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Building a Future Free of Age-Related Disease

Date Posted: May 10, 2018
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New Harvard Startup Wants to Reverse Aging in Dogs

Professor George Church of Harvard Medical School has co-founded a new startup company, Rejuvenate Bio, which has plans to reverse aging in dogs as a way to market anti-aging therapies for our furry friends before bringing them to us.

Dogs first, humans next

The company has already carried some initial tests on beagles and plans to reverse aging by using gene therapy to add new instructions to their DNA. If it works, the goal is ultimately to try the same approach in people, and George Church may be one the first human volunteers.

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

Church and the team also understand that developing therapies that address aging in humans and getting them approved would not be so easy. It would take too long to prove something worked. “You don’t want to go to the FDA and say we extend life by 20 years. They’d say, ‘Great, come back in 20 years with the data,'” Church said during the same event.

So, the team has taken a different tack; rather than aiming to increase human lifespan as its main focus, it is instead focusing on the typical age-related diseases common to dogs. The hope is that by targeting the aging processes directly, these diseases could be entirely prevented from developing. If successful, this would lend additional supporting evidence that directly treating aging to prevent age-related diseases could also work in humans.

Working on rejuvenation

In 2015, the Church lab at Harvard began testing rejuvenation therapies on mice by using gene therapy to deliver CRISPR, a new and superior gene editing system. Since then, the lab has been engaged in dozens of studies on aging with a view towards the rejuvenation of aged animals.

The team has used gene therapies to add additional instructions into the DNA of aged mice, using these instructions to regulate and modify the activity of various genes. The researchers increase or inhibit target gene expression, depending on its contribution to aging, in a bid to restore gene expression and the production of secreted molecules to youthful levels.

The lab has been working on a collection of over 60 different gene therapies and has been testing their effects both individually and in combinations. The team intends to publish a report on an approach that extends mouse lifespan by modifying two genes that protect against heart and kidney failure, obesity, and diabetes. Professor Church has commented that the results of this study are “pretty eye-popping”.

The new startup has been contacting dog breeders, veterinarians, and ethicists to discuss its plans for restoring youth and increasing the lifespan of dogs. Its plan is to gain a foothold in the pet market and then use that as the basis for moving therapies to people.

Starting a dog trial

Last year, the lab contacted the owners of Cavalier King Charles Spaniels, a breed of toy dogs, with plans for a trial of gene therapy to combat mitral valve disease, a common heart condition that kills almost 50% of this breed at age ten. The nature of the gene therapy is not yet public knowledge, though it may involve inhibiting the cytokine TGF-beta, which facilitates the scarring and thickening of heart valves, and the team has tested a similar therapy on mice to stop heart damage.

Some readers may recall that inhibiting TGF-beta also produced tissue regeneration in brain and muscle when tested by the Conboy lab in 2015 [1]. The Conboys famously demonstrated this and the fact that balancing blood factors to youthful levels encourages tissue rejuvenation. It may be that by reducing levels of this cytokine to those seen in youth, this heart condition may be prevented in these spaniels.

Earlier this year, company owners Davidsohn and Oliver traveled to Chicago to the breed’s national show, where several thousand dollars were raised to begin the trial. The president of the American Cavalier King Charles Spaniel Club, Patty Kanan, said that this research is “seriously meaningful to the American Cavalier King Charles Spaniel Club.”

Conclusion

There have, of course, been the usual detractors of this initiative, such as skeptics and fortune tellers predicting that it will not work before it is even tested. Thankfully, the people behind this new company, which is backed by the expertise and vision of George Church, plan to proceed and see if the data can prove the detractors wrong.

Fortune favors the bold, and these are the people in the field getting the important therapies tested. If this pays off, the potential is huge, because if a therapy works in dogs, you can be sure that the pressure to move it to humans will soon pile up.

Literature

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

Date Posted: May 9, 2018
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Sarah Constantin – The Longevity Research Institute

Today, we have an interview with the Longevity Research Institute, a new group set to launch in April 2018 of this year. The goal of the Institute is to identify therapies that can demonstrably extend healthy human lifespan by 2030 at the latest.

Searching for longevity

There are dozens of compounds and therapies that have been demonstrated to increase the lifespan of mammals. Recently, there have been some impressive examples of rejuvenation in animals using a variety of approaches, including partial cellular reprogramming, stem cell therapy, and senescent cell removal. More importantly, in many of these studies, age-related diseases have been delayed or even reversed.

Unfortunately, very few of these studies have had independent follow-ups or replication, and that is slowing down progress. The Longevity Research Institute is aiming to bridge the gap between basic science and commercial drug development.

It has chosen the field of aging research as its area of focus for one simple reason: age-related diseases are the leading cause of death globally. Heart disease, stroke, cancer, diabetes, Parkinson’s, Alzheimer’s and many more diseases are all caused by the various processes of aging.

The data from hundreds of animal studies tell us that aging is not a one-way process and that the rate of aging is something we can slow down or even reverse. Experimental results show that we can increase the healthy lifespan of animals significantly and delay the onset of age-related diseases in doing so. If we could translate those findings to humans, we could potentially increase the healthy period of life, known as healthspan, or even increase our lifespan beyond current norms while remaining healthy.

The majority of aging research consists of basic science that focuses on the mechanisms of aging, studies involving invertebrates like worms or fruit flies, and experiments that examine the effect of therapies on biomarkers of aging. However, the Longevity Research Institute believes that the way to find effective treatments that could translate to humans is by testing interventions on mammals to see if they increase lifespan or if they delay or reverse symptoms of aging, such as frailty, cognitive decline, and the prevalence of age-related diseases. Robust mammalian lifespan studies are quite rare in aging research due to their long duration and thus cost; the Institute believes they are worth doing despite this challenge.

Its philosophy is to be skeptical of results that depend on too many uncertain assumptions, such as particular mechanisms of aging or analogies between invertebrate and human biology. It believes that the closest way to measure the health and lifespan of a human is to measure the same things in mammals.

Replicating and Extending Lifespan Results

The majority of studies that have been shown to increase lifespan are rarely independently replicated to confirm the findings. There are therapies that, decades later, still have had no follow-up, and the Longevity Research Institute would like to change this situation.

To that end, it will be engaged in grant writing to obtain funds so that researchers studying aging will be able to conduct lifespan studies in mice and rats. The Longevity Research Institute also plans to commission its own studies and contract research organizations to carry them out.

It has a long list of promising interventions and is considering becoming involved with carboxyfullerenes, epithalamin, and stem cell transplants, for example. It is also interested in testing combinations of therapies to see if they have synergistic effects.

As translational research on aging is really a new, uncharted territory, the Institute is working with the Interventions Testing Program and METRICS to design reproducible animal studies. As part of that process, it will be testing genetically heterogeneous animals and using blind, randomized studies to reduce bias. A blind experiment is an experiment in which information about the test is hidden from participants, to reduce or eliminate bias, until after a trial outcome is known.

Best practices and transparency

Establishing best practices and protocol for translational aging research is a top priority here, and its work could help set the stage for future translational efforts. If superbly designed research protocols can be designed and made accessible to everyone, then they could be a real help in standardizing aging research and ensuring that the quality of results is the best it can be.

As part of its commitment to transparency and knowledge sharing, a condition of funding projects is that all experimental data will be made freely available to the public, as will pre-registration of experimental designs. The Institute will further protect this open science initiative by using blockchain technology to make immutable, publicly accessible records of everything it does.

We had the opportunity to talk with Sarah Constantin, Ph.D. and one of the key figures at the Longevity Research Institute, about their work. Sarah is a data scientist specializing in machine learning.

Your group believes that we need to conduct lifespan studies in mice in order to confirm that something might translate. However, some researchers believe that using multiple biomarkers of aging allows them to project, within a reasonable margin of error, changes to potential lifespan. This is becoming more relevant as the accuracy of biomarkers, and the use of comprehensive biomarker panels, becomes more commonplace. How do you respond to this?

There’s some very interesting stuff going on with biomarkers of aging.  We’re able to predict mortality with AUCs of 0.8-0.9, which is quite good, with aging biomarkers, including things like blood panels of inflammatory and metabolic markers, DNA methylation, and phenotypic markers such as BMI and frailty. Some of these biomarkers are things we’re planning to measure in our animal studies, and they should give us interim results on whether the interventions we’re testing affect the predictors of aging. I still believe that we can be most confident in whether a treatment promotes longevity when we’ve tracked its effects throughout an organism’s lifespan. We do know of examples (such as calorie restriction in primates) in which it’s equivocal whether the treatment extends lifespan but it clearly improves age-related biomarkers, and you have to do a lifespan study to distinguish those cases.

Advances in deep learning and systems pharmacology are allowing us to project interactions and potential therapies far more efficiently than ever before. What are your thoughts on these approaches, and will you be looking to use them in your work?

The deep learning and systems pharmacology approaches are actually where I started in biotech; I did machine learning at Recursion Pharmaceuticals, which is taking those approaches for doing phenotypic screens for genetic disease treatments. I think they’re really useful for drug discovery, at the beginning of the pipeline, where they can enable you to search a wider space of drug candidates. At LRI, we’re starting all the way at the other end of the pipeline, with drugs that have already been tested and shown promise in vivo. However, once we make some progress on those, then yes, it could make sense to start doing some of these machine learning-enabled approaches.

What is the ideal mouse strain for aging research, particularly lifespan studies, in your view?

Well, the Interventions Testing Program at the National Institute of Aging is using three-way heterozygous mouse crosses, which I think is the ideal. A single inbred strain of mouse doesn’t have much genetic diversity, so often what you’re testing is the effect of a treatment on that particular strain of mouse, and the results won’t transfer to another strain.

The use of progeria mice is common in aging research due to the shorter study time, but these models are often criticized as not being representative of true aging; what are your thoughts on the prevalence of progeria mice in aging research, and are they a relevant model for what we are trying to achieve?

I think progeria mice are an imperfect proxy. There are a lot of different kinds of progeria, and they exhibit some but not all of the typical symptoms of natural aging.  I’d have more confidence in studies done on aged mice than progeric mice.

We see that you have a strong commitment to ensuring public access to scientific knowledge. What inspired you to make such a wonderful and strong commitment to open science?

Well, coming from a data science background, I’m hyper-aware of how easy it is to fool yourself with data.  You can massage anything into a spurious result if you test enough hypotheses and pick your subgroups artfully. Really, the best way to guard against that is to share the raw data so that people can run their own analyses. Making science more open is how you make it more trustworthy.

Is there a publically viewable list of the targets that you are interested in testing?

The list is still evolving, but some of the first things we’re looking into testing are carboxyfullerenes, which seem to have neuroprotective and life-extending effects, and epithalamin, which is a pineal gland-derived peptide that’s been reported to extend lifespan and even reduce human mortality. Both of these are sort of in the sweet spot of not being the subject of that much research to date, but what there is is very promising, so the value of information is high.

What is likely to be your first target for studies, and what is the rationale behind your choice?

I think people should know that there’s a lot of low-hanging fruit in aging research — treatments that we have reason to believe might work but that we’d still have to test. The misperceptions are either that life extension is so speculative that we’ll never get there or that we already know how to do it and you just have to take the right supplements to live forever. I think the reality is that we’ll have to do a lot of experimental work, but it’s highly possible that, in time, we might find something that extends healthy lifespan in humans.

We would like to thank Sarah for taking the time to do this interview with us, and we look forward to seeing her team’s progress in the near future.

Date Posted: May 9, 2018
5 Comments

Life Extension Technology in Science Fiction

Today, we take an amusing look at how science fiction is often portrayed in a jarring way especially when dealing with the topic of life extension.

Those of us who fancy science fiction stories are used to all sorts of technological miracles taking place in them; some are plausible and might become reality at some point in the future, while others are mere fantasies, artistic liberties that are taken to tell a better story and will likely never translate into real-life technologies—or, if they will, they will do so at the cost of rethinking fundamental principles that we’ve thus far considered to be fully established.

In science fiction, we’ve seen faster-than-light travel, teleportation, portals, energy weapons, strong AI, telepathic powers, and radiation-induced superpowers of all kinds; unfortunately, the only “superpower” known to be actually induced by radiation thus far is cancer. Entire imaginary worlds have revolved around the existence of one or more of these marvels, and series and shows have assumed that they’re possible and imagined what our society would be like with them, but one particular possibility has been neglected or relegated to one or two episodes and then forgotten, as if it was of no importance whatsoever: the defeat of aging.

There is no elephant; but if there is, it’s okay

Star Trek, a popular space opera I have loved since my early teens, is famous for its optimistic depiction of a future where space travel is as common as trains are today. Space travel is not, per se, the topic of Star Trek; episodes don’t generally discuss whether space travel is feasible or desirable, nor do they praise or demonize it; quite simply, space travel is taken for granted as an everyday reality that functions as a plot device. Star Trek episodes answer the very general question, “What might life be like if we were a space-faring species?“

Now, just how many series can you recall, from the top of your head, doing the same thing with the defeat of aging in place of space travel? How many shows are there where people don’t die of aging anymore and this is not the topic being discussed but is rather just a background element? In other words, how many shows are there where aging is no longer a thing and the show doesn’t revolve around all the alleged problems and drawbacks of it? How many shows assume that aging has been medically conquered and try to answer the question, “What might life be like in a society where age-related diseases no longer exist?” Not many, I’m willing to bet.

However, many science fiction shows have an episode or two where the possibility to reverse aging is hinted at, sometimes very clearly, but none of the characters seem to realize the bleedingly obvious potential for an unprecedented medical revolution staring them right in the face. If anyone bothers reacting in any way at all, it’s normally just to dish out stale clichés and moral lessons about how the finitude of life is a blessing or how tampering with nature is unnatural and hence bad (which is a rather bizarre thing to say for someone standing on a spaceship traveling faster than the speed of light).

This is not so strange when you think about it. This is nothing but the umpteenth manifestation of the pro-aging trance, which blinds us to the tragedy of aging and forces us to do all manner of embarrassing mental gymnastics to pretend it’s some sort of blessing in disguise. Our acceptance of aging is so strong and pervasive that it’s slipped unnoticed into every layer of our society and culture, especially the arts.

Sometimes, this acceptance doesn’t necessarily lead us to praise aging rather than rage against it; some of us would gladly do away with it if they only knew that it might be possible, but they’ve grown so accustomed to its alleged inevitability that the possibility doesn’t even cross their minds. Some of the clearest examples of the different manifestations of the pro-aging trance in science fiction come mainly, but not exclusively, from Star Trek.

