away from science, away from progress, this fuels these for-profit companies to have incredible profit margins, and we’re talking 35 to 40% profit margin, more than Facebook, more than Google, more than Apple Computers.” Schmitt added, “The future, I think, is pretty clear; there is no way that this system is going to continue to perpetuate itself in the manner it has.”

Jason contacted us seeking our permission to use an old interview with Alexandra; however, when Elena, who conducted it, took a look at the project, she was so impressed that she was determined to help the team get an original piece of footage featuring Alexandra Elbakyan. Our supporters Ivan Kondratiev and Josh Conway helped with the footage and translation, and we contributed the resulting material to the movie.

On September 5th, the global premiere of Paywall: The Business of Scholarship will take place at 5:30 PM at the Landmark Theatre in Washington D.C.; in October, there will be a screening in the United Nations Headquarters in New York City, where it will be a part of the annual festival in support of Open Science. Information about other screenings, which are planned in multiple countries, can be found here.

LEAF fully stands by the idea that scientific knowledge should be free and that paywalls should be abolished, and commends the initiative by Schmitt’s team; indeed, we will be streaming the movie’s premiere on September 5th (a couple hours later than the Paywall team’s premiere) on our Facebook page.

Lifespan-X lecture

Tatjana Kochetkova, an expert in bioethics and human development, will hold a Lifespan-X lecture in Leiden, Netherlands. This event is part of our Lifespan-X series—Lifespan-branded events independently organized by our volunteers and supporters. More specific details are yet to be confirmed, so stay tuned for updates! We will also make an event page on Facebook with all the information you need.

Basel Life 2018

On September 11-14 in Basel, Switzerland, the Basel Life 2018 conference will take place. One of its many events will be the Aging and drug discovery symposium sponsored by Insilico Medicine and chaired by Dr. Morten Scheibye-Knudsen and Dr. Alex Zhavoronkov. This symposium will see leading experts in the field of aging research and top investors discussing the latest scientific discoveries as well as the possible commercialization of the fruits of longevity research.

Mechanisms of Aging and Age-Related Diseases

Elena Milova will be attending Mechanisms of Aging and Age-Related Diseases, an international educational event that will be held at Moscow Institute of Physics and Technology from September 30 to October 4, 2018. It is an extension of Biomembranes 2018, a conference intended to educate people about the science of the aging processes. We hope that Elena will get back with multiple interviews featuring the leading researchers.

Humans X Tech & BDYHAX East

There are also two events coming up in Pittsburgh, Pennsylvania at which Ryan O’Shea, host of the Rejuvenation Roundup podcast, will be speaking. On September 20, 2018, Ryan will be moderating a panel on human augmentation at the Thrival Innovation & Music Festival’s “Humans X Tech” symposium, where the ethics of life extension will be discussed. Two days later, on September 22, Ryan will be speaking at BDYHAX East, which will explore bioethics and gene editing technologies. Tickets for both of these events are now available but are selling quickly.

It’s good to see that progress in the field of rejuvenation never really stops, even during a restful summer month; it’s exciting to think about what else this year might have in store. Stay tuned to find out!

Date Posted: August 31, 2018

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Getting Aging Classified as a Disease – Daria Khaltourina

We are pleased to report that lobbyists have made more progress towards classifying aging as a disease. The World Health Organization (WHO) has implemented the extension code ‘Ageing-related’ (XT9T) in the latest version of the International Classification of Diseases (ICD).

The inclusion of the new code is thanks to the efforts of activists at the Biogerontology Research Foundation (BRF), the International Longevity Alliance (ILA), and the Council for Public Health and the Problems of Demography (CPHD). The proposal was developed by Daria Khaltourina (ILA), Anca Ioviţă (ILA), Franco Cortese (BRF), Yury Matveyev (CPHD), and Aleksey Alekseev (CPHD) with support from Alex Zhavoronkov of Insilico Medicine and other researchers in the field.

The impact of their work has been so successful that the news has even appeared in The Lancet, a prestigious weekly medical journal, where their success was reported most favorably.

What is the ICD?

In this short video, the WHO explains what the ICD is and why it is so important.

The previous version, the ICD-10, was released in 1983 and is now replaced by the new version, the ICD-11, which is expected to serve the medical community for many years, much as its predecessor has.

