Mois : juin 2024

For our readers in the Northern Hemisphere, the summer has begun! The weather isn’t the only thing heating up, as we have been busy advocating for research on aging!

Lifespan.io at the Rejuvenation Startup Summit

The Lifespan.io team was recently at the Rejuvenation Startup Summit in Berlin hosted by the Forever Healthy Foundation. This is one of the most important events on the longevity calendar, and several of us attended.

Michael Greve from the Forever Healthy Foundation giving the opening talk.

Building the largest industry in human history

This event aimed to support the growth of rejuvenation biotechnology to become the biggest industry in human history.

This is not an exaggeration; everyone ages and suffers from age-related diseases. There will be a huge market for treatments that help people stay biologically younger and prevent such diseases. Potentially, every single human being on the planet is a customer.

Lifespan.io’s Steve Hill and Arkadi Mazin with David Barzilai aka Agingdoc.

We are at a point in our field’s history when there are a number of therapies either in or near human clinical trials. All it will take is for one of those to succeed. Demonstrating that rejuvenation is possible and that aging can be slowed, halted, or even reversed will be a game changer.

That is the point at which wider public interest and attention should happen. The conversation will then turn to the potential of tackling aging, rather than reasons not to. More and more investment should then happen, and the pace of progress could snowball.

Conferences like the Rejuvenation Startup Summit are critical in helping science to reach this point.

A few years ago, the biggest bottleneck to progress was the lack of funding for preclinical research. Things have progressed since then, and getting therapies to clinical trials is now the bottleneck.

Moving from funding preclinical research to clinical trials is a big step, and this is where investors come in.

The riverside venue was packed with researchers, investors, and longevity advocates.

Many new biotech companies presented at the conference, and it was a good chance to meet and connect with others. There is no doubt that many deals resulted from the event, and this is the fuel that drives progress towards the clinic.

For more insights from the conference, check out “Everything Happens in Berlin”: Highlights from the Summit by Arkadi Mazin.

Effective communication for aging and longevity research

Stephanie Dainow, Lifespan.io’s Executive Director, gave a talk at the Rejuvenation Startup Summit. The talk focused on how to effectively communicate with investors, policymakers, and the public about rejuvenation biotechnology.

This is critically important if we want to continue to generate interest and support among the general public.

Lifespan.io’s Stephanie Dainow talks about the importance of effective communication.

Unfortunately, many researchers have difficulty communicating what they do to people without scientific backgrounds in a way that these interested people can understand. Talking with other academics is easy enough, but it can be difficult to discuss this science with people who have different fields of expertise.

To overcome what is perceived to be the biggest bottleneck to progress in the longevity field, namely, lack of funding, we need to find more effective ways to communicate. In fact, ineffective communication itself, Dainow argued, is the real bottleneck.

People have different levels of understanding of this topic, so we must adjust how we communicate to fit the audience. We shouldn’t assume that they will automatically understand, especially when discussing complicated biology. This is a common mistake, and it’s where we can often lose people’s interest.

Our approach to communication has three key points:

Find common ground
Meet them where they are
Choice of language matters

Find common ground

When you care about a cause, it’s easy to come out all guns blazing against anyone with a differing opinion, but this is counterproductive in the long run.

Misconceptions and resistance to the idea of longevity come from deeply-rooted beliefs and the fear of the unknown. However, the potential benefits and opportunities for a healthier and longer life are becoming increasingly tangible.

Instead of attacking someone’s core beliefs head-on and trying to change their mind, try to find common ground instead. This starting point should be something that is very compelling and undeniable. Ideally, it will be something that has a similar “fact of life” sense of permanence to it that the other person’s core beliefs have.

Something that people will generally accept is that aging leads to a gradual failure of bodily systems, frailty, and disease. This is an undeniable reality for everyone and is the truth that most of us accept. It is an inevitable consequence of living and a biological reality, and there is no argument against it.

Plus, we all understand what it feels like when our bodies aren’t working. After all, we have all experienced being sick or injured during our lives, and we know how bad that feels. Therefore, we can leverage this mutual understanding, which makes it possible to talk about rejuvenation biotechnology in the context of reducing suffering.