To not-so-boldly go

Dr. Beverly Crusher on Captain Picard’s Enterprise and the holographic doctor on Captain Janeway’s Voyager have performed nearly all the medical wonders you can imagine. They’ve triumphed over all sort of diseases, brought in people who were transmuted into aliens or assimilated by the Borg into cybernetic organisms and turned them back into humans, the list goes on. Yet, 300 years into the future, no one has yet figured out what to do about aging. Humans keep aging more or less at the same rate, or perhaps a bit slower than that, since most people seem to live to around 140 years old, although they still grow sick and decrepit.

However, every now and again, some characters in Star Trek do happen to stumble upon a cure for aging or a phenomenon that might hold the potential to become one. You’d be amazed to see how many different ways there are to undo aging in the 24th century and how, apparently, no one could care less about them.

In The Next Generation’s episode “Too short a season”, a very elderly and disabled Starfleet Admiral manages to get his hands on an alien concoction that is said to cause rejuvenation (even in humans, apparently, despite its alien origin). In an attempt to speed up the rejuvenation process in time to face an old enemy, the Admiral takes twice the recommended dose, obtaining the desired effect at the cost of his own life: the extremely accelerated process causes too much stress on his body, which gives in when he has been rejuvenated to about the age of 20. Not only did none of the characters seem even slightly interested in the potential of this miraculous cure—which, with some fine-tuning, could end the diseases of aging for good—the authors also managed to shoehorn in yet another lesson about the perils of tampering with nature.

In another, more fanciful, TNG episode, the Enterprise’s counselor Deanna Troi falls prey to a sly, manipulative negotiator who, through a strange ritual, manages to turn her into a receptacle of all his negative emotions. The burden quickly becomes too heavy and Deanna, just like other women that the negotiator exploited before her, experiences accelerated aging that almost kills her. Thankfully, the crafty Dr. Crusher manages to break the bond between the attacker and his victim, instantly rejuvenating Deanna and killing the negotiator, who turned into an old man in the blink of an eye. Perhaps the technique used by Dr. Crusher here could have been of some medical interest to treat the diseases of aging, but the idea didn’t seem to cross her mind.

Of particular interest in this same episode is a bit of small talk casually thrown around by Commander Riker. When the negotiator first boards the Enterprise, he is accompanied by an elderly, demented woman whom he passed for his mother. (She’s actually a chronologically young woman used as his current receptacle.) The “mother” eventually dies and the negotiator replaces her with Deanna, but before this happens, Deanna talks with Riker about how the sight of the elderly, mentally ill woman upset her. As they talk about it, the Commander nonchalantly comments that maybe, one day, we will all be like that elderly woman—as if the prospect of losing our health and wits is no cause for concern whatsoever.

In Star Trek IX, “Insurrection”, the crew of the Enterprise finds out that the particular location of a planet within a nebula exposes it to a type of radiation which has rejuvenative and regenerative effects, which are experienced by the crew themselves. Busy as they are foiling the villain’s plan to deport the local population of the planet, none of our heroes think that this beneficial radiation should be studied for its therapeutic potential. (Unsurprisingly, only the villain is interested in the properties of this radiation, and, naturally, he can’t think of a better way to reap its benefits than wreaking havoc on the planet. Once again, the moral of the story seems to be that only the bad guys would ever want to extend their lives, and they always do so at others’ expense. Sigh.)

In a Star Trek Voyager episode, the stuffy and stern Lieutenant Tuvok is stranded on an unknown planet in the company of a handful of local, alien kids who are terrified that a terrible monster will come and kill them if they get too close to a cave where their own people left them to die. Initially bewildered that a species might purposely try to kill its own young—an idea which he, as any good Vulcan would do, deems “illogical”—Tuvok eventually discovers that the children are actually elderly, and their species’ growth process works the other way around, almost a la Benjamin Button; they’re born as elderly grown-ups, and they rejuvenate and de-develop from adults into children as they approach the end of their lifespan; the monster is just a story.

Forget that this makes no biological or evolutionary sense whatsoever; forget the unique opportunity to study a spontaneous process of multicellular rejuvenation and its potential applications; forget that this would imply death in this species occurs only for the sake of ending each individual’s life, with no apparent cause. The really grave offense here is Tuvok’s parting words to the last of the terrified children after the rest have disappeared (read: died): there is nothing to fear at the “natural” end of her life cycle (why not? And why, then, is there anything to fear at the “unnatural” end of life?), which he can’t and doesn’t want to interfere with. Apparently, in this particular instance, the otherwise inflexibly logical Tuvok was glad to throw logic out the airlock. Though to be fair, under the circumstances, Tuvok couldn’t really do much else, and what is most despicable aren’t his actions as much as the message the authors tried to convey.

There are more examples of how Star Trek glosses over the problem of aging and how some characters have an ambivalent attitude towards death, but I’d rather stop here. Don’t get me wrong; I still love Star Trek, but in some respects, it didn’t go nearly as boldly as it could have.

Dr. Hypocrite

Dr. Who’s episodes are often just as scientifically cringeworthy as they are brilliantly hilarious—so much so that one is willing to turn a blind eye to the numerous examples of downright nonsense. However, I couldn’t bring myself to do so in the case of the episode “The Lazarus Experiment.”

An ingenious yet obviously unscrupulous elderly scientist invents a machine to rejuvenate people. In a public demonstration of his invention, the man steps into the fancy-looking piece of machinery, and after some light show, he leaves the contraption some fifty years younger. The Doctor and his trusty companion are nearby and visibly worried about what he’s just witnessed, he confronts the scientist about it. The Doctor knows how the machine works and tries to persuade the rejuvenated scientist that each man has his own time and that “It’s not the time [that you live] that matters, it’s the person [you are].” Forgetting clichés and non sequiturs, it is important to keep in mind that the Doctor belongs to a species whose members, despite their entirely human appearance, are able to regenerate whenever they’re close to death; at this point, the Doctor had regenerated ten times already (and his incarnations aren’t always very faithful to the original), and ironically, he was about to do it again in the very next episode, when his life was at risk. Each man might have his own time, but the Doctor has been postponing his meeting with the Reaper for a good nine hundred years (and counting).

To complete this rather hypocritical collection of clichés, the rejuvenated scientist eventually transforms into a monster—yet another “lesson” that trying to extend your life is a bad idea.

The example of “Passengers”

The movie “Passengers” is set on a fully automated starship in which people who want to start over on a new world are placed in stasis capsules and sent off to a faraway planet in a journey that will take 120 years. The unlucky main character’s capsule malfunctions and he wakes up, all alone, 90 years in advance. There’s no reason for me to spoil the plot further. There’s nothing in it that I criticize per se, and the whole story hinges on the fact that he, in his 30s or so, will be long gone before the ship may reach its destination; without aging, this plot wouldn’t make any sense. Yet, it is another example of a story where, apparently, in the future, we’ve made no progress against aging. I couldn’t help thinking about it the whole time; in the future portrayed by this movie, we managed to build a huge, fusion-powered starship that is full of stasis capsules that bring metabolism to a complete halt (for the very purpose of preventing death by aging during the trip) and then restart it, but we’re still unable to cure aging.

Conclusion

Superluminal starships, teleporters, and holodecks, despite the fact that they don’t exist yet and we’re not even sure that they can, are something we’re perfectly used to and can easily imagine, because many people have dared to describe what life with them might be like; however, very few, if any, have dared to envision and show a world without aging, even though the science that might take us there, early-stage as it may be, is already here. Furthermore, rather than showing curiosity towards this brave new world that might await us, many people show disinterest or even contempt.

Of course, stories in which humanity manages to overcome aging or death do exist, but generally, it’s a power that only a few have and is generally depicted as a burden to carry, even though there is no evidence that this would be the case.

It’s a glaring demonstration of foxes disdaining grapes, of an extremely long-term Stockholm syndrome, and of the pervasiveness of the pro-aging trance. It’s high time that we woke up from it.

Date Posted: May 8, 2018
4 Comments

Recoding Human Cells to Make them Virus Proof

On May 1, around 200 scientists from the Genome Project-write (GP-write) met in Boston and announced the first target of their project: the creation of cells that cannot be infected by viruses.

What is the Genome Project-write?

GP-write includes sub-projects like the Human Genome Project-write (HGP-write), which was formally announced on June 2, 2016, and is an extension of the Genome Projects, which were launched in 1984. These projects were created to develop ways to read DNA in microbes, plants and multiple animal species, including humans.

GP-write was initially met by some level of panic and alarm, as some of the media misrepresented the project and people’s imaginations ran amok. Suggestions of “secret meetings” and stories of scientists creating designer babies and superhumans were doing the rounds, regardless of the actual scientific reality of the project. However, stories of mutants, superhumans, and manbearpigs are greatly exaggerated.

The newly created GP-write project will be managed by the Center of Excellence for Engineering Biology, a new nonprofit organization. With a firm commitment to cost reduction, safety, and ethical conduct, there could be considerable scientific advances as a result of this project.

The Genome Project-write (GP-write) is an open, international research project led by a multidisciplinary group of scientific leaders who will oversee a reduction in the costs of engineering and testing large genomes in cell lines more than 1,000-fold within ten years.

GP-write will include whole genome engineering of human cell lines and other organisms of agricultural and public health significance. Thus, the Human Genome Project-write (HGP-write) will be a critical core activity within GP-write focused on synthesizing human genomes in whole or in part. It will also be explicitly limited to work in cells, and organoids derived from them only. Because of the special challenges surrounding human genomes, this activity will include an expanded examination of the ethical, legal and social implications of the project.

Engineering virus-resistant cells

Jef Boeke, one of the four leaders of GP-write, said, “There is very strong reason to believe that we can produce cells that would be completely resistant to all known viruses.” He continued further: “It should also be possible to engineer other traits, including resistance to prions and cancer.”

The project takes the original Human Genome Project and builds upon it. The GP-write project could see rapid progress, given the sheer number of collaborating labs comparing data, verifying the results, and conducting safety analysis. This could be a game changer for stem cell therapies, as these robust, virus-proof cells could be used to treat a variety of diseases.

The team plans to engineer resistance to viruses using a technique known as recoding; this depends on the fact that much of the genetic code is redundant. Each three-letter sequence of DNA letters is known as a codon, and these codes are specific to the production of a particular amino acid. The chart below shows the codons for each amino acid.

Amino AcidDNA codons
IsoleucineATT, ATC, ATA
LeucineCTT, CTC, CTA, CTG, TTA, TTG
ValineGTT, GTC, GTA, GTG
PhenylalanineTTT, TTC
MethionineATG
CysteineTGT, TGC
AlanineGCT, GCC, GCA, GCG
GlycineGGT, GGC, GGA, GGG
ProlineCCT, CCC, CCA, CCG
ThreonineACT, ACC, ACA, ACG
SerineTCT, TCC, TCA, TCG, AGT, AGC
TyrosineTAT, TAC
TryptophanTGG
GlutamineCAA, CAG
AsparagineAAT, AAC
HistidineCAT, CAC
Glutamic acidGAA, GAG
Aspartic acidGAT, GAC
LysineAAA, AAG
ArginineCGT, CGC, CGA, CGG, AGA, AGG
Stop codonsTAA, TAG, TGA

Hundreds or even thousands of amino acids are linked together to create proteins; these signal our cells to perform certain functions, and they include insulin, collagen, myosin, and many thousands of others.

Despite this deeper complexity, there are just 20 amino acids and a “stop” signal, and there are 64 combinations of the four DNA nucleotides. However, life can continue with only one codon for each amino acid. For example, during recoding, you might choose the GTT in, say, valine, and whenever the three redundant ones (GTC, GTA, and GTG) appear in the genome, they are replaced by GTT. This essentially means that every time one codon is replaced by another, you are removing one codon from the genetic codebook and reducing the complexity.

But why would we bother doing this?

Here is where the viral resistance comes in. Because the genes of a virus contain these redundant codons, the virus can enter the cell and take control of the cell’s genetic machinery. In the case of a recoded cell, the virus would not be able to take over the control system and use it to create more viruses; the cell would lack the ability to create the viral proteins it needs to proliferate, and so the cell would be immune to viral infection.

George Church, one of the GP-write project leaders, has already tested the approach in E.coli. His team replaced all 321 instances of one redundant codon in its genome, which rendered the bacteria resistant to the bacteriophage T7 virus. Church took this a step further in 2016 and replaced seven redundant codons in around half of the same bacteria’s genome [1]. This required the replacement of 62,214 redundant codons with synonymous alternatives across all protein-coding genes.

The project aims to make virus-proof human cells within 10 years, but to do that, the number of codon replacements would be around 400,000 in order to affect around 20,000 protein-coding genes. This is a monumental task, and it is why the GP-write leaders suggest that writing genomes from scratch, not editing them with CRISPR, is a better approach.

Jef Boeke said, “We have nothing against CRISPR. We love it and use it all the time. But we’re talking about changes that are just massive. It’s like if you’re editing a short story: if you’re changing so much of it, you might as well just rewrite the whole damn thing.”

In order to build a genome from scratch, it would mean synthesizing DNA one nucleotide at a time and joining thousands of these together. While it is possible to do this with today’s technology, it is a laborious and slow process. To give you an idea, it costs around a dollar to synthesize 10 DNA letters, meaning that it would cost $300 million to do the human genome.

The GP-write project team aims to drive down synthesis costs by a factor of 1,000, thus making the idea a much more practical proposition. Church has already indicated that he wants to synthesize all human genes through joining 200-letter-long strands, which we can do now with currently expensive technology. Those familiar with Church will almost certainly know that he has been instrumental in driving down the costs of gene editing in the past, and the members of this project are confident that they can do so again here.

Conclusion

There is huge potential here for not only reducing costs and contamination but also for creating in vivo therapies that potentially introduce replacement cells that are impervious to viruses, such as HIV, resistant to other diseases, such as cancer, and even resistant to damage from aging and radiation. A look at the goals of the project published last year makes it quite clear that the ultimate goal is to develop this for in vivo therapies, such as stem cell transplants.

There is an unmet need for an “Ultrasafe human cell line” designed to serve as a platform for many biomedical applications, from production of biologics, to modeling cell and tissue behaviors, to actual ex vivo and ultimately in vivo therapeutic applications.

As we improve our ability to edit and create genomes from scratch, a world of options opens up for combating diseases, and we look forward to seeing more progress from the GP-write team.