The new extension code

In the new ICD code, ‘ageing-related’ means “caused by pathological processes which persistently lead to the loss of organism’s adaptation and progress in older ages”. This is an important step forward for our field because ICD codes are a prerequisite for the registration of new drugs and therapies. It also marks the recognition that aging is a pathological process and represents a solid step forward in overcoming regulatory barriers to developing therapies that directly target the aging processes themselves.

This is also particularly good news, as WHO reports that by 2050, around 2 billion people (22% of the world’s population) will be age 60 or over. In 2015, that number was only 900 million (around 12%), but thanks to globally rising life expectancies, that number is soaring rapidly. It is projected that by 2020, there will be more people over 60 years old than children under 5.

This is commonly referred to as the “Silver Tsunami”, and it is a real concern because society will become increasingly unable to cope with the rising numbers of elderly and potentially sick people, as aging is the greatest risk factor for multiple age-related diseases. The solution to this problem is to develop therapies that address the aging processes to keep older people healthy, active, and contributing to society rather than being burdens on healthcare systems, and that is without even considering the personal benefit of keeping people alive and healthy.

While the inclusion of the new code in the ICD-11 cannot be regarded as the WHO officially accepting aging as a disease, it does show that the WHO recognizes that aging is the primary risk factor for age-related diseases such as cancer, diabetes, atherosclerosis, Parkinson’s, Alzheimer’s, amyloidosis, and osteoarthritis. This is good news, as we need a solution to the impending silver tsunami and the public health problem it poses.

We asked Dr. Aubrey de Grey, a leading biomedical gerontologist, what he thought about the new code.

The ICD is not just a taxonomy. It greatly influences how drugs are prescribed in most nations, because a physician’s justification for writing a prescription must typically be documented in terms of an ICD code describing the diagnosis. As such, the addition of an extension code to denote aging may have a really huge impact on the financial rewards that drug developers can expect to reap if they bring treatments for age-related ill-health to the market.

Is aging a disease?

There is also considerable debate as to if aging is a disease or not; we propose that it is a co-morbid syndrome and that aging fits the medical definition of a syndrome in every way as defined by the British Medical Association [2].

A syndrome is a set of medical signs and symptoms that are correlated with each other and, often, with a particular disease or disorder.

This really does describe aging perfectly: it is a group of symptoms (hallmarks) that consistently occur together and is a condition characterized by a set of associated symptoms. Ultimately, aging is an umbrella term describing a range of pathological changes; it may struggle to be accepted as a disease, but it already qualifies as a syndrome.

Regardless of semantics, one thing is clear: aging leads to pathology and to the diseases of old age, and it is a problem that needs to be addressed urgently for both personal and societal benefits. The next step will be for lobbyists to push forward to get WHO to officially recognize aging as a pathological process with identifiable and quantifiable clinical indications that can be intervened upon.

We had the opportunity to catch up with Daria Khaltourina, a member of the team of lobbyists who worked on the proposal and talk with her about the new code.

Why do you think there is so much resistance to the idea that aging, or at least its constituent processes, is a disease?

The idea that aging is a disease breaks the traditional worldview. People are used to thinking that aging is normal, and now it suddenly becomes a challenge to work against. Some people even approve it, welcoming generation change, which reminds me of Stockholm syndrome, as aging ultimately brings horrible diseases like stroke and cancer.

Some researchers resist calling aging a disease for semantic reasons. But, since a united definition of disease is lacking, these discussions can go on forever. Yet, there is a practical need to alleviate the burden of aging-related pathologies, which are not separate processes but are highly interconnected. We need to classify aging as a disease to officially enable the development of drugs and clinical practice guidelines to prevent and treat aging-related health damage.

Can you explain why clinical trials are important and why we need them to develop therapies against aging?

Human organisms are very complex and fragile, and the science does not yet explain comprehensively how our body works. Clinical trials are the only kind of properly organized scientific experiments specifically designed to test our guesses about the safety and effectiveness of medicines and other therapies.

Historically, the whole legislative framework for clinical trials comes from the Nuremberg Code, a set of research ethics principles for human experimentation set as a result of the subsequent Nuremberg trials at the end of the Second World War. Further, it was complemented by the Declaration of Helsinki, a set of ethical principles regarding human experimentation developed for the medical community by the World Medical Association. This led to the development of Good Clinical Practice (GCP), the international quality standard for clinical trials, which is being incorporated into the national legislation of many countries.

Promoting untested cures even with good intentions can eventually result in people experiencing the worst kinds of suffering. The same might happen sometimes to paid participants in clinical trials. The difference between clinical trials and self-experimentation is in global medical knowledge accumulation, which helps to prevent adverse effects and cure diseases in the future.