Aging leads to age-related diseases that cause suffering, and suffering is bad. No one in their right mind would argue that suffering is a positive thing or that it makes us happy. It is hard to argue against the idea that less suffering and more happiness are good and desirable things.

It’s also important to remember that it’s not just about solving a problem you think is important. It’s about making them see that your problem is also their problem and that they will benefit from you solving it.

Meet them where they are

If you want the wider public and people outside the field to engage with this topic, understand where they are and meet them there. Taking them on a journey that they personally relate to personally is a great way to do this.

Audiences may not be as engaged as those at the Rejuvenation Startup Summit, so plan accordingly.

Therefore, understand your audience, particularly their knowledge level, before jumping into the science of rejuvenation biotechnology. While talking, pause and ask if they understand or need a different explanation. You can also go back to a broader overview if needed. After all, anyone who does not understand what you are talking about will become confused and disinterested.

Stephanie gave an example of where failing to take the audience on a shared journey cost the presenter funding. At an event, a scientist talked about their research and company in order to seek funds.

In the audience were several high-net-worth individuals who listened and nodded as the speaker gave their presentation. Unfortunately for the presenter, the nodding was a pretense, and no one really understood what was being said.

Afterwards, Stephanie asked some of these people what they thought of the talk. The answer was not positive. They said that their heads were spinning trying to understand what was being said, and it made them uncomfortable.

When she asked if they would consider investing in the startup or other longevity projects, the answer was no. They believed that even if what was being said was real, it was not their area of expertise and understanding, so they could not get involved.

This unfortunate reaction can be translated to: “I’m too overwhelmed to be excited about learning more. I don’t understand it, and I don’t understand what the scientist was trying to explain.” Their perception of anything longevity-related is now tainted by this single experience. The idea has been rejected and any potential funding along with it.

So, lighten up, connect with the listener, and make sure you are both on the same page.

Choice of language matters

Your particular choice of words when talking about rejuvenation biotech is important. A wide range of people are interested in aging and rejuvenation research for different reasons.

Some people may be approaching the field from the wellness side, which makes them interested in learning about what can be done now to extend healthy life. Others may have a sick or elderly relative, so they’re looking for information about battling specific diseases or conditions. Others still may be motivated by a desire to use their resources to make the world a better place, which has put them on the search for philanthropic opportunities.

Whatever your own reason for supporting the research being done, take a look at this word cloud:

As you go through this list, pay attention to how you think and feel about each word.

When speaking with others, make an effort to understand their perspective. Choose words from this list that align with your audience. This will help them understand your message.

Be curious about your audience, find out what motivates them, and use that to frame how and what you are saying. This makes the conversation relatable and will help them to stay engaged with what you are talking about.

For example, if your audience is interested in maintaining good health, consider discussing preventative healthcare or damage repair. However, if they are passionate about organic products and yoga, the term ‘wellness’ may resonate. A medical doctor will understand the terms ‘regenerative medicine’ and ‘geroscience’. For individuals focused on maintaining youth and appearance, consider using the term ‘anti-aging’.

Above all, remember: communication matters just as much as the science.

Moving forward together for aging research

The Rejuvenation Startup Summit was also a great opportunity for the Lifespan.io and SENS Research Foundation teams to get together.

The Lifespan.io and the SENS Research Foundation teams meet over breakfast.

From Lifespan.io, we had Stephanie Dainow, executive director; Steve Hill, editor-in-chief; Christie Sacco, brand manager; Arkadi Mazin, journalist; and Paul Spiegel, board member. Representing SENS Research Foundation were Maria Entraigues Abramson, director of development; James Hale, associate director of partnerships; and Gary Abramson, creative & web lead.

In April, Lifespan.io and the SENS Research Foundation announced their intention to merge and form a new longevity entity. We will have more news to share about what the two organizations will be doing to drive progress in aging research in the future.

Last but not least, many thanks to Lifespan.io volunteer, Fatima Hill, for being our official photographer. We have a gallery of photos from the event for you to enjoy below.