Literature

[1] Ostrov, N., Landon, M., Guell, M., Kuznetsov, G., Teramoto, J., Cervantes, N., … & Shrock, E. (2016). Design, synthesis, and testing toward a 57-codon genome. Science, 353(6301), 819-822.

Date Posted: May 7, 2018
Comments Off on Fasting might boost intestinal stem cell function

Fasting might boost intestinal stem cell function

Stem cells supply the specialized cells that make up our tissues and organs; every time existing cells are lost for whatever reason, stem cells that can differentiate into that particular type of cell jump into action to compensate for the loss. However, this ability declines over time as aging progresses; indeed, stem cell exhaustion is one of the hallmarks of aging, and it affects our body by decreasing the regenerative capacity of its tissues, leading to immune dysfunction, muscle wasting, and even neurodegenerative diseases.

The lining of your intestine suffers from this problem as well. It consists of a fast-renewing tissue that typically renews itself entirely in a handful of days, and it is responsible for absorbing nutrients as well as keeping away unwanted substances; maintaining its regenerative abilities is therefore important for everyone, old or young; however, for older people, this is more challenging. However, a relatively easy way to boost intestinal stem cell (ISC) function might simply be fasting, according to a new study by a team of MIT biologists [1].

The study

The fact that caloric restriction yields health and longevity benefits in different kinds of organisms, possibly including humans, has already been known for a while. However, it is as of yet unclear what mechanisms cause this effect and to what extent people may benefit from it.

MIT researchers, including Maria Mihaylova, David Sabatini, and Chia-Wei Cheng, wanted to find out how fasting affects intestinal cells in particular. To this end, they set up an experiment in which murine intestinal stem cells were extracted from the animals after a mere 24-hour fast; the regenerative capacity of these cells was subsequently put to the test in a petri dish, where the scientists observed their ability to grow intestines as organoids, which are simplified and smaller versions of actual, full-size organs and are grown in vitro rather than in vivo. As it turned out, ISCs from fasting mice had twice the regenerative capacity of cells coming from controls, and the effect was observed both in young and elderly mice.

Once the effect was observed, the scientists tried to figure out exactly why fasting caused it. According to their analysis, fasting activates PPAR (peroxisome proliferator-activated receptor) transcription factors in ISCs, which switch on several genes that change ISC metabolism. Under these conditions, ISCs switch from metabolizing carbohydrates—which is what they would normally do—to metabolizing fatty acids instead. Suspecting that PPARs were connected to the observed benefits, the scientists repeated the experiment in mice in which the PPAR pathway was turned off and noticed that fasting didn’t help in this case; therefore, it seems that the positive effects of fasting on ISCs are due to its action on PPARs. Why this change enhances ISCs’ regenerative abilities is not yet clear, but this is what the scientists plan to find out next.

Interestingly, the MIT team managed to obtain the same effect without a need for fasting. They administered a molecule that mimicked the PPAR effects to non-fasting mice, and it gave them the same regenerative boost to their ISCs. This means that a drug to induce enhanced ISC regeneration in human patients might be possible without the patients having to go through the trouble of fasting, which can be difficult or simply not an option in certain cases. This type of drug would be especially useful for patients with impaired ISC regeneration, such as elderly people who suffer from intestinal infections or oncological patients undergoing chemotherapy—a side effect of which may, indeed, be damage to intestinal cells.

In addition to finding out how exactly the PPAR switch enhances ISC regeneration, the researchers would like to study whether the same beneficial effects of fasting can be obtained in different types of stem cells as well.

Literature

[1] Mihaylova M. M., Cheng C., Cao A. Q., …, Katajisto P., Sabatini D. M., Yilmaz O. H. Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging, Cell Stem Cell, Cell Press.

Date Posted: May 3, 2018
2 Comments

Undoing Aging 2018 – Dr. Nichola Conlon

Today, we have an interview with Dr. Nichola Conlon, one of the speakers at the Undoing Aging 2018 Conference in Berlin, hosted by the Forever Healthy Foundation and SENS Research Foundation.

Introducing Nuchido

Dr. Conlon is the CEO of Nuchido, a new company that is set to launch later this year and was encouraged in part by four recent breakthroughs in biogerontology, which each showed rejuvenation in mammals [1-9]. These studies, which were all published in leading peer-reviewed scientific journals, showed that rejuvenation of aged animals was possible via different mechanisms of action.

Taken as a whole, these recent results show without question that not only can rejuvenation be achieved in aged mammals, the scientific understanding of aging, and what might be done about it, is far ahead of the common conceptions that rejuvenation is not possible and that aging is a one-way process. Science shows us that nothing could be further from the truth.

Nuchido has set out to translate these advances in aging research into actionable therapies for humans by using a systems pharmacology approach to identify active molecules and combinations that can positively influence the aging processes. This approach is well-suited to the complexity of biological systems, particularly aging.

Unlike traditional pharmacological approaches, which use a one-drug, one-target approach, systems pharmacology addresses the complexity of a living biological network. It uses network impact analysis to identify the combinations of interventions that are most likely to have a significant impact on a biological network. It also uses this system to identify key areas of weakness within a biological network as leads for potential interventions.

Targeting NAD+ as a route to rejuvenation

During her presentation at Undoing Aging 2018, Dr. Conlon talked about how her company has used this approach. Her company identified the decline of NAD+ as being a potential target for therapy in order to restore youthful NAD+ levels and thus trigger rejuvenation.

Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in all living cells. It is a dinucleotide, which means that it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base, and the other contains nicotinamide.

In metabolism, NAD facilitates redox reactions, carrying electrons from one reaction to another. This means that NAD appears in two forms in the cell; NAD+ is an oxidizing agent that takes electrons from other molecules in order to become its reduced form, NADH. NADH can then become a reducing agent that donates the electrons it carries. The transfer of electrons is one of the main functions of NAD, though it also performs other cellular processes, playing a key role in energy metabolism and serving as a signaling molecule that regulates many cellular processes, including DNA repair.

Unfortunately, as we age, NAD+ levels decline, causing dysfunction and contributing to the aging process. Breakthrough research in 2017 demonstrated that the restoration of NAD+ levels to youthful concentrations was able to induce significant rejuvenation in mice. This was achieved through feeding the mice so-called NAD+ precursors, compounds that the body converts into NAD+ through a series of chemical reactions.

However, Nuchido does not believe that NAD+ precursor supplementation alone will deliver robust long-term benefits in humans. One reason for this is because NAD+ precursors are costly when the dosage is scaled up from mouse to human body weights. Another reason is that while increasing the input to a biological system may result in increased output in the short term, it is likely to lead to a decline of efficacy in the long term as the system readjusts to the new input level.

To address this, the company is using systems pharmacology to design therapeutic “cocktails” that contain multiple therapies to be delivered at once. This cocktail contains NAD+ precursors along with other compounds that act on the enzymes that produce and destroy NAD+; the ultimate aim is to increase the NAD+ in the system while also increasing and maintaining the activity of the machinery that produces NAD+.

The company created its first therapeutic cocktail called NCD201, which was designed for oral consumption. Working with a university laboratory, they tested its effect on a single 57-year-old male as an initial proof of concept for the approach.

According to Nuchido, the results showed that NAD levels during the two-week period of treatment with NCD201 were raised, on average, by 331% above the subject’s baseline (381% week 1, 272% week 2). The peak enhancement was 1,010% on Day 5, a value that corresponded to 4.27ng NAD/ug protein; this would be the NAD+ level of an average 19-year-old, while the average enhancement across both treatment weeks corresponded to a reduction in biomarker age of more than 20 years.

As NCD201 appears to be more potent than any other NAD+ induction approach currently known, Nuchido is now conducting further tests with a larger number of subjects.

Investigating senolytics

As your body ages, increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals, which encourage other nearby cells to also enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer.

The solution to this could be senolytics, a class of drugs or therapies that cause these problematic senescent cells to destroy themselves in order to reduce inflammation and improve tissue function.

Dr. Conlon informs us that Nuchido has submitted a collaborative research proposal to Professor Thomas von Zglinicki’s laboratory to screen and evaluate selective senolytic molecules. The current catalog of selective senolytics is small; the hope here is to work with Zglinicki’s laboratory to increase the number of senolytics via screening and applying a systems pharmacology approach to the search.

The ultimate goal

The company states that it initially aims to market consumer products that can be used in the near future and then follow up with more robust pharmaceutically regulated drugs further down the line.

We caught up with Dr. Conlon at Undoing Aging 2018 and talked to her about the company and its goals.

Can you tell us a little bit about yourself, your research background, and what first got you interested in aging research?

I have always been fascinated by the complexity of the human body.  I have always wondered how something can be designed so perfectly, allowing us to exist as we do.  So many complex processes are occurring in our bodies at any given second and for me that is mind-blowing.  I have always loved trying to learn and understand how it all works. Ultimately, this led to a career as a research scientist, initially specializing in drug and nutrient transport around the body.  A Ph.D. in epithelial physiology made me a molecular biologist by trade and my particular skill set was well suited to a career in drug development, which I actively pursued. It was at this point that I first became interested in aging research quite by accident.  During a job interview, I was asked: “If I could develop a drug to treat anything what would it be?”. My answer was aging. Drug discovery is focused on understanding what goes wrong in the body during disease and how we can manipulate the system using bioactive molecules to restore order.  Aging is a good example of how the body can become dysregulated in spectacular fashion. So why isn’t aging something that we should treat? This was something that struck a chord with me and from then on I have studied the science behind aging and rejuvenation.

Why do you think treating age-related diseases is important for society?

I would argue that it is not age-related diseases that we need to treat, but the underlying cause of these diseases which is actually aging itself.  The biggest risk factor for developing cancer, diabetes, Alzheimer’s and cardiovascular disease is age. Putting years on is worse for you than smoking cigarettes. If we continue to treat each disease individually then we will constantly be fighting a losing battle as the next set of age-related problems become apparent.  However, if we address the root cause of all these problems then there is a chance that we can address most of these diseases simultaneously, resulting in a much bigger improvement in the quality of life. Rather than spending a lot of money trying to tackle each disease individually why not tackle the root cause? This question is hugely important for society. Over the past century, modern medicine has made enormous strides in improving sanitation and eradicating disease resulting in a large increase in life expectancy.  No-one would argue that this is a bad thing. However, we are now in a situation where this extended aging has led to an increase in age-related disease, loss of mobility, frailty and physical discomfort. People are living a lot longer than the body was designed for and in developed countries an aging population is putting great strain on health and social services. Great progress has been made to stop us from dying young, but now we need to make sure we live these longer lives healthier.

Many people believe that aging is something that cannot be reversed despite the numerous examples that show it can. Why do you think there is such a gap between what the public believes about aging and what science shows us?

I think this is for two reasons.  The first is that until recently, even within the scientific community, aging was very much viewed as something inevitable. This, coupled with the fact that most consequences of aging are rather undesirable, has led to society accepting aging as an unavoidable part of life. As a result, our lives are structured around the idea of life as a finite commodity whose currency is time.  We view and plan our lives as a timeline: when to settle down, when and with whom to partner, when to get a mortgage, when to have kids, when to retire, when to start planning for our age-associated physical and mental decline. This timeline is usually based on what we have witnessed around us and what we are programmed to expect. The idea of age reversal makes people question this core structure of life and this can be difficult to comprehend.

The second reason is the lack of public understanding as to the objectives of age reversal. Many people presume that the increased lifespan resulting from reversing aging will simply increase the duration of the end portion of their lives, commonly perceived to be characterized by frailty and disease.  For this reason, many people refuse to accept age reversal as a positive concept. Longer in the nursing home! Many people don’t understand that the real goal of reversing aging is to improve the number of years we live in good health (so-called healthspan). Increased lifespan is simply a consequence of improved healthspan.

What is the biggest bottleneck in aging research that is holding back progress?

Failure to recognize the fact that aging is the biggest risk factor for all major diseases to which you and I will ultimately capitulate.  This lack of recognition by decision makers means that current funding and resources are pigeon-holed into research on specific diseases. For example, compared to cancer research, funding for aging research is minuscule despite the fact that the biggest risk factor for developing cancer is age. The current approach to deal with age-related disease is very much focused on damage control, trying to fix a problem when signs and symptoms have already started.  Surely a preventative strategy where research efforts target the root cause would be far more beneficial.

Can you tell us a bit more about how you use systems pharmacology to screen for candidates?

Biology is extraordinarily robust to almost every kind of insult or assault since evolution has selected biological function for this robustness.  Whilst this is mostly good news for mankind, it makes the process of drug discovery challenging since this underlying complexity must be addressed. Conventional drug discovery favors a reductionist approach, looking to design molecules to knock out very specific targets.  This approach underestimates the complexity of biology and as a result, has an incredibly high rate of failure. Approaches that focus on individual targets will seldom have a strong impact since biology displays a high level of redundancy. Knock one target out and you can bet there are several other backup pathways that will override the desired effect.

Unlike this reductionist approach to molecular discovery, systems pharmacology accounts for the robustness and complexity of biological systems by addressing network properties rather than single targets. By analyzing the networks that mediate the physiology we are trying to change, we identify specific combinations of multiple targets likely to have a great impact upon the network by taking advantage of specific network properties that pose areas of weakness in an otherwise highly robust system.  Multiple targeted interventions in biological networks always produce greater network impact than a single intervention. Such high-impact combinations are very rare and are unlikely to be found unless they are specifically optimized or searched for. This approach is highly suited to complex biological systems such as aging. We then leverage chemical biology data – not just what proteins stick to, but data on changes in expression or abundance, phosphorylation state changes, methylation, etc – to select molecules and combinations that deliver the interventions we are looking for.

How do you compensate for off-target effects and potential adverse interactions created by combinations of compounds?

At first glance, it may seem that using combinations of multiple compounds may increase the likelihood of off-target effects suggesting that this is a riskier strategy than intervening at a single target. This would only be true, however, if drug molecules did in fact only intervene at the designed “target”. But they don’t, as has become increasingly obvious as chemical biology has developed. It is now known that most or all drugs are promiscuous and rarely stick to one target and that their presence in a cell generates a host of “pleiotropic” effects that are made visible through chemical biology techniques. Hence, the presence of a molecule in the body can trigger a pattern of interventions in networks far beyond its designed primary “target”.  We mitigate the risk of potential off-target effects or negative synergy by using chemical biology to carefully assess combinations of molecules for their impact on the network as a whole, including, the specific binding footprint, downstream pleiotropic effects and potential polypharmacology due to active metabolites of a molecule.

What made you focus on NAD+ as an intervention against aging?