Publishing failed clinical trial results is also crucial because it stops wasting resources while aging and diseases are taking a toll on human life.

People might think that organizing a clinical trial is nearly impossible because it requires up to a billion dollars, which is a large figure even for the US. Yet, in cheaper countries like Russia, according to my knowledge, a full cycle of high-quality FDA/GCP-compliant clinical trials for a cheap drug might cost as little as 1 million USD, and for a gene or cell therapy, it might cost about 10 million USD.

Therefore, life extensionists should not avoid but rather promote the idea of new clinical trials on anti-aging cures.

How do you think the new code could help researchers, particularly in clinical trials? Can you describe how such a code might be used in a clinical trial?

Many aging-related syndromes and conditions have specific underlying mechanisms compared to those driven by infections or toxins. For example, aging-related immune deficiency is caused by programmed cessation of T-cell regeneration, while aging-related vascular pathologies are exacerbated by vascular elastic layer loss. Since these pathologies have special codes now, new treatments that address specific mechanisms of aging can be developed.

If effective T-cell regeneration methods are developed, this might result in a measurable decrease in mortality in older adults, at least due to flu and pneumonia. In this case, medical insurance organizations would have to include such life-saving therapies into their programs. In fact, every person after 60 years old would have such treatment prescribed, just as is the case now with pneumococcal vaccines. This makes the development of anti-aging technologies more lucrative for biomedical investors than before.

Do you think that these changes may be enough to encourage pharmaceutical companies to move into anti-aging drug development, and why?

Such changes look forthcoming, but they still might require some advocacy work to promote new opportunities to biomedical and pharmaceutical companies, in terms of both priority change and identification of the most promising R&D direction.

Can you explain the significance of the “Ageing-related” extension code, and does it relate to a reimbursement scheme, grants, or anything similar that currently exists in any country?

In general, of course, it is possible to get the payments for effective anti-aging technologies reimbursed by governments and insurance companies. The reimbursement schemes are decided nationally, and in each country, the process is different.

What will be the next step for your team in regards to making additions to the ICD?

We, as a group of the ICD proposal’s co-authors, are preparing papers for publication that explain our views. We will continue to advocate classifying aging as a disease, while a better description of specific aging-related conditions might also be helpful. Further progress in promoting the development of effective anti-aging therapies for clinical practice requires consultations with the medical community, including gerontologists, regulators, and biomedical, pharmaceutical, and insurance companies.

What can people do to get involved with your efforts?

People with biomedical and medical backgrounds could take part in writing research and analytical papers. IT specialists might help us with information management. Other longevity activists might help by generally promoting the cause and promoting specific campaigns, as has happened twice in promoting aging as the agenda of the World Health Organization. Strong support from the longevity community is instrumental.

What do you think will happen in aging research in the next 10-20 years; do you think we could have some effective therapies during this time?

I hope that we will have at least effective senolytics tested for primary prevention in high-quality clinical trials (longer than the currently published clinical trials of quercetin) and prescribed by the doctors all over the world if this approach turns out to be safe and effective.

Do you have a final take-home message for our readers?

Aging is the number one killer, so fighting aging is the most meaningful activity in the world.

We would like to thank Daria for taking the time to do this interview with us and give us some insight into how this step forward happened.

Conclusion

It remains to be seen if the inclusion of the new code will make it easier to develop therapies that directly target aging; however, progress will continue regardless. Naturally, we are in favor of anything that could make that progress easier, and we hope that these positive changes will encourage the pharmaceutical industry to throw its weight behind research focused on targeting the aging processes. Time will tell.

Literature

[1] The, L. D. E. (2018). Opening the door to treating ageing as a disease. The lancet. Diabetes & endocrinology, 6(8), 587.

[2] The British Medical Association (BMA) (2002). Illustrated Medical Dictionary. A Dorling Kindersley Boo. p. 536

Alexandra Elbakyan is the creator of Sci-Hub.

Date Posted: August 28, 2018

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Alexandra Elbakyan – The System is Holding Back Scientific Progress

Today, we have an interview with Sci-Hub creator Alexandra Elbakyan, who is committed to the free flow of scientific knowledge and is challenging the unfair journal system, which charges outrageous fees to view scientific publications.