Please feel free to post them on social media and mention the Lifespan.io Facebook, Lifespan.io Twitter, or Lifespan.io Linkedin pages. If you do, we’d love to see your posts.

Walking the walk at 0100 Conference Europe

In March Stephanie Dainow, Lifespan.io Executive Director, joined a panel at 0100 Conference in Amsterdam.

When it comes to longevity, you may talk to the talk, but can you walk the walk? Five panelists accepted the challenge! They took to the treadmills while having a discussion about the developing longevity tech industry.

Walking is a great activity for anyone serious about longevity.

The treadmills symbolize the determination needed to navigate long-term investments. They also represent the ability to create opportunities that can enhance our health. Additionally, exercise may help increase our lifespan by several years or more.

The panelists were:

Bill Liao from SOSV
Marc P. Bernegger from Maximon
Alex Colville from age1
Amol Sarva from LifeX Ventures
Stephanie Dainow from Lifespan.io

The panelists discussed the importance of exercise, age reversal therapies, and the opportunities in this growing field. They also addressed misconceptions and the potential impact on society and resources.

Key insights from the panel

Age-reversal interventions are becoming a reality through advancements in biotech.
Mental health and neurodegenerative disorders are also important aspects of longevity.
The field of longevity has gained mainstream attention and is supported by nonprofits, advocacy groups, and the media. This increased visibility has accelerated progress in the field.
The financial upside of longevity investments is substantial, with projections of a $200 billion market for the first approved aging drug. The field offers opportunities for both therapeutics and related industries.
Longevity investments can have a positive impact on resource consumption, as healthier, longer-lived individuals require fewer resources and contribute to a more sustainable society.
The convergence of technology, such as AI and big data, with advancements in biology and medicine is accelerating progress in the field of longevity and opening up new possibilities for interventions and treatments.
The focus on reducing suffering and improving quality of life through interventions that address age-related diseases, mental health, and overall well-being is at the core of the longevity field.

Lifespan.io at the 2024 SALT conference

Lifespan.io Executive Director, Stephanie Dainow hosted a panel at the SALT iConnections New York 2024 conference.

Stephanie Dainow hosts the Breakthroughs in Longevity panel.

The panel was titled “Breakthroughs in Longevity: How Programmable Biology is Helping Humans Live Healthier, Longer”. The panelists were:

Stephanie Dainow – Executive Director, Lifespan.io
Stephen Berenson – Managing Partner, Flagship Pioneering
Nir Barzilai – President, Academy for Health and Lifespan Research (AHLR)
Jeff Huber – Co-Founder & General Partner, Triatomic Capital
Abby Miller Levy – Managing Partner & Co-Founder, Primetime Partners

SALT is a global thought leadership forum and capital introduction platform encompassing finance, tech & public policy. It is comprised of a community of the world’s foremost investors, creators and thinkers.

The Breakthroughs in Longevity panelists.

Here’s to more connections, deeper discussion, and bigger and better communication for longevity.

Events like this help us to be a powerful force for longevity research, advocacy, journalism, and education! If you are interested in supporting us, please consider making a donation to our non-profit organization.

In a much-anticipated debate, prominent aging researchers Aubrey de Grey and Peter Fedichev presented their competing, but also overlapping, theories.

Gentlemen, draw your laser pointers!

When the non-profits Foresight Institute, Open Longevity, and Say Forever had the idea to hold debates on the best strategy to defeat aging, there was little question about whom they should invite first. Aubrey deGrey, head of LEV Foundation and one of the faces of the longevity field, and Peter Fedichev, CEO of Gero and a rising star in the same field, already had an impromptu debate last year in Zuzalu, the longevity/crypto/AI-themed pop-up city in Montenegro. I had the honor to witness that clash of titans, which kept a small but dedicated crowd on its toes for more than two hours.

The impromptu debate in Zuzalu. Photo: Arkadi Mazin

Now, almost exactly a year later, the two scientists agreed to settle the score, with a panel of four esteemed judges and a $10,000 prize at stake. Of course, the question at the heart of the debate is way too complex to be settled using current knowledge and two microphones.