Whilst initial results that we have shared publicly are related to NAD+, this is not the primary focus of Nuchido.  Our aims are broad, in-keeping with our belief that in order to impact ageing, interventions must be designed to target multiple underlying processes. Currently, we are focused on translating the results from four recent breakthroughs in biogerontology that have demonstrated rejuvenation in mammals, namely, selective removal of senescent cells, partial epigenetic reprogramming, increasing NAD+ titers and the rejuvenating properties of young blood.  Each of these results has demonstrated rejuvenation in mammals in vivo; each was from a recognized research institute or university and published in a leading peer-reviewed scientific journal, and each was motivated by a different underlying mechanism of action. Nuchido’s task has been to translate these scientific advances into interventions suitable for people, using our expertise in systems pharmacology to identify suitable active molecules and combinations.

Regarding candidate NCD201, when will the data be published, and are there plans to have this independently reproduced and verified?

Data will be published upon completion of a larger in vivo study which we anticipate will begin in the next couple of months.  A publication will be alongside our university partner laboratories, which are all led by well-known and respected scientists in the field of biogerontology.

What encouraged you to focus on senolytics as a therapy against aging?

In our view, the rejuvenation results following the removal of senescent cells represent a real breakthrough in the field of biogerontology.  Senescent cells are key players in the ageing phenotype. They accumulate with age, they are a major source of deleterious circulating and local inflammatory factors and they increasingly fail to perform their somatic duty, ultimately leading to organ failure.  Results demonstrating substantial multi-tissue regeneration following removal of just a small proportion of these cells are very promising for the field of rejuvenation. However, despite worthwhile funding for senolytic research, potent and selective senolytic candidates so far identified are very few. We fear this is because conventional drug discovery approaches still prevail.  We believe our approach can find desirable senolytic molecules more efficiently, faster and cheaper.

Regarding your near-term goal of marketing consumer products, this sounds like more supplements. Given the lack of data that supplements and supplement blends affect human lifespan in any way, why did you choose this route, and how will the products you offer differ?

The most obvious way that advances in rejuvenation can be translated into a benefit is through developing drugs that affect these mechanisms. However, Regulators do not currently recognise ageing itself as a disorder for which a drug can be regulated; drug clinical trials are likely to be very lengthy and costly in this area; probably too lengthy to accommodate patent monopoly periods; and the combination of time, cost and risk conspires to make it quite unlikely that anti-ageing drugs will be developed in number in any foreseeable future.

On the other hand, many molecules that affect these processes are known and considered to be safe. A way to derive benefit for people much more quickly and practically than through developing regulated drugs is to use combinations of these molecules as nutraceuticals or supplements, motivated by both the new scientific results and a systems pharmacology approach.

There are many supplements on the market today with a lot of promises and not much data.  We do not plan to follow suit. At Nuchido we pride ourselves on efficacious products and scientific credibility.  All the research we do will be published with the aim of advancing scientific understanding of the ageing process and of how it can be mitigated or reversed using our products.

How does this initial strategy fit into the longer-term goal of developing pharmaceutically regulated drugs?

The path to regulated drugs will undoubtedly be long, winding, and cosmologically expensive.  Current development takes on average 13 years and that does not include the hurdle of getting regulatory bodies to recognise ageing itself as a disorder for which a drug can be regulated.  But this does not mean we should sit back and wait. As we operate our discovery processes, we frequently encounter molecules that are more suitable as candidate drugs than as retail product candidates, and pre-clinical development of these assets can occur in the background.  Our foreground purpose, however, is to provide beneficial market-acceptable products, consisting of safe ingredients with proven efficacy, and to make these available to people who are not prepared to wait 13+ years. This business model benefits consumers by giving them products right now that they can use as part of an anti-ageing regime, and also benefits scientific research by generating income to fund further research and data.

What are the next steps for Nuchido?

The immediate future involves a larger in vivo study of NCD201.  Results from this study will be published, closely followed by productization of an oral supplement based on NCD201.  It remains the case, however, that potentially the largest target market for products that deliver real beneficial change in cellular and tissue ageing is skincare. Having gained initial evidence of high efficacy in enhancing NAD via an oral route with NCD201, we are working toward the formulation of NCD201 and similar cocktails for topical administration as anti-ageing skincare.

Do you have a take-home message for the readers?

I think the field of anti-ageing and rejuvenation research is on the cusp of something great.  A change is coming that is going to make us rethink the way we live our lives.

We would like to thank Dr. Conlon for taking the time to talk to us about her research and company, and for the superb talk she gave during the Undoing Aging 2018 conference.

Literature

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

[2] Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., … & Schoonjans, K. (2016). NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science, 352(6292), 1436-1443.

[3] 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.

[4] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[5] Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell, 15(5), 973-977.

[6] Zhu, Y., Tchkonia, T., Fuhrmann‐Stroissnigg, H., Dai, H. M., Ling, Y. Y., Stout, M. B., … & Wren, J. D. (2016). Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors. Aging Cell, 15(3), 428-435.

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

[8] Katsimpardi, L., Litterman, N. K., Schein, P. A., Miller, C. M., Loffredo, F. S., Wojtkiewicz, G. R., … & Rubin, L. L. (2014). Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science, 344(6184), 630-634.

[9] Shin, E. J., Wagers, A., & Jang, Y. C. (2016). Rejuvenation of aged neuromuscular junctions (NMJ) by exposure to a young systemic environment. The FASEB Journal, 30(1 Supplement), 767-5.

Date Posted: May 2, 2018
2 Comments

Aging is No Laughing Matter

If you watched a TV show, or read a comic book, where the difficulties and suffering of an oncological patient were portrayed in a disrespectful, humorous way, you would likely be outraged; at the very least, you would think that the show or comic book was in seriously bad taste. You’d probably think the same about similar material involving a disabled person or anyone who, because of an incurable disease, had only a short time to live spent in increasing misery—for example, a child affected by progeria, a disease that may best be described as a sort of accelerated aging syndrome that kills off its victims in their mid-twenties at the very latest.

Yet, it is not uncommon to see the diseases of old age, and even elderly people in general, being laughed at in just such a way without causing much outrage at all. Why is there a difference?

We’ve all seen this

You can probably recall plenty of examples of this phenomenon from your own experience. Who has never seen a sketch where the main characters are exasperated by a shriveled, elderly man who, holding up an old-fashioned ear trumpet, keeps getting wrong what they are saying despite all their efforts? How many times have cheap laughs been gotten because of an elderly person losing his or her dentures or a rambling old man exaggeratedly ranting about pretty much everything?

Speaking of ranting, this isn’t the usual rant on newer generations disrespecting older ones; and, admittedly, in certain circumstances, what is tragic may become tragicomic and make us laugh even when it should really make us cry. Being unable to hear, or having no teeth, is not fun at all, but being able to laugh at our own misfortunes is part of why we are such an adaptable species—though truth be told, the situations outlined above are examples of schadenfreude rather than the ability to laugh at oneself. Besides, it’s not just that people laugh at the adversities faced by other, elderly people; sometimes, people make impressions of themselves as old people and laugh at that. To refer again to TV shows, many of them each have an episode in which the main characters are shown as they will be far into the future, old and grey, with plenty of stereotypical gags accompanied by generous amounts of canned laughter. Again, this is probably part of the human ability to face the inevitable with a pinch of humor, but when you think about it, this is rather appalling.

I recall perfectly well friends of mine, in their early 20s, imitating elderly voices and postures and even shaking, imagining this will be them in 60 years, and laughing at it with gusto. I once witnessed a young acquaintance doing not only this but also saying that, when she’s old, she’d like to have her hair of the same “lovely” grey as that of an elderly lady passing by. A common type of acting exercise in theater is that of pretending to be of a different age; the director may ask you to present yourself as a toddler, a teenager, middle-aged, or elderly in order to show the rest of your acting group what that age is like. As an amateur actor, I’m very familiar with this, and invariably, when the director says, “Now you’re elderly, in your 90s,” everyone slows down, hunches over, shakes, pretends to aid himself or herself with a walker, and feigns confusion or poor eyesight—sometimes seriously, sometimes trying to add a humorous undertone to it. In a variant of this exercise, you’re asked to portray the timeline of human life; you start at one end of the room as a toddler, and as you walk your way to the opposite end, you act out infancy, teenage, adulthood, old age, and even death.

To be fair, this kind of exercise may easily make you laugh at any point of the performance, as actors tend to purposely exaggerate every step for fun; however, more than once, as I rather uncomfortably had to perform this myself, I stopped to wonder whether others realized that the final moments of their own performances were probably not too unlike what their final years will be, barring rejuvenation. Did they realize that this was no fantasy scenario? That one day the very frailty they made fun of will have the last laugh? That it probably won’t be so amusing anymore when an order from the director will no longer be enough to make them stop shaking, walk straight without aids, and see properly again?

There’s nothing wrong with the acting exercise per se, and it is certainly not meant to be disrespectful, but what we all should wonder is, how do most people not realize the horrifying reality of aging, even when they have just acted it out? Maybe some do; I never dared asking, fearing that it would be inappropriate in the context. Perhaps I should have.

Why do we do this?

The psychological mechanisms that we developed over the course of millennia to cope with aging are obviously the culprit here, not only making us fail to notice the obvious but making us sugar the pill as well. In many popular media and forms of entertainment—such as cartoons, comics, and TV shows—old people are often shown as slow, decrepit, and perhaps somewhat demented, but all of it is presented not as the tragedy that it is but in a rather humorous light instead, and a thousand other afflictions of old age are neglected all the while. (After all, some people may laugh when they imagine themselves old, but very few people laugh when they imagine themselves having heart disease or cancer.) This is not very different from the good old gag of the falling grand piano. It’s hilarious to see Bugs Bunny crushed by a grand piano falling from the top of a skyscraper and then see him get up shortly thereafter, faltering about cross-eyed, while miniature grand pianos circle his head. Except if you saw this happening for real to a person, you wouldn’t find it funny in the least, and the odds are that the person would never get up again.

If we portrayed aging more accurately, would we still find it funny? Laughing at something tragic while it happens, when we’re powerless to stop it, is an understandable coping mechanism. Laughing at the very same thing when it’s far ahead and might be prevented if we only got serious about it, on the other hand, is just irresponsible.

Probably none of this is intentional. Most people simply don’t realize the magnitude of the problem that they’re laughing at nor the fact that we now stand a decent chance of solving it. Sometimes, we laugh at things that really shouldn’t be laughed at, and it’s not automatically a crime if such a thing happens to be aging; I can see how some aspects of it may appear funny if you are able to ignore the tragedy going on behind the scenes. However, after all these years spent in advocacy, I am no longer able to ignore it, and I have stopped finding gags about aging funny altogether. I’ll laugh about it again once the final nail is put into its coffin.

Date Posted: May 1, 2018
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Rejuvenation Roundup April 2018

As April ends and, at least in the Northern Hemisphere, summer approaches, let’s have a look at the progress of worldwide efforts to extend the summer of life.

Kazan 2018: Interventions to Extend Healthspan and Lifespan

The highlight of April was unquestionably the Interventions to Extend Healthspan and Lifespan Conference, which was held in Kazan, Russia on April 23-26. Featuring over 40 distinguished speakers from the field of aging research, this conference, which was the fifth in the series, included talks on epigenetics, genomics, metabolomics, aging biomarkers, bioinformatics, effective advocacy, and more. LEAF board director Elena Milova attended the event and had the chance to interview several of the experts present, such as Dr. Andrei Gudkov and Professor David Gems. We will publish more interviews of these speakers in the coming weeks, so stay tuned!

In the beginning of April, Elena and a famous Russian sociologist, Anton Smolkin, organized a sociological study in Russia to see whether, and how much, people who regularly read about rejuvenation research accept the idea of healthy life extension more than the general public. The results of the study will be published later this year, but what we can say for certain is that the share of supporters is 2-3 times greater among the readers, and these people are much more interested in significantly extending healthy life (from several human lifespans to an indefinitely long life in good health). Unlike the results of a previous study in the general public, women were found to prefer a more conservative scenario of life extension compared to men in this new study, which is an intriguing result and is probably going to be the topic of the next study.

These results were reported by Elena at the conference in Kazan during her talk on the subject of how to effectively communicate with the general public to inform them about the exciting prospects offered by rejuvenation biotechnologies.

SRF and the Undoing Aging conference

As you certainly recall, last month, the first Undoing Aging conference took place in Berlin, Germany. If you wish you had attended but couldn’t, fear not; the organizers of the conference are uploading videos of the conference talks on UA’s website. Speaking of the conference, this month, we have published some of the interviews that LEAF had the pleasure to get from the researchers who joined the event, namely those of Dr. Brian Kennedy and Dr. Jonathan Clark. We’ve also got an interview with LEAF’s own President, Keith Comito, discussing various aspects of professional rejuvenation advocacy. We’d like to thank journalist Anna Dobryukha of Komsomolskaya Pravda for her most valuable collaboration on all these interviews; in case you missed out on it, take a look at her interview with the Ether cryptocurrency billionaire Vitalik Buterin, which we translated for our blog.

Senolytics are all the rage these days, and with good reason, since they stand a good chance of becoming the very first rejuvenation biotechnology to reach the clinic. Senescent cells, which senolytics are meant to selectively destroy, have been implicated in all sorts of age-related conditions, and that includes Parkinson’s disease. In this article, Michael Rae from SENS Research Foundation discusses senescent astrocytes (a type of brain cell), their involvement in Parkinson’s disease, and how research on a banned pesticide set scientists on the right track.

Fight Aging’s digest

Mitochondria, the powerhouses of the cell, appear to be involved in many of the pathways that we may have to work on in order to slow down and reverse the course of aging. The main issue with them is that, over time, they accumulate unwanted, random mutations to their own DNA and wind up taking over their own cells, turning them into free-radical production facilities. However, the scientific community hasn’t yet reached consensus on what mtDNA mutations matter and how they come to be.

In other news, interesting progress has been made towards a vaccine against LDL cholesterol, which is also known as “bad cholesterol”. This molecule plays a central role in heart disease, and its accumulation in blood vessels may lead to fatal strokes. Thanks to progression in vaccination technology, scientists are now able to turn the immune system against this threat as well—at least in mice. On the subject of heart disease, in this post, FA! presents a study about high- and low-risk plaques in atherosclerosis.