Hiding scientific knowledge behind paywalls

Around 70% of scientific publications are hidden behind paywalls, restricting access to knowledge and progress. We believe that this is unfair and that putting profit before the health of others is morally repugnant, and this is part of why we support the concept of Open Science, particularly the work of Alexandra Elbakyan.

Alexandra is the founder of Sci-Hub, a website devoted to providing scientists, students, and researchers with free access to scientific publications that would otherwise be locked behind paywalls.

Sci-Hub bypasses the publishers’ paywalls by allowing access through educational institution proxies. Sci-Hub then stores papers in its own repository for anyone to obtain and benefit from the knowledge contained. It is thought that over 67 million scientific publications and articles are now available via the Sci-Hub service.

The system is holding back scientific progress

Many researchers have told us that Sci-Hub is really important in helping them gain access to research that they could otherwise not reach due to the unreasonable prices of academic journals. When researchers working on new, potentially life-saving, medicines and therapies cannot review the existing data due to the cost of accessing this information, it becomes a very serious matter indeed, because they cannot build on top of existing data to push our knowledge further.

Our colleagues at non-profit public health organizations claim that their quite modest budgets don’t allow them to subscribe to any scientific academic journals. They consider themselves lucky if some of their members happen to be affiliated with scientific institutions and can find full-text articles for them. How can they make any sort of informed decision about public health if they cannot get a full picture of the problems they are dealing with?

The third type of complaint comes from doctors who wish to remain properly informed about the most recent clinical trial results in order to be able to help their patients better. This is where the situation becomes really sad.

The lack of access to science is a serious problem

When both scientists and the public are complaining about a lack of access, this highlights the significance of the problem. Of course, everyone deserves fair compensation for the jobs they are doing, but it is very hard to justify why the results of taxpayer-funded research cannot be freely accessed by the public when they have already paid for it once.

On one hand, the current model of placing science behind paywalls is not only limiting public access to knowledge, it is also holding back scientific progress. On the other hand, the attempts to change this system often face quite strong resistance. Sci-Hub is facing legal action by publishers who argue that putting their articles into open access is theft and wish to close Sci-Hub down. It is our view that the system needs to change and that a fairer way that facilitates the sharing of knowledge should be created for the benefit of society and scientific progress. Luckily, Alexandra’s activities keep the attention of the global community on this critical issue, and in the last few years, we have seen Open Science initiatives develop in many countries, particularly in the European Union.

LEAF Director Elena Milova interviewed Alexandra last year, and Elena was fortunate enough to get in touch with Alexandra recently and interview her about the progress in her work.

We would like to thank Alexandra Elbakyan for taking the time to speak with us about the ongoing battle for open access to scientific research and why the current academic journal system is broken. We appreciate the work that she is doing for the scientific community.

Paywall: The Business of Scholarship

It seems that we are not alone in our disgust for the current paywalling of science by academic journals. Earlier this year, researchers at Clarkson University in Potsdam, New York decided that this problem deserves the attention of decision makers and the general public, and they started producing a documentary in order to reveal the flaws of the existing system of scientific publications and to propose solutions. This documentary is Paywall: The Business of Scholarship.

The producer of the documentary, journalist and filmmaker Jason Schmitt, contacted university representatives, university and public libraries, open access publishing houses, and researchers around the globe to ask them if they have ever hit paywalls and how paywalls affected their professional activities. They were brave enough to reveal the unpleasant truth about the problem of paywalls, and their stories were collected into a powerful film.

lifespan.io conducted an interview with Alexandra Elbakyan last year, and Jason contacted us to ask our permission to include it in the movie. However, when Elena took a look at the project’s website, she decided that the team deserved much more support, so she found a way to create new footage with Alexandra specifically for the documentary. Preparing it was truly a team effort: our supporter from Russia Ivan Kondratiev served as an operator, and Josh Conway, who was our volunteer editor at the time, agreed to help Elena edit the translation.

On September 5th, the global premiere of Paywall: The Business of Scholarship will take place at 5:30 PM at the Landmark Theatre in Washington, D.C.; in October, there will be a screening at the United Nations Headquarters in New York City, where it will be included in the annual festival in support of open science.

We are very happy that we were able to contribute to the very important cause of scientific progress and the open sharing of knowledge. The movie has an open license, which basically means that anyone is entitled to spread it however they want. Once the movie is released, we suggest that you help spread it as widely as possible so that more heads can work on the problem of paywalls and find a way to solve them.

Update September 6th: You can find the full film in both English and Russian language format.

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