The debate mostly clarified the participants’ positions, which turned out to share many similarities but also some important differences. What is undebatable, though, is that this was one of the most fascinating and eye-opening longevity-related events of the year and that such debates should become a frequently honored tradition.

The jury included Prof. David Furman (Buck/Stanford), Prof. Dorota Skowronska-Krawczyk (UCI), Prof. Guo Huang (UCSF), Prof. Thomas Stoeger (Northwestern), and Prof. Mattew Yosefzadeh (Columbia).

At the center of the disagreement was our ability to reverse aging in the near future. Aubrey is much more optimistic about that than Peter. From that rather straightforward point, the journey down the rabbit hole began.

The importance of education

Aubrey took the stage first, focusing this initial part of his talk on the current longevity ecosystem rather than the science of aging reversal. The first thing we can do to extend the human lifespan, he said, is education. In this context, he mentioned several organizations, including Longevity Biotech Fellowship, which educates people seeking a career in longevity, and Lifespan.io, which he called “a fantastic, really important organization”.

Warm words were also reserved for the XPRIZE in healthspan, the Alliance for Longevity Initiatives, and the Dublin Longevity Declaration – “the single most important piece of advocacy in several years.” Aubrey praised “the emergence of new jurisdictions,” first and foremost, Prospera, the special economic zone in Honduras, which offers a streamlined and efficient regulatory system for young biotech companies.

The reign of entropy

When his turn arrived, Peter dived into the biology part head-first. His theory, which made quite a splash when it was first published a couple of years ago, borrows heavily from his background in physics. Peter claims that he and his company were able to detect two types of age-related signals in some biological data, including epigenetics.

When they performed a principal component analysis on their methylation dataset, Peter said, they saw one principal component increasing linearly with age and the other one increasing exponentially. Here is how Peter interprets this: normal cellular processes produce heat, which, in turn, inevitably causes some amount of damage, such as genetic and epigenetic alterations. This damage is stochastic, and the alterations are unrelated to each other. As a result, all cells accumulate different patterns of those changes.

Some of those changes are benign, yet, with time, they begin to affect cellular function, creating stress. The body reacts to this stress by activating various compensatory mechanisms, but since everything in the organism is tied together so tightly, problems in one place create more problems in another, and the organism gets more and more out of balance.

Yellow squares are methylation changes that reflect the cell’s normal workings, i.e., biological pathways performing essential functions. Pathways correlate with each other. This work produces heat which produces stochastic damage (red squares). The linear accumulation of this damage (the bottom graph) induces even more stress responses, which is reflected by the top graph’s increasing curvature.

Humans are already an exceptionally long-lived species, which means we have excellent mechanisms of controlling damage and stress (not as good as some other species, such as the naked mole rat or the bowhead whale). Therefore, in humans, the accumulation of instability occurs very slowly, but it occurs nevertheless, and in the last part of our lives, it becomes conspicuous, with numerous things going out of control in a feedback loop, causing pathology. As more stress accumulates, the organism becomes less resilient to it and eventually “goes over the cliff”, leading to death.

As an illustration (conceived by me, not Peter), imagine a tightrope walker. He is very good at what he does, so, initially, he walks nonchalantly on a brand-new, perfectly tight rope over the abyss, experiencing little discomfort. Imagine now that the rope starts disintegrating slowly due to the elements. At first, the walker manages to expertly correct his stance when he encounters those slight imperfections, but as they multiply, it’s becoming increasingly hard, and he’s spending more and more energy, even as he’s getting increasingly tired.

At this point, even a small increase in the density of imperfections causes a large increase in energy expenditure. We see that he’s walking slowly, noticeably wobbling. Finally, one more step becomes too much – he starts waving his hands wildly in a desperate attempt to keep his balance, which only gets him more and more out of balance. I don’t need to tell you what happens next.

In this model, it is not the biomarkers that increase exponentially. In fact, probably not a single biomarker changes exponentially with age; otherwise, we’d see very large increases in older people, and we only see something like that in life-threatening medical situations.

Instead, what we usually see is a linear increase in the variability and/or a change in the average level of the biomarker. Take blood pressure for example: with age, it increases gradually, and its variability increases as well. Both changes are considered alarming. Levels of cholesterol generally slowly increase with age, and levels of VO2max decline.