Long Long Life

The life extension community is expanding, and it is doing so quickly. The idea of healthy life extension is becoming more popular every day, and it’s changing from a fringe topic to a popular one that is frequently dealt with and debated on different parts of the Internet. You can see this when you notice how many new websites on the subject are launched, and one example is Long Long Life, which was founded by three French scientists: Dr. Guilhem Velvé Casquillas, Mathieu Velvé Casquillas, and Dr. Christophe Pannetier. While LLF was launched in 2017, we would like you to take a look at some of its recent articles, including one about telomeres as a tool to determine the physiological age of cells and one about lysosomes in brain aging.

CGP Grey strikes again

You probably remember that last year, at the same time that Kurzgesagt released its first video made in collaboration with lifespan.io, the popular YouTuber CGP Grey published a video titled “Why die?” explaining the rationale behind the fight against aging. In late April, Grey confirmed his support to the cause by publishing an animated version of Prof. Nick Bostrom’s “The Fable of the Dragon-Tyrant“, a very on-point metaphor for the curse of aging and how humanity, after rationalizing and silently accepting it for millennia, is finally on course to put an end to it. We are glad to see that more and more content popularizers embrace our cause, and we look forward to Grey’s future contributions to it.

LEAF last month

In April, LEAF interviewed Dr. Josh Mitteldorf, an astrophysicist who, somewhat in the same vein as Dr. Aubrey de Grey, switched careers to dedicate himself to aging research. In the article, Dr. Mitteldorf talks to LEAF volunteer Tam Hunt about his views on programmed aging and progress in the field.

Wanting to preserve one’s youthful looks is often associated with vanity and is generally seen as a shallow pursuit. However, as we discussed in two separate articles, not only is there nothing inherently wrong with preferring to look young rather than old, but the typical elderly looks are the most superficial aspect of a serious health concern.

In other news, more interesting discoveries have been made in the field of Alzheimer’s disease research; as reported by Steve Hill, scientists have managed to reverse amyloid deposition—the likely cause of AD—by intervening on a single gene in mice. It’s too early to celebrate, but it’s interesting progress nonetheless.

Finally, in the April Journal Club, Dr. Oliver Medvedik and Steve Hill discussed a new study that showed how a single gene mutation could dramatically increase your chances of developing Alzheimer’s disease. The researchers also showed that by converting the gene back to its original form, the risk of developing the disease was massively reduced.

Date Posted: April 30, 2018
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Interventions to Extend Healthspan and Lifespan 2018 – Professor David Gems

Elena Milova was at the Interventions to extend healthspan and lifespan 2018 conference in Kazan. This is an important conference in the aging research field, and it includes a variety of leading experts giving talks about their research. During the event, Elena had the opportunity to talk with professor David Gems about his work and his views on aging.

Professor Gems is a British geneticist and biogerontologist. He is Professor of Biology of Ageing at University College London, where he is also Deputy Director of the Institute of Healthy Ageing. His work focuses on understanding aging through the genetics of the nematode worm C. elegans.

How do you think we age; are we programmed to die, do we wear out, or is the truth a mixture of both?

Senescence appears to be the result of a combination of different types of etiology, including the action of wild-type (i.e. normal, non-mutant) genes, and various sorts of damage (including mechanical damage or mechanical senescence, which involves a type of wearing-out process). Which is more important likely depends on the species and on the pathology. For example, some pathologies in C. elegans appear to be the result of futile run-on of biological programs. However, in most types of mammalian cancer (which is largely a disease of aging), damage to DNA clearly plays an important role.

Why do you think aging exists at all?

The answer to this is provided by the evolutionary theory of aging. Aging occurs because the strength of natural selection reduces with increasing age after the onset of reproduction. Evolution selects gene variants that maximize fitness in early life, even though they may promote senescent pathology later. By this view, senescence is a form of complex genetic disease caused by wild-type genes.

What do you think about the role of epigenetic changes and how they regulate gene expression; are they one of the drivers of aging or a consequence?

There has been a lot of interesting work on this during the last decade. Manipulating epigenetic changes can affect lifespan, and epigenetic alterations such as DNA methylation are excellent biomarkers of biological age. Yet it seems far from clear that such changes somehow represent a primary cause of aging.

Do you have a favorite aging hypothesis, and why?

Yes, I do. Currently, I believe that senescence is not a disease syndrome with a single etiology; rather, it is a set of disease syndromes and stand-alone diseases with multiple etiologies. I believe that the predominant type of cause of aging is wild-type gene action in later life, as predicted by Williams’ antagonistic pleiotropy theory, but that stochastic damage also plays a role, depending upon the species, for example, DNA damage and mechanical damage (mechanical senescence).

Your research focuses on C. elegans worms. How relevant to human aging is what we learn from these worms?

The precise answer to this question will only become clear when we achieve a better understanding of aging in C. elegans. Some aspects of the biology of aging in C. elegans are highly relevant to human aging. For example, C. elegans lifespan can be greatly extended by inhibition of the insulin/IGF-1 and mTOR signaling pathways, which were subsequently shown to influence the aging rate in humans. It is my belief that a full understanding of the proximate mechanisms of aging in C. elegans, downstream of and regulated by the signaling pathways that affect aging, will contribute to a broad understanding of the nature of the aging process, just as gene function was first understood by studying simple organisms like bacteria and bacterial viruses. Critically, in a simple animal like C. elegans, we have a good chance of achieving a full understanding of aging. In this respect, the worm has yet to give up some of its greatest treasures.

Do you agree with the statement that we have all that is necessary to cure aging in the worm, given the numerous interventions that increase their lifespan; could we technically cure aging in worms with the technology we have now?

The statement is certainly false. Some interventions cause large increases in lifespan in C. elegans, in terms of fold change in lifespan. However, in these cases, the animals still die of senescence.

Can aging, or rather the various processes that constitute aging, be considered a disease or perhaps a co-morbid syndrome?

Asking whether aging is a disease is confusing since the word has at least 3 distinct meanings: calendar aging, adult age-related changes of any kind (good, bad or neutral), and senescence. Unsurprisingly, therefore, discussions of this question are often confused.

Senescence, by definition, is a process of deterioration, so, arguably, it is a disease or, to be more precise, a collection of diseases and disease syndromes (since it clearly has no single, simple cause).

The current approach of treating age-related diseases is essentially the same as we treat infectious diseases: we wait for the diagnosis and then treat the symptoms. This approach is one of diminishing returns. What do you think of the idea to treat the various aging processes driving these diseases in order to prevent or reverse a whole slew of them at once?

Like most people working on the biology of aging, I believe so. This can be achieved in the laboratory in short-lived animals, such as mice. What is currently lacking is a demonstration that this can be achieved in human beings.

It has been projected that if you eliminated all cancers, it would only add about 3 or 4 years of lifespan, as people would just die of another age-related disease. Do you think a preventive approach that targets the aging processes might yield more impressive gains in terms of healthspan and lifespan?

Like most people working on the biology of aging, I believe so.

Do you take any personal health and longevity measures yourself?

I don’t take any sort of anti-aging drugs or supplements. However, if there were any with proven efficacy and demonstrated safety, I would gladly take them.

What is the biggest bottleneck to progress in aging research, in your view?

There are many, but I find it hard to say which is the biggest. To name a few…

  1. Lack of sufficient research funding (obvious, but true).
  2. The entrenched configuration of the medical research establishment that leads to diseases of aging being studied separately (in silos).
  3. Lack of public awareness of the potential of current progress in biogerontology, due to it being drowned out by bogus information generated by commercial anti-aging medicine peddlers, swindlers of the elderly, and self-publicizing mountebanks.
  4. The drain of time and resources engendered by the need to publish in high-impact journals due to the use of journal impact factors as performance measures
  5. As often happens in science, a lack of imagination and of encouragement and support for original approaches.

We would like to thank Professor Gems for taking the time to do this interview with us and sharing his insights.

Date Posted: April 27, 2018
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CGP Grey: The Fable of the Dragon-Tyrant

There’s a good chance that ten or fifteen years from now, we’ll look back at this moment in history and realize that we were living through the beginning of a revolution, the first baby steps of what would eventually become a global movement. Maybe it’ll take longer, but just like it was for human flight, the unmistakable signs of the upcoming paradigm shift are all around us.

The tide is turning on aging research

If you are paying attention to the field of rejuvenation biotechnology, you’re noticing how more and more experts have dared to “come out” and speak of aging not only as a medical problem to be solved but also one that we might just be able to relegate to medical history books in the relatively near term; you’re noticing the technical progress, big and small; how the topic is moving from fringe to mainstream; how more people join the cause; and how previously dismissive and uninterested people now react to this change, either by disputing the feasibility or desirability of defeating aging.

Similar signs were visible at the dawn of the age of flying machines, including enthusiastic pioneers, harsh critics and skeptics, progress and setbacks, and increasing interest of the public; however, while disputing the feasibility of human flight was common, very few people went around saying that it wasn’t desirable and predicting that all manner of disaster would strike had we ever managed to get an airplane working.

In the age of information technology, one such sign of impending change is when popular content creators begin to show increasing interest in a previously largely neglected subject—which, with some luck, may, in turn, be just a preamble to the subject going viral. In the case of rejuvenation biotechnologies, the earliest of these signs are certainly the two videos Kurzgesagt created in collaboration with the lifespan.io team in late 2017—“End Aging?” and “Cure Aging?”—as well as the plain-spoken “Why die?” by CGP Grey, who took the matter even further, criticizing not only the human acceptance of aging but the alleged necessity and desirability to “die at some point” altogether.

Fable of the Dragon-Tyrant animated

Showing remarkable interest, commitment, and even courage—given that such a bold stance on aging and death is regrettably still somewhat unpopular and easily attracts gratuitous hostility—CGP Grey has produced a second video, this time an animated version of Prof. Nick Bostrom’s “The Fable of the Dragon-Tyrant”. The fable is a powerful metaphor for aging and the acceptance mechanisms that have led humans to schedule their entire lives around its diktat.

Once upon a time, the planet was tyrannized by a giant dragon. The dragon stood taller than the largest cathedral, and it was covered with thick black scales. Its red eyes glowed with hate, and from its terrible jaws flowed an incessant stream of evil-smelling yellowish-green slime. It demanded from humankind a blood-curdling tribute: to satisfy its enormous appetite, ten thousand men and women had to be delivered every evening at the onset of dark to the foot of the mountain where the dragon-tyrant lived. Sometimes the dragon would devour these unfortunate souls upon arrival; sometimes again it would lock them up in the mountain where they would wither away for months or years before eventually being consumed.

We unanimously praise CGP Grey’s skilfully and faithfully crafted rendition of the fable and his dedication to the cause. We look forward to seeing more of his much-needed contributions; in the meanwhile, you can enjoy The Fable of the Dragon-Tyrant below.

Date Posted: April 27, 2018
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Goldenrod Extract has a Senolytic Effect

Today, we have a new study showing that a common, plant-based compound could help clear out unwanted senescent cells, which accumulate with age and produce inflammatory signals that drive age-related disease progression.

Taking out the trash

A new study has investigated a natural, plant-based compound for its ability to destroy senescent cells [1]. These cells accumulate with age due to the aging immune system becoming increasingly poor at removing them; this leads to a build-up of these cells and the secretions they produce, which cause chronic inflammation. These proinflammatory secretions are known as the senescence-associated secretory phenotype (SASP).

This inflammation from senescent cells and other sources combines to form “inflammaging”, a chronic smoldering background of inflammation that causes cellular dysfunction, reduces tissue repair, and blocks stem cell activity, thus leading to eventual organ and tissue failure. In a way, senescent cells can be thought of as being like garbage left lying in the street, and their presence harms the local environment, which, in this case, is the adjacent bodily tissues.

Researchers believe that helping the body remove these senescent cells using drugs known as senolytics could be a pathway to preventing age-related diseases and keeping us healthy as we grow older.

The researchers here investigated Solidago virgaurea, also known as goldenrod, which is traditionally used as an anti-inflammatory herbal medicine. This is the first time that extracts from this plant have been studied in relation to cellular senescence.

Abstract There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life- and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp. alpestris, which exhibited weak senolytic activity, delayed the acquisition of a senescent phenotype and induced a papillary phenotype with improved functionality in human dermal fibroblasts. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

Conclusion

The results show that the extract was effective at slowing down the cells’ journey to senescence and could suppress a number of proinflammatory pathways. This may seem impressive at first glance; however, the effect is rather small, and this is a cell culture study. What happens in culture is not always what happens in the body; therefore, these marginal improvements should be taken with a large pinch of salt. In other words, don’t rush out and buy goldenrod supplements based on this initial data.

Literature

[1] Lämmermann, I., Terlecki-Zaniewicz, L., Weinmüllner, R., Schosserer, M., Dellago, H., de Matos Branco, A. D., … & Morizot, F. (2018). Blocking negative effects of senescence in human skin fibroblasts with a plant extract. npj Aging and Mechanisms of Disease, 4(1), 4.

Andrei Gudkov is an aging and cancer researcher.
Date Posted: April 26, 2018
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Interventions to Extend Healthspan and Lifespan 2018 – Dr. Andrei Gudkov

Elena Milova is at the Interventions to extend healthspan and lifespan 2018 conference in Kazan this week. This is an important conference in the aging research field, and it includes a variety of leading experts giving talks about their research. One of these experts is Dr. Andrei Gudkov, and Elena had the opportunity to talk with him about his research.

Dr. Andrei V. Gudkov, Ph.D., D.Sci, is a Scientific Co-Founder of Cleveland Biolabs, Inc. and has been its Chief Scientific Officer since June 2003. Dr. Gudkov serves as Chief Scientific Officer and Founder at Everon Biosciences, Inc. He co-founded Mega Biotech & Electronics Co., Ltd. and serves as its Chief Scientific Officer. Dr. Gudkov serves as Senior Vice President of Basic Science at Roswell Park Cancer Institute. He has over 25 years of experience in biomedical research. Prior to 1990, he worked with the National Cancer Research Center in Moscow (USSR), where he led a broad research program focused on virology and cancer drug resistance.

In 1990, he re-established his lab at the University of Illinois at Chicago, where he became a tenured faculty member in the Department of Molecular Genetics. In 1999, he defined p53 as a major determinant of cancer treatment side effects and suggested this protein as a target for therapeutic suppression. In 2001, Dr. Gudkov moved his laboratory to the Lerner Research Institute at the Cleveland Clinic Foundation, where he served as Chairman of the Department of Molecular Biology and Professor of Biochemistry at Case Western Reserve University. He has served as a Director of Cleveland Biolabs, Inc. since June 2003.

You have talked about the presence of dormant viruses that may act like a lifespan clock. Microbial burden is known to contribute to the aging process by contributing to inflammaging and immune system decline. How can we destroy persistent viruses like CMV, and other viruses that lie dormant in the body for years but replicate greatly during aging and cause chronic inflammation?

This is indeed a very serious question, and, honestly, I don’t have a good answer to that. The concept I am dealing with is actually our endogenous viruses, which are an integral part of our genome and have been there for millions of years. They are not actually viruses in all aspects of this definition; for example, they do not have an extracellular life, they only multiply by expanding inside the genome of a given cell. The cell solved the problem of having them inside by keeping them silent, basically asleep, which tells me that our evolution could not solve the problem of getting rid of these viruses. For dozens of millions of years of existence, the best we could do as their host was to keep them silent.

There is no mechanism of excision or eradication, so to me, it means one very depressing thing if we think about the viruses that are not endogenous but exogenous. The herpes virus is a great example; there are plenty of others as well, but herpes viruses are the most harmful right now, including CMV and Epstein-Barr. They are not endogenous, they are not encoded in our genes, but they live inside the cells which we cannot afford to kill, for example, the neurons. Killing every infected neuron will cause some deficiency in neuronal function, and we do not have a mechanism of eradication to keep the cell clean of them.

Since during these millions of years of evolution, our own organism could not solve this problem, my prediction is very depressing; most likely, we will not be able to do it. Nature is usually quite sophisticated in finding solutions for these types of things, which means that we need to follow nature and try to keep them under control rather than getting rid of them. I don’t think you can make a clean, virus-free environment; I think you can make an environment where viruses are controlled and kept harmless.

Research suggests that “inflammaging” plays a key role in aging; many publications also suggest that of the various sources of this chronic age-related inflammation, senescent cell accumulation and the SASP it produces is the primary culprit. Would you agree that this is the case, and what might we expect to see if therapies to remove these problem cells are used in people?

I have a different view from the majority. I was one of the big fans of senescent cells, and I was 100% inspired by the idea of finding them, eradicating them, and using that for rejuvenation. However, after we spent several years very focused on an extensive study of senescent cells in vivo, we realized that for a major portion of the mouse lifespan, we simply cannot find these cells. This is not because they don’t exist; I think they appear pretty frequently during our lives and mice’s lives, but they are being very efficiently eradicated by the immune system. Actually, we made the prediction that senescent cells are sources of SASP, this famous secretion that we don’t like, but I would say that it was never really proven. The fact that they secrete it is proven; there is no question. Whether the changes in inflammation in vivo with age are due to the activity of senescent cells is a big question, because when we tried to find these cells in, for example, an irradiated organism, most of the cells that people thought were senescent before the existence of conventional biomarkers appeared to be just parts of the immune system, which is malfunctioning in aging and created the appearance of senescent cells. Macrophages frequently become positive for biomarkers of senescent cells, and people using these biomarkers without looking carefully call them senescent. You might say that does not matter because the whole concept did not change that much; who cares what you name these cells? If certain cells with certain properties accumulate with life and if they secrete something bad, the concept is still intact, and I agree with that.

However, knowing the nature of these cells, we can choose the right weapon against them, and as long as we try to kill the cells that we can make senescent in culture and think we are killing the same cells in vivo, I think that we are on the wrong path. This is my first problem; my second problem is that the accumulation of senescent cells means a malfunction of the immune system because the normal immune system gets rid of them very efficiently. If you kill a cell that cannot be removed by the immune system, you are not getting rid of this potential garbage; you turn it into a different type of garbage. Because to eradicate a senescent cell, something needs to find it and eat it, swallow it, such as a macrophage. If this function is not working very well and you simply help the immune system by killing these cells, they still remain in the same place where they were; they’re just dead. Maybe this is good or not; maybe this will indeed help another branch of the immune system to clean up. I think, in general, that this is not obvious; first, it’s not obvious to me that senescent cells are unique in creating the “smell” of garbage that leads to inflammation or if it’s only one of many types of cells that become damaged and accumulate with age. I’m not sure that killing them physically really helps to improve the situation, because you are creating a wave of remains that has to be taken care of, too.

I personally chose an approach to invest in the immune system and repair its function so that it can do its job better, instead of us thinking that we can substitute it. So far, in medicine, substitution of lost function has only worked well in orthopedics but not in other areas. Therefore, I think that we need to either invest in a mechanism that blocks the appearance of senescent cells or invest into the mechanism of natural eradication to make the immune system work better. For example, if the part of the immune system that is responsible for clearing senescent cells gets exhausted, you can always try to redirect adaptive immunity against them by vaccination; I would see that as a more appealing thing. I want to make a disclaimer that everything I’m saying is my personal opinion which may be completely wrong, and I’m not going to be surprised or unhappy if it appears to be wrong; it is a normal process of people having different opinions, and I am only giving my personal view.

Your work also shows the role of senescence-associated macrophages (SAMs), and the data suggests they could be a target for potential anti-aging therapies. Do you think targeting these cells, in particular, is more important than other types of senescent cells, and why?

Honestly, I don’t know; the fact that we see an accumulation of cells of certain types with age doesn’t necessarily mean that they are the cause of frailty and the cause of the problem. I can easily imagine they could because macrophages are secreting cells, and the job of macrophages is to secrete proinflammatory cytokines. If they accumulate in these unusual macrophages, I would say that it’s a reasonable hypothesis that they may be contributors to this general change of environment. The problem is that A: we need to do more to prove if it’s right or wrong, B: we believe that one of the ways to deal with them is not necessarily killing them but reprogramming them, because macrophages are parts of the immune system that are known to have many faces, and they usually change their phenotype depending on the specific request from the organism for a specific function, and since they have many faces, I think there is a potential approach to convince them to turn into something better. However, this territory was just found, it’s unexplored, and everything I am saying is just a pipe dream at the moment. Another thing is that killing macrophages is a technically extremely difficult task; this is why I am talking about reprogramming, because macrophages are among the most resistant, to everything, cells in the body. The reason for that is based on common sense; they are made by nature to eat and digest garbage, poisons basically. It is hard to kill them because they are resistant to what they usually eat.

Are these SAMs fully senescent, or could they potentially be rescued by manipulating their polarization rather than destroyed, and returned to work?

It’s a good question, and I think I answered that; I can only tell you that we published another paper showing that their properties are reversible and inducible, so you can either mimic their appearance with certain environmental conditions or reprogram them into something else. We know that technically we can do this in vitro, but whether it’s applicable in vivo and whether that would change the environment, I have no idea yet.

It is generally considered that the main reason senescent cells accumulate in the first place is due to dysfunction of the immune system. If the SAMs can be removed, might we expect that senescent cell clearance via the immune system would be significantly improved?

Again, this is something we do not know; we can do bone marrow transplantation and start the blood and immune systems from scratch; however, when you look deep into that, you find that not every aspect of immunity or hematopoiesis is substitutable by donor bone marrow. There are certain types of cells that are only given to us once and forever. Tissue-resident macrophages, which sit in our bodies, under our skin for example, and form a shield against any damage that comes from outside, are actually poorly recycled. That is why tattoos are possible; tattoos are live cells that swallow the dye; these macrophages stay in the same places where they have always been. The fact that tattoos remain for the majority of lifespan means that these cells that swallow them stay alive and in the same place for as long as we can see the tattoo.

Assuming that immune system clearance of senescent cells could be restored to youthful levels again, would we even need senolytics that target non-SAMs?

As I explained earlier, senescent cells played an enormously important and positive role in gerontology, even if eventually it appears that they are not the main players; they have played the role of navigators, brought us to the right questions, and brought us to observations we would not have otherwise made. So as frequently happens in science, those who are behind the initial concept of senescence may not be exactly right, but they moved science in the right direction. I believe that the role of senescent cells is an exaggeration, I think that they are one of many types of garbage that accumulates with age; they simply brought us to the problem of a malfunctioning immune system whose normal function is to deal with this garbage.

Would you please share your thoughts on identifying senescent cells?

I am not personally working on that, because I think there are higher priorities. I find these cells very peculiar, but I still think that they only exist as long as we keep them away from the environment of the organism and leave them in culture; the moment you put them in the organism, they get eaten up and disappear. Since we know how this happens, and in part the mechanism, I am not that interested in finding out how to kill them better for the reasons mentioned earlier. Having their biomarkers would be very good and important, and it would be nice to have it. I am not sure if it is possible. We should not think that biomarkers of everything exist; it might be that we already know everything about them, the best biomarkers are already found, and they are not that great, but they are what we are left with.

Do you take any personal health and longevity measures yourself?

There is a legend that people whose brains are always working have less chance of developing Alzheimer’s; it’s probably the only precaution I am taking. I tell myself that I am working on solutions that will allow me to stay young regardless of maintaining bad habits and an unhealthy lifestyle. (laughs) We may be able to find pharmacological approaches to neutralize this problem, and when we have them, I will certainly be using them. I will say that I am very close to using the first things we are developing when they enter clinical trials; the moment I have the legal right to inject myself without jeopardizing the program, I will certainly do that.

What therapies do you think are the most promising at the moment, the ones that we might see in 5-10 years?

I think there are several. Being able to have rapamycin broadly used is a very real prospect, it will not change everything and will not overturn the problem, but it may improve our general health. Then, a lot will go towards immunization; we will be treating and training our immune system to be more responsive to accumulating types of things, so the adaptive immune system will help the innate immune system to do the job. I personally think that the cardinal improvement will come from inhibition of the endogenous DNA damage, which is ongoing in us every second of our lives. The big role, if not the biggest role, is played by the constant activity of retrotransposons. These get sporadically activated in a small proportion of cells for short periods of time, which is sufficient to create an overall increase in the number of retrotransposons and mutations in somatic cells, leading to an accumulation of damaged cells by exhausting the immune system, which has to deal with them, and putting even more pressure on it. If I had to make a prediction, I would say that ten years down the road, just as every bottle of water today has fluoride to prevent caries, it will have reverse transcriptase inhibitors to prevent cancer and aging. We are working towards that, and when we have a safe inhibitor, I will not be surprised if it is given to everybody.

What is the biggest bottleneck to progress in aging research, in your view?

There are no bottlenecks today. I think that development is in great shape; it is an excellent area that has quickly evolved thanks to the attention of the community and the attention of high-caliber scientists who are migrating to this field in large numbers. It’s very democratic; it’s open to new ideas, it’s very dynamic, and it currently allows us to follow multiple major directions without restriction.

We would like to thank Dr. Gudkov for taking the time to do this interview with us, and we look forward to seeing his future progress.

Date Posted: April 26, 2018
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Some People Worry they Would be Forced to use Rejuvenation

Hard to believe but some people are worried that when rejuvenation biotechnology is available they may be forced to use it.

Might rejuvenation become an imposition?

Suppose that, on a nice day not too far into the future, while everything is going reasonably well in your life and you are enjoying yourself, you walk into the doctor’s office for a regular checkup. The doctor finds nothing wrong with you, but in order to minimize your risk of developing diseases that are likely to strike people in your age range, she recommends that you undergo senolytic treatment. The treatment is safe, with no serious adverse effects, it is administered simply through injections, and it is either state-subsidized or otherwise affordable. In your opinion, what are the odds that you would refuse the doctor’s prescription and say that you’d rather take the risk of getting sick?

Assuming that you are in your right mind, your answer is likely something along the lines of “not a chance.” If there are medicines that will spare you the trouble of getting sick, even seriously so, you will probably want to take them.

The example above outlines perfectly well why it is highly unlikely that rejuvenation treatments might ever become an imposition—you cannot impose something on people who actually want it. Yet, if you discuss the topic of rejuvenation long enough with a sufficient number of people, you are likely to eventually bump into someone who will raise the rather bizarre concern that these treatments might eventually be directly or indirectly imposed on people who do not want them. However improbable this may be, for the sake of completeness, let’s discuss the possibility.

Two important remarks

Before we delve into the ramifications of this concern, we should take notice of two facts. The first is that the concern of rejuvenation becoming a legally required direct imposition is absolutely incompatible with the concern that it might be just a privilege for the rich. It’s clear that if rejuvenation is a luxury good that only very few can afford and get, then it’s not being imposed on the populace; conversely, if rejuvenation is imposed on the populace, then it’s clearly not just for a few lucky ones.

The second fact is that, even if the concern of rejuvenation becoming an imposition were justified, this would not constitute a valid reason to halt the development of rejuvenation therapies, as that would cause a worse imposition on a different group of people, namely those who do not want to experience age-related decay and death. Even assuming that everyone on the planet were legally obligated to take rejuvenation treatments, it would be easier to evade this obligation than it would be to escape age-related diseases and death in a world without rejuvenation, where staying alive and in good health indefinitely would be utterly impossible. In simpler terms, would you say that we should ban blood transfusions altogether to make sure that the relatively few people who refuse them on religious grounds can never be forced to have any? Once again, your answer is probably negative.

Direct imposition

In the context of this discussion, “direct imposition” of rejuvenation means that laws are in force saying that everyone must undergo rejuvenation treatments whether they want them or not.

The right to refuse treatment is often a thorny matter, as people tend to basically bicker about which moral system deserves the most respect: the idea that life is sacred and under no circumstances should anyone be allowed to dispose of his or her own life, or the idea that patients should be free to decide for themselves. However, this issue only becomes relevant in end-of-life situations, when religious beliefs are involved, or when a patient is sick with an incurable, incapacitating, but non-lethal disease that makes his or her life unbearable.

It’s important to notice how these cases differ from those of patients having to choose whether they want rejuvenation for themselves. Rejuvenation is most definitely not about postponing the inevitable at the cost of prolonging suffering, and it’s not about extending misery in the name of the sanctity of life; it’s about maintaining health for as long as possible, preventing diseases that may cause misery and suffering altogether. The right to refuse rejuvenation should therefore not be compared to the right to refuse aggressive end-of-life care; rather, it should be compared to the right to refuse vaccines, as they both are examples of preventive medicine. It should be noted that people who refuse vaccines almost always do so due to scientific misconceptions or religious conviction, not the desire to suffer from infectious diseases.

Unlike infectious diseases, age-related diseases are noncommunicable and so do not endanger people other than those who contract them, but they do place a heavy burden on both the patient’s loved ones and society at large. Elderly people who are no longer able to take care of themselves, or require constant and expensive medical assistance, cause emotional distress to their families as well as financial problems either for their families or society; someone, whoever that may be, has to pay for elderly care expenses, and given that the number of people over the age of eighty is expected to triple by 2050, this will soon become unsustainable.