So, the exponential signal thaat Peter is talking about is a composite measure of instability. We might not be able to map it to all the specific interdependent molecular processes it reflects, but according to Peter, we see that it strongly correlates with morbidity and mortality. Without knowing what it is exactly, Peter calls it “the dynamic component of aging.” The second one, which increases linearly due to the stochastic damage caused by metabolic processes, reflects the increase in entropy and is named “the entropic component of aging.”

An important part of Peter’s theory says that various species age differently. Mice live for 2-3 years because they are, essentially, not very good at walking this tightrope. Or, as Peter puts it, mice are “tiny explosions”: they start disintegrating almost immediately after they are born, entering the death spiral that humans enter many decades later. This makes mice popular models in biomedical research in general, although many interventions that work in mice fail in humans, but especially poor models in aging research.

Aging in mice is dominated by the dynamic component, which also reacts well to interventions because it reflects interdependent biological pathways. Affecting a pathway may bring back some of the stability and calm things down overall, and this, Peter says, is what we see with our current geroprotectors.

However, in humans, the dynamic component becomes dominant (“we become mice”, as Peter puts it) only during the last couple of decades of life or so. By affecting this component with interventions without stopping the entropic (stochastic) damage from accumulating, we can add, Peter estimates, about a decade to average life expectancy. If we can also stop the entropic damage in its tracks, we can keep a person stable much longer.

The central tenet of Peter’s theory is that reversing the entropic element of aging is extremely hard, because entropy doesn’t like to be reversed (try unmixing two liquids or, if you’re up to a really hard challenge, unbreaking an egg). Without reversing it, he argues, we cannot achieve actual rejuvenation. This bleak prospect, however, is only for the foreseeable future since, technically, Peter admits, there is no “hard limit” on reversing entropic damage, and with technology much more advanced than ours, this can be done.

So, Peter’s answer to the debate’s main question is that we need to concentrate on slowing the accumulation of entropic damage. Otherwise, according to this view, we can only achieve very limited life extension. If we manage to stop the entropic element and reign in the dynamic element of aging, we can keep people at their current age for a long time. However, we cannot rejuvenate people without finding a way to reverse the entropic element, which is extremely hard.

The maintenance approach

Next, Aubrey took the stand to paint his picture of aging.

Aging, he said, consists of the combination of two processes. The first one is “a lifelong process whereby metabolism, in other words, the network of processes that keeps us alive from one day to the next, generates changes to the molecular and cellular structure of the body that accumulate over time.” This is what Aubrey calls damage. Accumulation of damage due to normal metabolic processes looks a lot like Peter’s “entropic element of aging.” With time, the increasing damage causes pathology.

Aubrey offered an interesting narrative of how medicine’s efforts to counter aging have changed over time. Encouraged by early successes against infectious diseases, scientists thought it would be just as easy to reverse aging-related pathologies. Obviously, it did not happen. Attempts to alter metabolism so that it creates less damage have not been very successful either. This is why Aubrey has always seen removing damage (“the maintenance approach”) as the only feasible way to disconnect metabolism from pathology and, hence, to slow and hopefully reverse aging.

Since metabolic processes cause many types of damage, a key part of this approach is combination therapies. Unfortunately, the whole system of incentives, both in academia and in biotech, is built to favor single interventions. Aubrey himself is working on the combination approach in the ongoing RMR (Robust Mouse Rejuvenation) study. Still, combining two, three, or even four therapies is just the first step.

An important feature of Aubrey’s concept is that developing pathologies heavily influence the amount of damage produced by metabolism. Again, this bears some similarity to Peter’s idea that pathways produce increasingly more stochastic damage.

Aubrey said that, like Peter, he defines two types of damage: chemically defined damage and chemically undefined damage. The first type is, for example, “something that can be distinguished as damage versus not damage by an enzyme.”

This includes the accumulation of waste products, such as amyloids and crosslinks (chemical bonds between proteins in the extracellular matrix) along with the loss of cells, including stem cells. On the other hand, genetic and epigenetic changes are “chemically undetectable”: enzymes cannot identify sequences with deleterious alterations.