A comprehensive rejuvenation platform could prevent this problem from ever manifesting altogether, as chronologically old people would be just as healthy as chronologically young people generally are; they would thus retain their independence, both physical and financial, and would not burden the economy with extra health expenditures any more than a young person typically does. So, in a way, one might argue that rejuvenation biotechnology may help prevent certain global issues in the same way that vaccines may prevent pandemics, and it would therefore not be a bad idea to make rejuvenation treatments compulsory. However, this will hardly ever be necessary; people rarely desire disease and sickness for themselves, and if therapies are available to prevent them, odds are that they will undergo said therapies voluntarily.

It is important to keep in mind, however, that refusing rejuvenation treatments ultimately means voluntarily exposing oneself to a higher risk of chronic, debilitating conditions that are often difficult and expensive to manage. Therefore, if rejuvenation were available, and a person refused to take it on whatever grounds, that person should also be ready to accept the consequences that may derive from this choice. If I chose to refuse rejuvenation treatments and ended up needing hospitalization or other forms of continuous care as a direct consequence of my own choice, it would be unfair of me to ask third parties to pay for the resulting expenses or my relatives to look after me. It does not make sense to expect other people to pay for the medical expenses of somebody who has actively decided not to take available preventative measures against the risk of age-related diseases. This would be especially true if rejuvenation therapies were subsidized, wholly or partially, by the government.

Indirect imposition

Rejuvenation would be indirectly imposed if, although free to refuse it, you were seriously discriminated against if you did so. One example that was once presented to me as a serious potential problem is that of discrimination in the workplace. What if employers refuse to hire people who do not take rejuvenation? This concern is nowhere near as justified as it might appear at first glance.

If you are a chronologically young person, no older than about forty, then you don’t need rejuvenation treatments, and there’s no reason that you should take them. Assuming that your potential employer likes asking candidates their opinions on rejuvenation in order to decide if he should hire them—and you could easily lie about that and get away with it—he really wouldn’t be interested in whether you would undergo a certain treatment or not in twenty years or so, especially since you’re likely to have a different job in a few years’ time anyway.

If you are chronologically old, and you refuse to take rejuvenation, then your potential employer would have all the right to worry about that and take it into account when making his decision, because there is a significant chance that in relatively little time, you would no longer be able to perform the job for which you are applying—which, by the way, is the very reason that retirement exists.

More generally, we should remind ourselves that rejuvenation is a set of medical treatments that will be prescribed to people by doctors at the right time; it’s not like cosmetic surgery, or fancy make-up, or the latest smartphone model. It’s not something that you would buy at will to show off your social status or to better fit in your group; rather, it’s like antibiotics or cancer drugs. People who refuse to take the medicines they need today may come across as weird, ignorant, or irresponsible, but they are hardly a group that experiences widespread discrimination. That being said, is it possible that people will frown upon you if you decide that you do not want to be rejuvenated and want to grow old and die the old-fashioned way? Certainly, but it is not sensible to oppose rejuvenation for this reason, just as it is not sensible to oppose the existence of cell phones because of any social stigma associated with not using one.

One last observation worth making is that it is theoretically plausible for rejuvenation to become an instrument of indirect discrimination while still being a privilege for the rich. One could imagine a world in which rejuvenation treatments are still rather expensive and where older people who cannot afford them are discriminated against. Luckily, due to widespread demand and the fact that governments would have a strong economic motive to subsidize rejuvenation treatments rather than extremely expensive end-of-life care, this scenario appears unlikely.

Conclusion

Everyone wants to be healthy. If given the choice between being healthy for as long as you lived and becoming seriously sick at some point, you would probably choose the former. Rejuvenation is all about staying healthy for as long as possible. This is why we will hardly ever have to worry about rejuvenation becoming an imposition—you don’t need to impose what people want.

Date Posted: April 25, 2018
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Undoing Aging with Keith Comito

The Undoing Aging conference, a collaboration between the SENS Research Foundation and Michael Greve’s Forever Healthy Foundation, took place on March 15-17 in Berlin, which saw many researchers, advocates, investors, and other important members of the longevity community gather together to learn about the latest progress in rejuvenation biotechnology.

As we had arranged a travel grant for Anna Dobryukha, one of the best Russian journalists writing about aging, longevity, and rejuvenation research, to join us, it made sense to collaborate with her on the most interesting interviews. Anna works for Komsomolskaya Pravda, one of the largest Russian publishing houses, which has a newspaper, a radio station, and a website with over 40 million readers. Anna has also published an article based on this and other interviews taken during the conference which you can find here.

During the conference, Anna and Elena interviewed LEAF president Keith Comito about crowdfunding and the challenges we face as full-time advocates in the field. Anna (A), Keith (K), Elena Milova (E), and Steve Hill (S) were all present and can be identified by the corresponding letters in the dialogue below.

K: My name is Keith Comito. I am a computer programmer, mathematician, and president of the Lifespan Extension Advocacy Foundation, which works to raise funds and awareness for research aimed at extending healthy human lifespan.

E: Vera Gorbunova said that one of the main bottlenecks is the deficiency of funding, so what do you think are the most promising ways to increase funding for fundamental and translational gerontology?

K: Sure. Funding for this research can come from multiple sources. You have government funding, private foundations, large philanthropic donors, the public, and the crowd, and we feel that in order to best increase funding you have to hit all these aspects simultaneously. If you look at previous examples of, say, cancer advocacy or the movement to remediate and cure AIDS, you can see a specific progression: there is a grassroots movement that builds up and perhaps raises some amount of funds, on the order of millions of dollars, to address the problem. But the truly powerful effect here is to galvanize a large, significant portion of the population to recognize and get behind solving the problem at hand.

Then the successful advocates of the past have utilized the resulting societal pressure to lean on government, because that is where you can get the big money, on the order of billions, dedicated to research. So, an effective strategy is to be clear about this, about the process of funding itself and how to maximize getting money and attention into this research.

It is important to get people involved when successes occur; don’t just keep it in the bubble — use that momentum to also engage governments and engage large foundations, such as the Bill Gates Foundation. I think we are starting to see that happen. Events like this help because they engage investment capital, just as raising the public profile of this research through crowdfunded and crowdsourced initiatives is also a way to introduce investors into this space. This then becomes a 1-2-3 combo; once you have a very large investor make a very public investment into a company like Unity, for example, the rest of the community says, “This is valid; this is now something to look at and invest into.” This, in turn, continues to raise the profile of this field of research, growing the grassroots support behind it, increasing pressure on governments, etc.

E: Could you please give an approximate evaluation of what share of funding comes from crowdfunding initiatives and what share of funding comes from the government?

K: As far as I know, right now, the amount of funds coming from crowdfunding would be comparatively quite small.

A: What percentage? Maybe about 10 percent? Or less?

K: I would say even lower. Maybe even less than one percent. This is speculative. To give you some numbers to help with this calculation, on the projects we’ve crowdfunded — I think we have crowdfunded the largest amount of funds for this kind of research per project as compared to Experiment.com or other such sites — we average around fifty thousand per project. A typical government grant for regular researchers exceeds one hundred thousand. Large-scale initiatives from the government can be hundreds of millions or more. So, I would say that there is a very small percentage coming from crowdfunding right now.

E: May I add something? If you have a look at the Buck Institute budget, you will see that approximately 40 percent comes from crowdfunded initiatives. But they have their own fundraising department, and it has to be taken into account. Another big part of their funding includes government grants. A very small part is the support they receive from their previous research, which is now giving them back some money because of their existing patents. So, if you need an example of an organization doing research in this field, you could just have a look at Buck’s reports from the last few years. There, you can see the approximate shares of their budget.

K: It also depends on how you define crowdfunding. I think that most people would think of it as what you would do on Kickstarter or Indiegogo, but I suppose you can also consider the kind of direct fundraising by an organization that you mention as a form of crowdfunding as well. An organization like Buck or SENS can say “We want to do this research; we are soliciting donations from our community to help this” — this is crowdfunding in a sense, and would raise the earlier-discussed percentage.

E: Anna would like to know the proportions of state funding and private funding, and I say that it pretty much depends on the country. For instance, in Russia, fundraising for scientific research is not customary yet; we are still developing this culture. But, in Western countries, it is the opposite; most of the money comes from private initiatives and private donors, and a smaller share comes from government grants like in Buck’s case. But, we cannot really say it is ten times more or ten times less; it depends.

K: We can certainly look up the US budget and how much is allocated to help the NIH; if we want to get more precise numbers on this, there are ways we can dig into it.

E: We can, but another problem is that it is very hard to separate the funding that goes into medical research related to the diseases of aging and the mechanisms of aging. Sometimes, it’s a project that combines both. So, again, if you have a look at the numbers, the amount that goes to age-related diseases is huge, but it doesn’t really involve our community.

E: So, crowdfunding does not seem to be the main instrument for allocating funds into gerontology. Still, you put a serious weight on crowdfunding as a way to create innovative therapies. So, you obviously see some perspectives; why, exactly, do you perceive this method as a promising one; does it have to do with the education of the society that comes together with the process of crowdfunding?

K: That’s a great question. There are multiple angles why we feel this is important and why we focus on it. One is that when we were first starting as an organization, we assessed that one of the main issues of our field is that there are a lot of people who talk about it and who want it to happen, but there is not a lot of action among the community. So, we felt that it was very important to have a continuous, clear call to action. This way, any time someone’s talking about this, it’s not just “Oh, what an interesting idea, now you can go along with the rest of your life”; it’s “Oh, what an interesting idea, and if you want to do something about it in an exciting way, here’s how you can get involved.” That’s a gateway to becoming further involved with the community. So that’s one benefit.

Another benefit involves — I’m not sure if you are familiar this term — the valley of death. A lot of companies die after their initial proofs of concept because it costs millions of dollars to do competitor analysis and go through the FDA, etc. So, while we are not crowdfunding that amount of money, we can serve as a bridge through the valley of death because if there is a company that has a very promising idea and is looking to prove its concept, we can get the community excited about that and help that company get the initial funds to be able to do that proof of concept — and here’s the important part: while doing that, we’ve informed everyone about it, so we can handshake that company with investors afterwards to bridge the valley of death.

E: Maybe you can mention the experience with CellAge, which received its first share of funding from investors right after its campaign?

K: Right, so Elena is bringing up a specific example of this; a company that we crowdfunded, CellAge, working on senescent cell targeting mechanisms. That company raised about 30,000 dollars from our crowdfunding campaign, but we were approached by and also approached investors right after that. Then, the company successfully raised a round of investment and is continuing along, so that is a specific example of how that happened.

E: Would you like to add something to this commentary; maybe there are some ideas you would like to share?

K: In general, my message to the community, especially to laypeople who are becoming interested in this field, is that there is a tendency to think that the researchers and organizations in this field have it all under control and don’t need any help, so you cannot contribute anything, but this is not true. I am speaking a little for everyone here, but I believe that the sense from other organizations is also that help of every kind is needed, no matter what you can do, whether that’s graphic design, PR, the research itself, a little money, or a little bit of time to just talk to people or make a connection that we are looking to make. It is a very exciting field, a growing field that I believe will become very profitable in the near future as well, but we are still at the very beginning phase of it becoming mainstream.

Thus it is a great time for anyone who wants to get involved in any way to get involved. That help is needed, and you are looking at the chance to affect the lives of everyone you know and love. If you seek meaning and purpose in your life, this is a great way to actualize that.

My broad message is to get involved because this is important, whether you want indefinite life extension or just don’t want your mom and dad to get Alzheimer’s disease. Especially, as the population is aging, this is something we are all going to encounter, and I’ve been through that personally — my parents and myself were primary caregivers for my grandmother who had very protracted, horrible Alzheimer’s disease. Nobody wants that, so I think it is very important to realize that we are in this together and that we should all work together towards this grand purpose of overcoming age-related diseases.

E: Sometimes, in the comments under Anna’s articles, people are asking questions like “Why extend life, it is probably going to be so boring?”, “Our lives are already so tough; we wouldn’t want to live longer,” and on and on.

K: Sure, this is the area I personally find most interesting to talk about, because passionate beliefs often breed intense conflict, and life extension is certainly an idea that creates passionate believers. When you meet people who aren’t on the same page, it is easy to think “Oh, that person is an idiot” or “They just don’t get it”, and I don’t think that’s the right approach. If you haven’t killed yourself, you obviously enjoy living, so I strongly believe there is a survival aspect that is absolutely reachable with reasoned and compassionate conversation. So, what I would suggest is to be aware of something called cognitive biases, the flaws in our mental hardware that make it particularly difficult to think or fantasize about what it would be like to live longer. You imagine it like being someone else deep in the future instead of imaging it as you would actually experience it, living in the now, day after day after day.

One question I like to ask people, say a fifty-year-old, is, “Would you like to live fifty more healthy years?” Most people say something like, “No, eighty is quite long enough; it’s been a good life and I don’t want to drag it on” etc., but built into that are a couple of interesting cognitive flaws that can be exposed. So that’s my first question, but then I ask, “Do you want to be alive tomorrow?” Everyone says yes. Then I ask, “Assuming nothing changes and you’re just as healthy, your family is just as healthy, do you think your answer to that question will change tomorrow?” And most people say, “No…tomorrow I would also say that I would want to be alive the next day.” So, by a sort of mathematical induction, you are saying that you want to live fifty years longer, assuming good health, which is what this is all about, assuming that we succeed with improving health.

So with this people will often realize there is something discordant in their answers. Why? It’s because of this idea of cognitive biases — that when I ask you the latter two questions, you are thinking of it like infinite tomorrows, and it’s easy to put yourself into the position of saying “If I’m healthy, I would want to live the next day.” As a corollary to this, if you talk to very healthy 85-year-olds and their lives are going great, and you ask if they want to be alive next year, they say, “Absolutely.” But if you ask a 20-year-old, “Do you want to be 85?” most of them reply “No, no.” So, it’s kind of a flaw in reasoning; that’s one aspect of it.

Another common critique is “I don’t want to be decrepit; I don’t want to be the way I think of a 100-year-old, extended by 20 years.” This is a perfectly logical fear. So, when we engage as advocates, we have to understand that this fear indeed makes perfect sense; we don’t want that either. The important thing that we need to convey is that the only way you will get significant life extension is if you get significant health extension. So, that nightmare scenario is not what is going to happen; in fact, if you look at it in some ways, that dark state of affairs is actually what is maximized by the current system of healthcare, which can involve being hooked up to dialysis machines for the last ten years of your life or having your identity slowly eroded by Alzheimer’s. We are already in that situation, and we’re trying to change it. It’s on us to explain that successfully.

To address the boredom question — it’s related to the earlier issues — but the boredom question involves various psychological concepts, like the hedonic treadmill for instance. You imagine that in the future your sensibilities are going to be vastly different from the way they currently are now, but in general, they won’t be. If you win the lottery, you feel amazing for a couple of weeks, then you return to the same level of happiness. If you suffer a terrible tragedy, so too do you gradually return to roughly your same base level. The same thing happens with time; the fact of the matter is that, generally, you are going to have a sense of life similar to how it is now; not vastly different. You will be as bored then approximately as much as you are bored now — so don’t be bored, or boring!

It’s also not just about boredom; some people think it will be even worse than that — that you will have no ambition if you live longer as if you need a short life to light a fire under you so that you do something. This idea is even in fiction; works like the Lord of the Rings have elves that are slow to act because they live for thousands of years, unlike the humans who are impelled to action because they are going to die. To that, Aubrey once had a funny line at a conference: he basically said, “If you are a young man whose hormones are raging and you meet a beautiful woman, and you want to talk to her, you are not going to be like, ‘I’m not going to die anytime soon, so I can talk to her in 20 years.’” That one made me laugh.

S: Bear in mind that the world changes so rapidly, even looking back to the 1990s, which in my mind was only very recent, but it really was a long time ago. So much has changed from the 1990s, the internet, smartphones, everything is so different; there are so many experiences, VR, and there will be even more, and it’s going to come faster, and faster, and faster.

K: To be fair that is a bit speculative, but I believe this as well. It kind of depends on how optimistic about the future you are. I personally think that the number of things that you can do is going to increase, so, if anything, you would be just as bored or less bored than you are now. This assumes, again, that you are healthy and able to take advantage of these things instead of being infirm in a bed, which is why health is such an important part of life extension.

We would like to thank Anna and Elena for taking the time to do this interview and to Keith for providing us with some insight into how he sees the task of popularizing the idea of healthy longevity and the challenges involved in doing so.

Date Posted: April 24, 2018
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Undoing Aging with Brian Kennedy

The Undoing Aging conference, a collaboration between the SENS Research Foundation and Michael Greve’s Forever Healthy Foundation, took place on March 15-17 in Berlin, which saw many researchers, advocates, investors, and other important members of the longevity community gather together to learn about the latest progress in rejuvenation biotechnology.

LEAF arranged a travel grant for Anna Dobryukha, one of the best Russian journalists writing about aging, longevity, and rejuvenation research, to join us, so it made sense to collaborate with her on the most interesting interviews. Anna works for Komsomolskaya Pravda, one of the largest Russian publishing houses, which has a newspaper, a radio station, and a website with over 40 million readers.

Today, we have an interview that Anna did with professor Brian Kennedy during the conference. Professor Kennedy is an important figure in the aging research field, and he studies multiple mechanisms known to influence lifespan, such as sirtuins and the TOR pathway.

TOR created considerable interest when it was shown recently that the drug rapamycin, a compound that inhibits TOR, can reliably extend mouse lifespan. One of the goals of his research is to determine whether pathways like TOR can be manipulated to treat age-related diseases.

The interview included Anna Dobryukha and Brian Kennedy, plus Elena Milova, and Steve Hill from LEAF.

Elena: So, my first question is who is aging faster, do different aspects of aging become visible for men or women?

Brian: Well, it’s been known for a long time that women live longer than men, and the question has always been, is that because men are more likely to die of things unrelated to aging, or is it because women just age more slowly? Most people feel that women age slightly more slowly, but the interesting thing is that if you look at the demographics over the last 20 or 30 years, the increase in lifespan is happening more in men than women, so it suggests that men are catching up to women in most countries. That may also suggest that the lifestyle factors in men have, in the past, been accelerating aging, and now that’s being reduced.

Elena: At what age do men normally start to get aging, and what age do women start to get aging, approximately?

Brian: I think that depends on how you define aging. The processes that are causing aging are going on, in my opinion, throughout life; it’s just that your body adapts to damage and things that happen throughout most of your life, and, at some point, you can’t adapt anymore, and when you can’t adapt, that’s when you start getting sick and you get one disease or another. Those chronic diseases are starting in our 50s and 60s, and I’m not sure if anyone’s looked carefully at the onset of those diseases in men and women, at least in terms of whether there’s a consistent trend; it’s certainly true that women are more susceptible to some diseases and men others, but I’m not sure if it’s been shown that women have a general delay in the onset of chronic disease. That question’s hard to answer; it depends on what you mean by “when does aging start?” I think that there are a lot of processes that are happening throughout adulthood; it’s just that we don’t notice them until enough bad things happen that our bodies can’t compensate.

Elena: What can you say about the difference of how women and men age? What is the difference, and how much is it?

Brian: I think that, first of all, one of the striking features is that if we look at animal models, the drugs and genetic mutations that extend lifespan, almost all of them work better in one sex than the other; sometimes, it’s females better than males, sometimes, it’s males better than females, and I think that’s telling us that there are intrinsic differences in how men and women age. One of the things that seems to be true, although it’s early stage, is that anti-inflammatory factors tend to work better in males, and so that suggests to me that the levels of chronic inflammation that happen during aging may be more of a factor in men than women. That’s the kind of information that we are starting to learn from these studies, but it’s still early days. I would also say that the hormonal influences on aging are probably big drivers in the differences of how men and women age. We’re testing that now using a variety of mouse genetic models, but it’s still preliminary. Women undergo a rapid loss of estrogen with menopause. In fact, in old age, men tend to have higher estrogen levels than women, whereas with testosterone, there’s a gradual decline, and that’s led a lot of people to speculate as to whether replacing these hormones is good for aging or not. It’s not clear. It’s possible that the loss of testosterone is more of a compensatory factor and that it’s protective. Most of the studies that supplement testosterone don’t suggest that it makes men live longer, so there’s a lot to be done still with trying to understand estrogen and testosterone, and it’s highly debated in literature, especially when it comes to things like estrogen replacement therapy. If you want to start an argument, ask people whether estrogen replacement therapy’s a good idea or not, and you can sit back and have your coffee while everybody argues.

Anna: Can you please give us some examples of drugs or supplements that are known to affect men and women differently?

Brian: Well, one of the drugs, rapamycin, has a bigger effect in females than males, for lifespan in animals. We don’t have much human data on these drugs for aging yet. We’re still going based on animal data, but things like aspirin and 17-alpha-estradiol [Alfatradiol], and acarbose, which is a diabetes drug, extend lifespan in male animals and not females, in mice.

Anna: So, for males, they’re better?

Brian: Yes, they work better for males, and we really don’t know why. That was a surprising observation, especially with acarbose, which blocks carbohydrate uptake in the gut. There’s still big questions to be answered in that area. But we need to know, because as we start doing clinical trials in humans looking at aging, it’s going to be really important to try to identify the subgroups that are going to respond the best so that we get significant results. Being able to predict whether something is going to work in males or females is highly beneficial in that context.

Anna: Could you please name the main factors why men live shorter lives than women?

Brian: Certainly, one factor is that there’s a blip in mortality in men right around the teenage years into early adulthood that doesn’t tend to exist in women. That’s one contributing factor; we call that testosterone poisoning, jokingly. There are also certain chronic diseases that men are more likely to get earlier; more women suffer from heart disease with aging, but men tend to get it earlier than women do, so it’s more of a later-age disease in women. There’s a differential onset of a number of different diseases, and there are environmental factors too, like smoking, especially in Russia, alcohol consumption, which is much higher in men. Alcohol consumption is actually probably protective at low levels, but at high levels, it’s very toxic.

Anna: There was an article recently about the effects of pregnancy on life expectancy. Apparently, it was said that pregnancy can make women age faster. What do you think about it?

Brian: I think it still remains controversial. There have been studies on both sides; there’ve been studies that say that women who have multiple pregnancies are likely to live longer. I haven’t seen that recent study, but I think that’s a very controversial area of research still. It’s unclear whether pregnancy is protective or actually detrimental for aging, at least in my mind.

Anna: How does sexual behavior affect life expectancy in men and women; is there a difference or not?

Brian: I haven’t seen strong data on that. My sense is that maintaining sexual activity is probably healthy, provided it’s done in a safe way, probably in both sexes. But I can’t cite hard data supporting that; I think that’s a general perception, and I’m not sure how much is hopeful thinking. Unsafe sex practice is certainly a risk factor.

Elena: Can we say that an anti-aging treatment that reverses aging completely is going to be different for men and women?

Brian: I think that what we’ll find is that whenever we test interventions, we’ll find a lot of them that’ll have different effects in men and women. In general, I think it is going to be possible to extend lifespan and healthspan in both men and women, but I think we’ll find that some interventions, just like in the animal models, work better in men and others work better in women.

Anna: We’ve met with you a few times already, and we’ve seen many things develop in the rejuvenation industry. What are the main breakthroughs so far, and what can we expect in the future?

Brian: I think there’ve been two major breakthroughs in the last five to ten years. The first is that instead of one or two potential interventions, now we have dozens of potential interventions that may work for aging, and I don’t know which ones are going to translate to humans yet, but we have so many shots on goal now that I think some of these shots are going to go in, so that excites me. The other thing is that we now have a number of candidate biomarkers of aging. I’m not sure if any of them are completely validated yet, but a number of them look quite strong. That is really critical as we go into human testing. We have to have something to measure, and we have good candidate markers to measure now. The next step is to really test these interventions in humans, and that’s one of the things that I’m looking to do in Singapore, but I think other people are as well. We’ve learned a lot, and we have to start understanding how these things affect humans, or we’re going to reach a bottleneck.

Anna: What fields of research do you find the most promising so far?

Brian: I think there’s a whole range of different translational approaches to aging. Some are testable now, like drugs, and others are still being developed, like gene therapy and plasma replacement, that sort of thing. I’m not sure, in the long run, which is going to be the most prominent. My main goal is to show that some of the early things work, even if they have small effects, because I think once people begin to realize that we can change aging and extend healthspan, then there will be plenty of resources to do the more fancy things down the road.

Steve: We all know that you work on metabolism; what are your thoughts in regards to people like myself practicing calorie restriction in an effort to improve health and hit longevity escape velocity?

Brian: I think that calorie restriction is likely to affect aging in humans. I don’t know if it’ll get you all the way to escape velocity, but I think it’s likely to work. The problem is, I don’t recommend it generally because I think that it’s very difficult to effectively do calorie restriction, and if you’re going to cut your calories way down, you still have to get the right balance of macronutrients and all the micronutrients you need. Most people that aren’t educated probably don’t do that effectively, and they end up being malnourished. That is why I like to encourage intermittent fasting approaches and other fasting strategies because I think they’re safer, and they’re likely to give you some of the benefits of calorie restriction at the same time.

Steve: So, something along the lines of Valter Longo’s strategy.

Brian: I am a member of his board, so full disclosure, but El Nutro is one of the ways to do it. There’s also the 5-2 diet and time-restricted eating, and I think all of them show promise. I can’t really even tell you which ones are going to work better than others at this point.

Steve: Well, everybody’s different as well, so they react to diets differently, so it is difficult, isn’t it?

Brian: Not only do people react to diets differently, but it’s affected by exercise. One of the debates right now is whether you need a low-protein diet or a high-protein diet. I think that’s going to be highly influenced by how much you exercise during the day as well, and we’re still not doing enough studies where we compare multiple lifestyle factors against each other in a matrix. I think that might underscore some of the differences we see in optimal diets for people.

Steve: Exercise is certainly a good strategy for aging because there was a study last week released by Birmingham University that showed that thymic shrinking was greatly reduced for cyclists who were very active for most of their lives. They seemed to think it was interleukin-7 that promoted growth and offset the shrinkage. I think exercise is probably one of the best things that you can do for anti-aging right now right?

Brian: No arguments there; I agree.

Anna: What do you feel are the main bottlenecks that are slowing down research on aging and the development of anti-aging treatments right now?

Brian: I think that it’s resources and also effective strategies that do clinical trials. Like I said before, we’ve learned a lot from animal models; don’t get me wrong; there’s a lot to be done on animal models, and I think they still need to be funded. But we certainly know enough now that we’re ready to start testing things in humans, and there’s just not enough of that going on right now.

Anna: Do you have any ideas to share on the best way to solve this? What can our community do, what can academia do, and what should regulatory agencies be doing in order to have translational medicine?

Brian: I don’t know that anybody has the right answers. We are looking, in Singapore, to try to do short- to intermediate-term studies trying to cross-compare the effects of a list of interventions against a list of potential biomarkers so that we can begin to link these specific interventions to biomarkers. But it’s a bit of a guessing game; we don’t know if three to six months of intervention is sufficient to have big changes on the epigenome or not. We don’t know what it’s going to do to other factors that are measuring aging as well. It’s a little bit of a guessing game right now. The other way to do it is to do what Nir Barzilai’s doing and do very long-term trials looking at prevention of multiple diseases, but that costs a fortune, and it’s hard; we’d like to test ten different interventions, not just one. I’m not sure which of us has the right answer or if any of us do at this point, but if you don’t get in there and start trying, you’re not going to figure it out. Ultimately, we’ll figure out the best way to do it.

Steve: I’m involved with mice, which are easier to control from a genetic point of view; they don’t vary that much, but humans can vary a great deal.

Brian: I would agree with that, but I also think that the variation we see with the aging of Black 6 mice is striking given that they have an identical genotype going in. So, you’re right, I think we are going to find personalized issues with human aging. The more we learn how to predict who’s going to respond to what intervention, the better chance we have of showing efficacy. Right now, it’s pilot studies, but hopefully, we’ll get enough knowledge from those that we’ll be able to design the right ones in the next generation.

Steve: That’s the problem with humans, you see; they’re under an ad libitum diet regime. People eat different diets; they exercise or don’t exercise, they have different lifestyles; how do you factor that in with studies? I suppose the only choice, really, is larger cohorts to compensate for it.

Brian: Larger means more expensive, too.

Steve: Yeah, that’s the problem, but I can’t see any way of avoiding it.

Brian: Ultimately, it may be the case. If we can just start getting pilot data, we can at least do power calculations based on the pilot data and then know what size we need to look at.

Anna: Thank you very much.

We would like to thank Anna for collaborating with LEAF at the conference and Professor Kennedy for taking the time to do this interview.

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