According to Aubrey, both he and Peter agree that it is possible, even if not easy, to remove damage of the first type, but they disagree on how much harder it is to fix the damage that Peter calls entropic and Aubrey calls undetectable or informatic. Notably, although some elements of Aubrey’s and Peter’s theories resemble each other, they don’t necessarily overlap perfectly. Comparing the two theories will probably take more work.

“We know that (informatic damage) can be removed,” Aubrey said, “if you’ve got some kind of oracle, an external source of information that says, this is damage, this is not damage. But we don’t have that oracle, and we certainly don’t have a way to communicate that oracle to cells.”

However, Aubrey is optimistic because of “informatic redundancy” – the idea that the information about a particular cell type’s “pristine” epigenome is retained even if a certain amount of epigenetic damage accumulates. Partial cellular reprogramming is a way to restore this information without sacrificing the cell’s differentiation and without the need for an oracle.

Aubrey is still not sure that experiments in partial reprogramming tell us this, but he thinks that recent research leans towards his hypothesis. His disagreement with Peter is that “the amount of rejuvenation that we can do without an oracle is much greater than it might seem.”

David Sinclair uses an appropriate metaphor. Sinclair, too, puts a lot of hope in restoring epigenetic information using partial cellular reprogramming. He has also achieved some practical success, restoring crushed optical nerves in rodents and non-human primates.

Sinclair likens partial reprogramming to removing scratches from an old CD (hopefully, you remember what that is). Scratches, i.e., epigenetic noise, obscure valuable epigenetic information, but the latter can still be restored, at least up to a certain point. Sinclair also suspects that there is a “backup copy” of this epigenetic information hidden in the cell. He does not have a sound theory about the mechanism yet, but in one of his recent papers, he makes interesting suggestions about how a cellular mechanism of recording epigenetic changes might work.

“The epigenome is what matters”

In the second round, Peter agreed with Aubrey on two issues. First, that a strong positive feedback loop between pathology and the amount of damage produced by biological processes exists, and it kicks in much faster in mice, which shapes the way they age. Second, he agrees about the existence of defined and undefined damage.

“I think it’s a very good definition,” he said, “because we are an evolutionarily sophisticated species, meaning that most of the time, we have options to remove a lot of defined damage. We may not use them for whatever reasons, but the options exist.” Hence, by ramping up those inbuilt mechanisms, we can enzymatically remove a lot of this chemically defined damage.

Still, Peter brought up other types of undefined damage, such as activated retrotransposons that insert themselves back into the genome – damage that, he said, will be much harder to remove. He also mentioned genetic mutations, the rate of which is strongly associated with lifespan across species. Our ability to identify and fix those types of damage might be limited. “There is no evidence,” Peter said, “that (epigenetic mutations are) even the largest part of the story.”

Aubrey countered by noting that cellular reprogramming “just works,” and since differentiation affects only the epigenome but not the genome, “it must be telling us that the epigenome is what matters.” He agreed with Peter that partial cellular reprogramming has not shown a drastic effect on lifespan in mice and that there seems to be a narrow therapeutic window (applying too much of the reprogramming factors kills the animal).

However, he noted, all the experiments we have seen only tested cellular reprogramming alone, without fixing other types of damage. This might be the reason why effects from reprogramming max out quickly. Another reason is that we are just not very skilled at it yet. In the next round of RMR, Aubrey plans to include partial reprogramming so that it can be tested in combination with other interventions.

Next, Aubrey asked Peter about some of the interventions to go after genetic and epigenetic damage. Peter suggested that it might be possible to remove most damaged cells, such as senescent or cancerous cells. Peter sees studying biological noise (the inevitable stochastic damage stemming from the operation of the biological machine that is our body) as essential and is glad to see this field of research growing quickly.

Hundreds of years or a couple of decades?

At this point, a judge’s question returned the discussion to its original topic: Can we rejuvenate the human body? Aubrey answered first by saying that we can definitely “restore some aspects of the structure, function, and composition of the body,” which is rejuvenation by definition. The real question, however, is can we achieve comprehensive rejuvenation, or are there changes to the body’s structure and composition that cannot be reversed with foreseeable technology?

“My belief,” he said, “is that the amount of informatic redundancy that exists in the genome and the epigenome is sufficient for us to be able to comprehensively rejuvenate the body in the foreseeable future.” Aubrey added that he always thought that fixing chemically identifiable damage can only get us so far, and at some point, the accumulation of mutations and epimutations in itself will become deadly. However, he is convinced that the relative contribution of those mutations to aging is so small that, if we find ways to remove all other damage, we will be able to live for hundreds of years.

“Peter’s contention, as I understand it,” he continued, “is that this limit is going to hit us within as little as 10 or 20 years beyond where we can already get. In other words, we can only get 10 or 20 years from the chemically detectable aspects of rejuvenation. I believe, actually, no, we can probably get hundreds of years.”

Peter generally agreed with Aubrey’s representation of his position. He thinks that the longevity field and the pharma industry are mostly going after chemically identifiable damage, and we can only expect limited gains from this approach. The only way to stop aging is by preventing the growth of entropy, which is quite hard (“to struggle against the second law is the last thing that you want to do”) – and that’s even before we start thinking about reversing entropy, which would be required for true rejuvenation.

We go to the scorecards

After another couple of questions from the judges, the debate was officially scored 38 for Aubrey, 42 for Peter, and the proceedings moved on to questions from the audience, which turned out to be just as challenging and insightful.

One of the questions involved an embryonic reset: the apparent erasure of damage, except for genetic mutations, that occurs somewhere during early embryonic development and allows old organisms to produce perfectly young offspring in the never-ending cycle of life. Can an embryonic reset be used to create rejuvenation therapies?

Both Aubrey and Peter responded to the effect of an embryonic reset being analogous to the factory reset of a cell phone, which makes it hard to use it for therapies in vivo. However, the mechanisms of such an embryonic reset and its relation to the Yamanaka factors are being actively studied, including by Vadim Gladyshev’s team at Harvard.

Another question pointed at Peter was about whether we have proof of a causative relationship between entropic damage and aging. Peter admitted that, at the moment, it was “a neat theoretical argument that relies on a certain physical intuition” and the most natural explanation.

“I have to confess,” he said, “that direct evidence does not exist because we don’t have an experiment where this damage is either reduced or stopped, and then we would see some effect on lifespan. Mice simply don’t give us such an opportunity right now, so at this time, this argument flows from modeling. We have a model that relates this linear damage to this hyperbolic activation of stress responses that actually kill the animal.”

A member of the audience pointed out that entropy can be reversed if you pay an energetic penalty. In other words, entropy can be reversed in an open system that can draw energy from outside.

Peter said that the problem was not the amount of energy needed – according to estimates, it would only take one cookie a day to fix all our DNA – but the amount of information we have about genetic and epigenetic states and the level of control: “If you can measure all states in your system, and if you can come up with a very exact intervention, you can do whatever you want.”

An elephant in the room addressed in another question was tissue and organ replacement. This direction holds a promise of major shortcuts in our quest for body rejuvenation. After all, do we need to care about the accumulation of damage on a cellular level when we can replace large chunks of our body with perfectly young ones?

Aubrey said that we should invest in this direction but not make it our main focus, although “we’re quite likely to end up needing to do macroscopic interventions for a short while as we reach longevity escape velocity.” Peter’s take was more sympathetic: he called organ replacement “the last resort against the second law of thermodynamics,” which has a lot of potential.

Hope is the last thing ever lost

With that, the debate came to a close, leaving the audience wanting more. It was admirably amicable and thoughtful and showcased the deep mutual respect between the debaters. Among the noteworthy things that I felt did not get proper attention are two promising directions of research, both of which are related to the nefarious entropic damage at the center of Peter’s theory.

First, many species have developed superior mechanisms of damage control, including DNA repair, and researchers such as Vera Gorbunova are working on understanding those mechanisms and translating them for humans. Second, there are budding attempts to reverse the burden of mutations. At the recent Rejuvenation Startup Summit in Berlin, the company Matter Bio presented its vision for identifying and fixing DNA mutations in vivo.

For me, the main takeaway from the debate was more in line with Aubrey’s optimistic vision. Both slowing and reversing aging are theoretically possible, and there are numerous avenues we can pursue toward both of those goals (just take a look at our Rejuvenation Roadmap).

Eventually, we will probably end up with a wide range of interventions, which would include effective waste clearance, cellular reprogramming in vitro and in vivo, clearance of aberrant cells and mitochondria, restoring the extracellular matrix, tissue and organ replacement, elimination of mutations, and many others. While this approach does not look like a “silver bullet” for aging, it gives us realistic hope.

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Researchers have published a potential new method of treating the age-related muscle loss known as sarcopenia in Aging Cell.

A return to NAD+

We have previously published information relating to exercise and NAD+ levels, and previous work has investigated the relationship between NAD+ and sarcopenia, the crippling loss of muscle that is all too common in older people [1]. Unsurprisingly, this disorder is closely tied to metabolic dysfunction [2], of which NAD+ plays a large part.

However, there are still no approved drugs for the treatment of sarcopenia, and the effectiveness of established dietary and exercise interventions is limited [3]. Therefore, instead of focusing on NAD+ precursors, such as NMN and NR, this work focuses on a related compound, nicotinamide N-methyltransferase (NNMT), which affects the methylation of both nicotinamide and DNA [4].

A clear biomarker

This experiment began with a gene expression analysis of muscle samples taken from older and younger people. The differentially expressed genes were also related to fundamental metabolic pathways, including AMPK and lipid metabolism. These genes had also been previously implicated in fatty liver disease, diabetes, and obesity.

One of the core genes that was strongly upregulated with sarcopenia was NNMT, which was also found to be significantly upregulated in older muscle compared to young muscle. Sarcopenia-related gene expression changes had significant overlap with the age-related gene expression changes, including fundamental aspects of metabolism and NAD+ processing.

NNMT was least expressed in young people, more expressed in older people, and even more expressed in older people with sarcopenia. Analyzing a previous dataset found that NMN supplementation decreased NNMT expression in older Black 6 mice.

A potential for treatment

With NNMT’s status as a biomarker confirmed, these researchers decided to target it directly. Using a mouse model of accelerated aging using D-galactose for five weeks, they found that the artificially aged mice, as expected, had reduced grip strength; however, this loss of strength was partially ameliorated with NNMT inhibition over this time period, which also rescued some of the muscle size lost to D-galactose.

Encouraged, the researchers then turned to naturally aged mice. 19-month-old Black 6 mice were given an NNMT inhibitor for five weeks and compared to a similarly aged control group. The results were very encouraging: their age-related loss of lean mass was attentulated, their grips under electrical stimulation were considerably stronger, metabolic factors such as AMPK and NAD+ were considerably greater, and their cross-sectional muscle mass was larger.

While it is not yet clear what treatment to reduce NNMT could be used for human beings, this metabolic compound is certainly a clear target for interventions. If the metabolic problems underlying sarcopenia could be attenuated through a small molecule or gene therapy, a great many older people would be better protected from this serious disorder and its accompanying loss of independence and lifespan.

Literature

[1] Cruz-Jentoft, A. J., Baeyens, J. P., Bauer, J. M., Boirie, Y., Cederholm, T., Landi, F., … & Zamboni, M. (2010). Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and ageing, 39(4), 412-423.

[2] Daily, J. W., & Park, S. (2022). Sarcopenia is a cause and consequence of metabolic dysregulation in aging humans: effects of gut dysbiosis, glucose dysregulation, diet and lifestyle. Cells, 11(3), 338.

[3] Mellen, R. H., Girotto, O. S., Marques, E. B., Laurindo, L. F., Grippa, P. C., Mendes, C. G., … & Quesada, K. (2023). Insights into pathogenesis, nutritional and drug approach in sarcopenia: a systematic review. Biomedicines, 11(1), 136.

[4] Roberti, A., Fernández, A. F., & Fraga, M. F. (2021). Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation. Molecular Metabolism, 45, 101165.